Human emotion processing accuracy, negative biases, and fMRI activation are associated with childhood trauma.

Introduction: Emerging literature suggests that childhood trauma may influence facial emotion perception (FEP), with the potential to negatively bias both emotion perception and reactions to emotion-related inputs. Negative emotion perception biases are associated with a range of psychiatric and behavioral problems, potentially due or as a result of difficult social interactions. Unfortunately, there is a poor understanding of whether observed negative biases are related to childhood trauma history, depression history, or processes common to (and potentially causative of) both experiences. Methods: The present cross-sectional study examines the relation between FEP and neural activation during FEP with retrospectively reported childhood trauma in young adult participants with remitted major depressive disorder (rMDD, n = 41) and without psychiatric histories (healthy controls [HC], n = 34). Accuracy of emotion categorization and negative bias errors during FEP and brain activation were each measured during exposure to fearful, angry, happy, sad, and neutral faces. We examined participant behavioral and neural responses in relation to total reported severity of childhood abuse and neglect (assessed with the Childhood Trauma Questionnaire, CTQ). Results: Results corrected for multiple comparisons indicate that higher trauma scores were associated with greater likelihood of miscategorizing happy faces as angry. Activation in the right middle frontal gyrus (MFG) positively correlated with trauma scores when participants viewed faces that they correctly categorized as angry, fearful, sad, and happy. Discussion: Identifying the neural mechanisms by which childhood trauma and MDD may change facial emotion perception could inform targeted prevention efforts for MDD or related interpersonal difficulties.

Inflammation, depressive symptoms, and emotion perception in adolescence.

BACKGROUND: Individuals with depression often demonstrate an altered peripheral inflammatory profile, as well as emotion perception difficulties. However, correlations of inflammation with overall depression severity are inconsistent and inflammation may only contribute to specific symptoms. Moreover, measurement of the association between inflammation and emotion perception is sparse in adolescence, despite representing a formative window of emotional development and high-risk period for depression onset. METHODS: Serum interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1ß were measured in 34 adolescents aged 12-17 with DSM-IV depressive disorders (DEP) and 29 healthy controls (HC). Participants were evaluated using the Children's Depression Rating Scale-Revised (CDRS-R) and symptom subscales were extracted based on factor analysis. Participants also completed a performance-based measure of emotion perception, the Facial Emotion Perception Test (FEPT), which assesses the accuracy of categorizing angry, fearful, sad, happy, and neutral facial emotions. RESULTS: IL-6 and TNF-α correlated with reported depressed mood and somatic symptoms, respectively, but not total CDRS-R score, anhedonia or observed mood, across both DEP and HC. DEP demonstrated lower accuracy for identifying angry facial expressions. Higher IL-6 was inversely related to accuracy and discrimination of angry and neutral faces across all participants. IL-1ß was associated with reduced discrimination of fearful faces. CONCLUSIONS: Inflammatory markers were sensitive to affective and somatic symptoms of depression and processing of emotional threat in adolescents. In particular, IL-6 was elevated in depressed adolescents and therefore may represent a specific target for modulating depressive symptoms and emotion processing.

Anticipation of monetary reward in amygdala, insula, caudate are predictors of pleasure sensitivity to d-Amphetamine administration.

BACKGROUND: Drug addiction and dependence continue as an unresolved source of morbidity and mortality. Two approaches to identifying risk for abuse and addiction are psychopharmacological challenge studies and neuroimaging experiments. The present study combined these two approaches by examining associations between self-reported euphoria or liking after a dose of d-amphetamine and neural-based responses to anticipation of a monetary reward. METHODS: Healthy young adults (N = 73) aged 19 and 26, without any history of alcohol/substance dependence completed four laboratory sessions in which they received oral d-amphetamine (20 mg) or placebo, and completed drug effect questionnaires. On a separate session they underwent a functional magnetic resonance imaging scan while they completed a monetary incentive delay task. During the task, we recorded neural signal related to anticipation of winning $5 or $1.50 compared to winning no money (WinMoney-WinZero), in reward related regions. RESULTS: Liking of amphetamine during the drug sessions was related to differences in activation during the WinMoney-WinZero conditions - in the amygdala (positive), insula (negative) and caudate (negative). In posthoc analyses, liking of amphetamine was also positively correlated with activation of the amygdala during anticipation of large rewards and negatively related to activation of the left insula to both small and large anticipated rewards. CONCLUSIONS: These findings suggest that individual differences in key regions of the reward network are related to rewarding subjective effects of a stimulant drug. To further clarify these relationships, future pharmacofMRI studies could probe the influence of amphetamine at the neural level during reward anticipation.

Using resting-state intrinsic network connectivity to identify suicide risk in mood disorders.

BACKGROUND: Little is known about the neural substrates of suicide risk in mood disorders. Improving the identification of biomarkers of suicide risk, as indicated by a history of suicide-related behavior (SB), could lead to more targeted treatments to reduce risk. METHODS: Participants were 18 young adults with a mood disorder with a history of SB (as indicated by endorsing a past suicide attempt), 60 with a mood disorder with a history of suicidal ideation (SI) but not SB, 52 with a mood disorder with no history of SI or SB (MD), and 82 healthy comparison participants (HC). Resting-state functional connectivity within and between intrinsic neural networks, including cognitive control network (CCN), salience and emotion network (SEN), and default mode network (DMN), was compared between groups. RESULTS: Several fronto-parietal regions (k > 57, p < 0.005) were identified in which individuals with SB demonstrated distinct patterns of connectivity within (in the CCN) and across networks (CCN-SEN and CCN-DMN). Connectivity with some of these same regions also distinguished the SB group when participants were re-scanned after 1-4 months. Extracted data defined SB group membership with good accuracy, sensitivity, and specificity (79-88%). CONCLUSIONS: These results suggest that individuals with a history of SB in the context of mood disorders may show reliably distinct patterns of intrinsic network connectivity, even when compared to those with mood disorders without SB. Resting-state fMRI is a promising tool for identifying subtypes of patients with mood disorders who may be at risk for suicidal behavior.

Pre-scan cortisol is differentially associated with enhanced connectivity to the cognitive control network in young adults with a history of depression.

BACKGROUND: We have previously demonstrated that pre-scan salivary cortisol is associated with attentuated frontal-subcortical brain activation during emotion processesing and semantic list-learning paradigms in depressed subjects. Additionally, altered functional connectivity is observed after remission of acute depression symptoms (rMDD). It is unknown whether cortisol also predicts altered functional connectivity during remission. METHODS: Participants were 47 healthy controls (HC) and 73 rMDD, 18-30 years old who provided salivary cortisol samples before and after undergoing resting-state fMRI. We tested whether salivary cortisol by diagnosis interactions were associated with seed-based resting connectivity of the default mode (DMN) and salience and emotion (SN) networks using whole-brain, cluster-level corrected (p < .01) regression in SPM8. RESULTS: Pre-scan cortisol predicted decreased (HC) and increased (rMDD) cross-network connectivity to the dorsal anterior cingulate, dorso-medial and lateral- prefrontal cortex, brain stem and cerebellum (all seeds) and precuneus (DMN seeds). By and large, pre/post-scan cortisol change predicted the same pattern of findings. In network analyses, cortisol predominantly predicted enhanced cross-network connectivity to cognitive control network regions in rMDD. CONCLUSIONS: The association of cortisol with connections of default and salience networks to executive brain networks differs between individuals with and without a history of depression. Further investigation is needed to better understand the role of cortisol and related stress hormones as a potential primary and interactive driver of network coherence in depression.

The Titrated Monetary Incentive Delay Task: Sensitivity, convergent and divergent validity, and neural correlates in an RDoC sample.

INTRODUCTION: Neuropsychological tests are designed to assay brain function via performance measurements. Many tests corresponding to visual and motor cortex function have been validated. Tests probing reward circuitry, including the ventral striatum (VS), could benefit assessment of numerous neurological and psychiatric disorders in which reward or VS function is disturbed. The present study sought to examine convergent and divergent validity of our modified, titrated version of the Monetary Incentive Delay Task, such that it may in the future stand as a validated neuropsychological test for reward function. METHOD: Participants were 132 individuals with a history of mood disturbance (HMD) and 43 healthy comparisons, ages 18-30 years. In addition to a standard neuropsychological battery and symptom measures, participants completed a modified version of the Monetary Incentive Delay Task (T-MIDT) during functional magnetic resonance imaging (fMRI), which involved a multistage titration procedure to incrementally increase or decrease the response window time per each participant's psychomotor speed and optimize individual performance. RESULTS: Across groups after titration, performance on the T-MIDT diverged from measures of processing speed, attention, and spatial working memory, but not inhibitory control. Performance in the HMD group was differentially correlated with executive function measures before and after titration. The reward circuit (e.g., subcortical, insular, medial prefrontal) was activated during reward anticipation. CONCLUSION: The present findings provide preliminary evidence that the T-MIDT measures a construct distinct from many executive functions and that individualized titration of the task parameters is critical in parsing reward from executive function. The T-MIDT correlated with residual mood symptoms in individuals with remitted depression or bipolar disorder, implying that behavioral or brain activation group differences are only to be observed in the active state of illness.

Self-reported affective biases, but not all affective performance biases, are present in depression remission.

OBJECTIVE: Individuals with active major depressive disorder (MDD) have shown affective biases in cognitive flexibility and memory, particularly for negatively valenced stimuli. We evaluated whether impairments in affective flexibility would remain even during remission (rMDD), potentially representing trait- or scar-like effects of illness. METHOD: Participants completed the Emotion Card Sort Test (ECST), a measure of cognitive flexibility containing emotionally valenced stimuli, and the Emotion Word Stimulus Test (EWST), a measure of affective biases in delayed recall and recognition memory, and several self-report measures. RESULTS: Healthy controls (HCs; n = 35) and individuals with rMDD (n = 93) did not differ on performance for any of the three word types on the ECST or EWT. However, individuals with rMDD demonstrated greater negative bias on EWT recognition trials relative to HCs (d = .36). On self-report measures, individuals with rMDD exhibited greater levels of neuroticism, problems with attentional control, pessimistic attributional style, and negative automatic thoughts compared to HCs. CONCLUSIONS: These results provide initial evidence that some performance, but not self-reported, indices of affective bias may improve during remission from MDD. Results of this study could suggest that some components of affective bias may represent state feature of illness and others trait-like risk or scar features. PRACTITIONER POINTS: This study suggests that self-reported affective biases may persist in remission of major depressive disorder (rMDD). Affective attentional biases and affective memory biases were not demonstrated in individuals with rMDD, with the exception of a bias for recognizing negatively versus neutrally valenced stimuli. CAUTIONS OR LIMITATIONS: A limitation of this study was its cross-sectional design. Under ideal conditions, the same individuals would be studied in both the active and remitted phases of illness. Another limitation of this study was the smaller number of healthy controls relative to individuals with rMDD.

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.

Cluster analysis with MOODS-SR illustrates a potential bipolar disorder risk phenotype in young adults with remitted major depressive disorder.

OBJECTIVES: Delays in the diagnosis and detection of bipolar disorder can lead to adverse consequences, including improper treatment and increased suicide risk. The Mood Spectrum Self-Report Measure (MOODS-SR) was designed to capture the full spectrum of lifetime mood symptomology with factor scores for depression and mania symptom constellations. The utility of the MOODS-SR as a tool to investigate homogeneous subgroups was examined, with particular focus on a possible bipolar risk subgroup. Moreover, potential patterns of differences in MOODS-SR subtypes were probed using cognitive vulnerabilities, neuropsychological functioning, and ventral striatum connectivity. METHODS: K-mean cluster analysis based on factor scores of MOODS-SR was used to determine homogeneous subgroupings within a healthy and remitted depressed young adult sample (N = 86). Between-group comparisons (based on cluster subgroupings) were conducted on measures of cognitive vulnerabilities, neuropsychological functioning, and ventral striatum rs-fMRI connectivity. RESULTS: Three groups of participants were identified: one with minimal symptomology, one with moderate primarily depressive symptomology, and one with more severe manic and depressive symptomology. Differences in impulsivity, neuroticism, conscientiousness, facial perception accuracy, and rs-fMRI connectivity exist between moderate and severe groups. CONCLUSIONS: Within a sample of people with and without depression histories, a severe subgroup was identified with potentially increased risk of developing bipolar disorder through use of the MOODS-SR. This small subgroup had higher levels of lifetime depression and mania symptoms. Additionally, differences in traits, affective processing, and connectivity exist between those with a more prototypic unipolar subgrouping and those with potential risk for developing bipolar disorder.

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.

Integrated cross-network connectivity of amygdala, insula, and subgenual cingulate associated with facial emotion perception in healthy controls and remitted major depressive disorder.

Emotion perception deficits could be due to disrupted connectivity of key nodes in the salience and emotion network (SEN), including the amygdala, subgenual anterior cingulate cortex (sgACC), and insula. We examined SEN resting-state (rs-)fMRI connectivity in rMDD in relation to Facial Emotion Perception Test (FEPT) performance. Fifty-two medication-free people ages 18 to 23 years participated. Twenty-seven had major depressive disorder (MDD) in remission (rMDD, 10 males), as MDD is associated with emotion perception deficits and alterations in rsfMRI. Twenty-five healthy controls (10 males) also participated. Participants completed the FEPT during fMRI, in addition to an 8-minute eyes-open resting-state scan. Seed regions of interest were defined in the amygdala, anterior insula and sgACC. Multiple regression analyses co-varied diagnostic group, sex and movement parameters. Emotion perception accuracy was positively associated with connectivity between amygdala seeds and regions primarily in the SEN and cognitive control network (CCN), and also the default mode network (DMN). Accuracy was also positively associated with connectivity between the sgACC seeds and other SEN regions, and the DMN, particularly for the right sgACC. Connectivity negatively associated with emotion perception was mostly with regions outside of these three networks, other than the left insula and part of the DMN. This study is the first to our knowledge to demonstrate relationships between facial emotion processing and resting-state connectivity with SEN nodes and between SEN nodes and regions located within other neural networks.