Does reward processing moderate or mediate the link between childhood adversity and psychopathology: A longitudinal study.

Childhood adversity is common and associated with elevated risk for transdiagnostic psychopathology. Reward processing has been implicated in the link between adversity and psychopathology, but whether it serves as a mediator or moderator is unclear. This study examined whether alterations in behavioral and neural reward processing function as a mechanism or moderator of psychopathology outcomes following adversity experiences, including threat (i.e., trauma) and deprivation. A longitudinal community sample of 10-15-year-old youths was assessed across two waves (Wave 1: n = 228; Wave 2: n = 206). Wave 1 assessed adverse experiences, psychopathology symptoms, reward processing on a monetary incentive delay task, and resting-state fMRI. At Wave 2, psychopathology symptoms were reassessed. Greater threat experiences were associated with blunted behavioral reward sensitivity, which, in turn, predicted increases in depression symptoms over time and mediated the prospective association between threat and depression symptoms. In contrast, reward sensitivity moderated the association between deprivation experiences and prospective externalizing symptoms such that the positive association of deprivation with increasing externalizing symptoms was absent for children with high levels of reward sensitivity.

Brain morphometry in older adults with and without dementia using extremely rapid structural scans.

T1-weighted structural MRI is widely used to measure brain morphometry (e.g., cortical thickness and subcortical volumes). Accelerated scans as fast as one minute or less are now available but it is unclear if they are adequate for quantitative morphometry. Here we compared the measurement properties of a widely adopted 1.0 mm resolution scan from the Alzheimer's Disease Neuroimaging Initiative (ADNI = 5'12'') with two variants of highly accelerated 1.0 mm scans (compressed-sensing, CSx6 = 1'12''; and wave-controlled aliasing in parallel imaging, WAVEx9 = 1'09'') in a test-retest study of 37 older adults aged 54 to 86 (including 19 individuals diagnosed with a neurodegenerative dementia). Rapid scans produced highly reliable morphometric measures that largely matched the quality of morphometrics derived from the ADNI scan. Regions of lower reliability and relative divergence between ADNI and rapid scan alternatives tended to occur in midline regions and regions with susceptibility-induced artifacts. Critically, the rapid scans yielded morphometric measures similar to the ADNI scan in regions of high atrophy. The results converge to suggest that, for many current uses, extremely rapid scans can replace longer scans. As a final test, we explored the possibility of a 0'49'' 1.2 mm CSx6 structural scan, which also showed promise. Rapid structural scans may benefit MRI studies by shortening the scan session and reducing cost, minimizing opportunity for movement, creating room for additional scan sequences, and allowing for the repetition of structural scans to increase precision of the estimates.

Childhood trauma, earlier pubertal timing, and psychopathology in adolescence: The role of corticolimbic development.

Earlier pubertal development appears to be one pathway through which childhood trauma contributes to psychopathology in adolescence. Puberty-related changes in neural networks involved in emotion processing, namely the amygdala-medial prefrontal (mPFC) circuit, may be a potential mechanism linking trauma and adolescent psychopathology. Our participants were 227 youth between 10 and 13 years of age who completed assessments of threat and deprivation-related experiences of adversity, pubertal stage, and internalizing and externalizing symptoms. A subset (n = 149) also underwent a functional MRI scan while passively viewing fearful and calm faces. Potential mechanisms linking childhood trauma with psychopathology, encompassing earlier pubertal timing and neural response to aversive stimuli were explored. Earlier pubertal development was associated with childhood trauma as well as increased externalizing symptoms in boys only. Earlier pubertal timing in males and females was negatively associated with activation in bilateral amygdala, hippocampal, and fusiform regions when comparing fearful and calm faces. However, amygdala-mPFC connectivity showed no association with pubertal timing or psychopathology symptoms. These findings do not support accelerated amygdala-mPFC development as a mechanism linking childhood trauma and psychopathology, but instead provide support for the role of pubertal development in normative decreases in limbic activation across development.

Precision Brain Morphometry Using Cluster Scanning.

Measurement error limits the statistical power to detect group differences and longitudinal change in structural MRI morphometric measures (e.g., hippocampal volume, prefrontal thickness). Recent advances in scan acceleration enable extremely fast T1-weighted scans (~1 minute) to achieve morphometric errors that are close to the errors in longer traditional scans. As acceleration allows multiple scans to be acquired in rapid succession, it becomes possible to pool estimates to increase measurement precision, a strategy known as "cluster scanning." Here we explored brain morphometry using cluster scanning in a test-retest study of 40 individuals (12 younger adults, 18 cognitively unimpaired older adults, and 10 adults diagnosed with mild cognitive impairment or Alzheimer's Dementia). Morphometric errors from a single compressed sensing (CS) 1.0mm scan with 6x acceleration (CSx6) were, on average, 12% larger than a traditional scan using the Alzheimer's Disease Neuroimaging Initiative (ADNI) protocol. Pooled estimates from four clustered CSx6 acquisitions led to errors that were 34% smaller than ADNI despite having a shorter total acquisition time. Given a fixed amount of time, a gain in measurement precision can thus be achieved by acquiring multiple rapid scans instead of a single traditional scan. Errors were further reduced when estimates were pooled from eight CSx6 scans (51% smaller than ADNI). Neither pooling across a break nor pooling across multiple scan resolutions boosted this benefit. We discuss the potential of cluster scanning to improve morphometric precision, boost statistical power, and produce more sensitive disease progression biomarkers.

The impact of familial risk and early life adversity on emotion and reward processing networks in youth at-risk for bipolar disorder.

A recently developed risk calculator for bipolar disorder (BD) accounts for clinical and parental psychopathology. Yet, it is understood that both familial predisposition and early life adversity contribute to the development of BD. How the interplay between these two factors influence emotion and reward processing networks in youth at risk for BD remains unclear. In this exploratory analysis, offspring of BD parents performed emotion and reward processing tasks while undergoing a fMRI scan. Risk calculator score was used to assess risk for developing BD in the next 5 years. Environmental risk was tabulated using the Stressful Life Events Schedule (SLES). Emotion and reward processing networks were investigated for genetic and/or environment interactions. Interaction effects were found between risk calculator scores, negative SLES score and activity in right amygdala and bilateral fusiform gyri during the emotion processing task, as well as activity in the fronto-, striatal, and parietal regions during the reward processing task. Our findings are preliminary; however, they support the unique and interactive contributions of both familial and environmental risk factors on emotion and reward processing within OBP. They also identify potential neural targets to guide development of interventions for youth at greatest risk for psychiatric disorders.

Cortical thickness correlates of cognitive performance in cognitively-matched individuals with and without schizophrenia.

Schizophrenia is characterized by psychosis and, in most cases, cognitive impairment. It is unclear, however, whether these elements of the disorder represent distinct or related disease processes. Accordingly, this study investigated 3-way interactions between group, cognition and cortical thickness in cognitively-matched patients with schizophrenia and healthy control groups. Patients and healthy controls were group-matched on demographics and a broadly-based index of cognitive performance. T1-weighted images were processed using Freesurfer. Variable selection techniques were applied to determine which regions best predicted 3-way interaction effects. Independent variables included age, sex, IQ, and 87 regional cortical thickness values strongly associated with group or cognition. Antipsychotic treatment effects were also investigated. Twenty regions were selected by the best fitting model. The top 6 regions included the left pre- and post-central, left superior frontal and temporal and right rostral and caudal middle frontal cortices. No antipsychotic treatment effects were seen. Cortical thinning in schizophrenia exists even in the absence of cognitive impairment. Our findings support the separation of psychosis and cognitive impairment as independent disease processes, with distinct relations with cortical thickness in prefrontal cortical areas. Parsing out these two disease processes will increase understanding of heterogeneity in schizophrenia and may modify treatment targets.

Baseline and follow-up activity and functional connectivity in reward neural circuitries in offspring at risk for bipolar disorder.

Bipolar disorder (BD) is a serious psychiatric illness with demonstrated abnormalities in reward processing circuitry. Examining this circuitry in youth at familial risk for BD may provide further insight into the underlying mechanisms of BD development. In this study, we compared offspring of bipolar parents (OBP, n = 32), offspring of comparison parents with non-BD psychopathology (OCP, n = 36), and offspring of healthy parents (OHP, n = 39) during a functional magnetic resonance imaging reward processing task. Elastic net regression analyses identified 26 activity, functional connectivity (FC), and demographic variables that explained 34.24% of the variance in group (λ = 0.224). ANOVA and post-hoc analyses revealed that OBP had significantly lower right ventral striatum-left caudal anterior cingulate FC to loss (OBP versus OCP: p = 0.028, OBP versus OHP: p = 0.015) and greater right pars orbitalis-left (OBP versus OCP: p = 0.003, OBP versus OHP: p = 0.036) and -right (OBP versus OCP: p = 0.001, OBP versus OHP: p = 0.038) orbitofrontal cortex FC to reward versus OCP and OHP, respectively. These findings were not affected by non-BD psychopathology, psychotropic medication use, or symptomatology. There were no changes in, or relationships between, neuroimaging or symptom measures at follow-up (mean(SD) = 2.70(1.22) year inter-scan interval) in a subset of youth with follow-up data (OBP, n = 14; OCP, n = 8; OHP, n = 19). These findings suggest that lower right ventral striatum-left caudal anterior cingulate FC to loss and greater right pars orbitalis-orbitofrontal cortex FC to reward may be trait-level neural markers that may reflect risk for BD in at-risk youth. These findings comprise important steps toward identifying neural markers of BD risk, which may enhance early identification and guide interventions for youth at familial risk for BD.

Trauma-associated anterior cingulate connectivity during reward learning predicts affective and anxiety states in young adults.

BACKGROUND: Trauma exposure is associated with development of depression and anxiety; yet, some individuals are resilient to these trauma-associated effects. Differentiating mechanisms underlying development of negative affect and resilience following trauma is critical for developing effective interventions. One pathway through which trauma could exert its effects on negative affect is reward-learning networks. In this study, we examined relationships among lifetime trauma, reward-learning network function, and emotional states in young adults. METHODS: One hundred eleven young adults self-reported trauma and emotional states and underwent functional magnetic resonance imaging during a monetary reward task. Trauma-associated neural activation and functional connectivity were analyzed during reward prediction error (RPE). Relationships between trauma-associated neural functioning and affective and anxiety symptoms were examined. RESULTS: Number of traumatic events was associated with greater ventral anterior cingulate cortex (vACC) activation, and lower vACC connectivity with the right insula, frontopolar, inferior parietal, and temporoparietal regions, during RPE. Lower trauma-associated vACC connectivity with frontoparietal regions implicated in regulatory and decision-making processes was associated with heightened affective and anxiety symptoms; lower vACC connectivity with insular regions implicated in interoception was associated with lower affective and anxiety symptoms. CONCLUSIONS: In a young adult sample, two pathways linked the impact of trauma on reward-learning networks with higher v. lower negative affective and anxiety symptoms. The disconnection between vACC and regions implicated in decision-making and self-referential processes may reflect aberrant regulatory but appropriate self-focused mechanisms, respectively, conferring risk for v. resilience against negative affective and anxiety symptoms.

White matter - emotion processing activity relationships in youth offspring of bipolar parents.

BACKGROUND: Early detection of Bipolar Disorder (BD) is critical for targeting interventions to delay or prevent illness onset. Yet, the absence of objective BD biomarkers makes accurately identifying at-risk youth difficult. In this study, we examined how relationships between white matter tract (WMT) structure and activity in emotion processing neural circuitry differentiate youth at risk for BD from youth at risk for other psychiatric disorders. METHODS: Offspring (ages 8-17) of parents with BD (OBP, n = 32), offspring of comparison parents with non-BD psychopathology (OCP, n = 30), and offspring of healthy parents (OHP, n = 24) underwent diffusion tensor and functional magnetic resonance imaging while performing an emotional face processing task. Penalized and multiple regression analyses included GROUP(OBP,OCP)xWMT interactions as main independent variables, and emotion processing activity as dependent variables, to determine significant group differences in WMT-activity relationships. RESULTS: 8 GROUPxWMT interaction variables contributed to 16.5% of the variance in amygdala and prefrontal cortical activity to happy faces. Of these, significant group differences in slopes (inverse for OBP, positive for OCP) existed for the relationship between forceps minor radial diffusivity and rostral anterior cingulate activity (p = 0.014). Slopes remained significantly different in unmedicated youth without psychiatric disorders (p = 0.017) and were moderated by affective lability symptoms (F(1,29) = 5.566, p = 0.036). LIMITATIONS: Relatively small sample sizes were included. CONCLUSIONS: Forceps minor radial diffusivity-rostral anterior cingulate activity relationships may reflect underlying neuropathological processes that contribute to affectively labile youth at risk for BD and may help differentiate them from youth at risk for other psychiatric disorders.

The Impact of Caregiving on the Association Between Infant Emotional Behavior and Resting State Neural Network Functional Topology.

The extent to which neural networks underlying emotional behavior in infancy serve as precursors of later behavioral and emotional problems is unclear. Even less is known about caregiving influences on these early brain-behavior relationships. To study brain-emotional behavior relationships in infants, we examined resting-state functional network metrics and infant emotional behavior in the context of early maternal caregiving. We assessed 46 3-month-old infants and their mothers from a community sample. Infants underwent functional MRI during sleep. Resting-state data were processed using graph theory techniques to examine specific nodal metrics as indicators of network functionality. Infant positive and negative emotional behaviors, and positive, negative and mental-state talk (MST) indices of maternal caregiving were coded independently from filmed interactions. Regression analyses tested associations among nodal metrics and infant emotionality, and the moderating effects of maternal behavior on these relationships. All results were FDR corrected at alpha = 0.05. While relationships between infant emotional behavior or maternal caregiving, and nodal metrics were weak, higher levels of maternal MST strengthened associations between infant positive emotionality and nodal metrics within prefrontal (p < 0.0001), and occipital (p < 0.0001) cortices more generally. Positive and negative aspects of maternal caregiving had little effect. Our findings suggest that maternal MST may play an important role in strengthening links between emotion regulation neural circuitry and early infant positive behavior. They also provide objective neural markers that could inform and monitor caregiving-based interventions designed to improve the health and well-being of vulnerable infants at-risk for behavioral and emotional problems.

Association of Neuroimaging Measures of Emotion Processing and Regulation Neural Circuitries With Symptoms of Bipolar Disorder in Offspring at Risk for Bipolar Disorder.

Importance: Bipolar disorder (BD) is difficult to distinguish from other psychiatric disorders. Neuroimaging studies can identify objective markers of BD risk. Objective: To identify neuroimaging measures in emotion processing and regulation neural circuitries and their associations with symptoms specific to youth at risk for BD. Design, Setting, and Participants: This cross-sectional (August 1, 2011, to July 31, 2017) and longitudinal (February 1, 2013, to November 30, 2017) neuroimaging study performed at the University of Pittsburgh Medical Center compared a sample of 31 offspring of parents with BD (OBP) with 28 offspring of comparison parents with non-BD psychopathologies (OCP) and 21 offspring of healthy parents (OHP); OBP, OCP, and OHP were recruited from the Bipolar Offspring Study and the Longitudinal Assessment of Manic Symptoms Study. Main Outcomes and Measures: Group differences in activity and functional connectivity during emotional face processing and n-back task performance in amygdala, dorsolateral and ventrolateral prefrontal cortices (PFC), caudal anterior cingulate cortices (cACC), and rostral anterior cingulate cortices (rACC) neuroimaging measures showing between-group differences and symptom severity (anxiety, affective lability, depression, mania). We hypothesized that elevated amygdala activity and/or lower PFC activity and abnormal amygdala to PFC functional connectivity would distinguish OBP from OCP and OHP, and magnitudes of these abnormalities would positively correlate with elevated symptom severity. We explored associations between changes in neuroimaging and symptom measures over follow-up (mean [SD], 2.9 [1.4] years) in a subset of participants (n = 30). Results: Eighty participants were included (mean [SD] age, 14.2 (2.1) years; 35 female). Twelve neuroimaging measures explained 51% of the variance in the results of neuroimaging measures overall. Of the 12, 9 showed significant main associations of the group; however, after post hoc analyses and Bonferroni corrections, only 7 showed statistically significant associations between groups (corrected P < .05 for all). Of the 7, 2 showed significant relationships with symptoms. Offspring of parents with BD had greater right rACC activity when regulating attention to happy faces vs OCP (mean [SD] difference, 0.744 [0.249]; 95% CI, 0.134-1.354; P = .01), which positively correlated with affective lability severity (ρ = 0.304; uncorrected P = .006). Offspring of parents with BD had greater amygdala to left cACC functional connectivity when regulating attention to fearful faces vs OCP (mean [SD] difference, 0.493 [0.169]; 95% CI, 0.079-0.908; P = .01). Increases in this measure positively correlated with increases in affective lability over follow-up (r = 0.541; P = .003). Conclusions and Relevance: Greater anterior cingulate cortex activity and functional connectivity during emotion regulation tasks may be specific markers of BD risk. These findings highlight potential neural targets to aid earlier identification of and guide new treatment developments for BD.

Cortical thickness in symptomatic and asymptomatic bipolar offspring.

Children of parents diagnosed with bipolar disorder are at greater risk for developing a variety of psychiatric disorders, however, the reasons remain unknown. The present study aimed to investigate gray matter integrity in high-risk bipolar offspring (HRO) and healthy offspring (HCO) using cortical thickness techniques. Here we examined healthy control offspring (HCO; n=20) and HRO with (n=17) or without (n=13) psychiatric symptoms. T1-weighted images were collected from all offspring, and cortical thickness and age-cortical thickness correlations were compared. HRO showed cortical thinning in superior and inferior temporal regions, supramarginal, and caudal and rostral middle frontal regions compared to HCO. When comparing HRO with and without psychiatric symptoms, we found cortical thinning in symptomatic offspring in the superior frontal and somatosensory related cortices. Age-thickness correlations showed a relatively consistent negative relationship in most regions in HCO, while the reverse was true for the HRO. These regions included parahippocampal, lateral orbitofrontal, and inferior temporal regions. Our study provides evidence of cortical thickness reductions among symptomatic and asymptomatic high-risk offspring during youth. Some of these alterations, found in regions of emotion processing and regulation, are evident only when associated with the presence of psychiatric symptoms.

Cortical thickness in bipolar disorder: a systematic review.

OBJECTIVES: Bipolar disorder (BD) is a debilitating illness, the psychopathology of which is associated with aberrant structural and functional differences in the brain. Despite the many advances in psychiatric research, our understanding of the complex neurobiological underpinnings of BD remains incomplete. The aim of this review was to critically examine all available published magnetic resonance imaging (MRI) research reporting cortical thickness in BD with respect to a healthy population and/or other psychiatric samples. METHODS: The systematic search encompassed all relevant studies published until November 2014. Relevant papers were identified through an online search of select databases (MEDLINE and EMBASE) using key terms bipolar disorder or mania, and cortical thickness. Two independent raters determined the eligibility of papers and performed separate data extraction to ensure quality and accuracy of reporting. RESULTS: A total of 17 papers met the criteria and were included in this review. Compared to a healthy population, the majority of studies reported decreased cortical thickness in the left anterior cingulate/paracingulate and the left superior temporal gyrus, as well as several prefrontal regions bilaterally in patients with BD. Studies also show consistency of cortical thinning in individuals with BD and schizophrenia in frontal and temporal regions, suggesting some common neuropathology. CONCLUSIONS: This systematic review further supports a link between specific structural brain abnormalities and BD. Future studies should investigate cortical thickness with respect to at-risk populations to determine whether these neuropathologies develop before or after the onset of BD.

Accuracy of emotion labeling in children of parents diagnosed with bipolar disorder.

BACKGROUND: Emotion labeling deficits have been posited as an endophenotype for bipolar disorder (BD) as they have been observed in both patients and their first-degree relatives. It remains unclear whether these deficits exist secondary to the development of psychiatric symptoms or whether they can be attributed to risk for psychopathology. To explore this, we investigated emotion processing in symptomatic and asymptomatic high-risk bipolar offspring (HRO) and healthy children of healthy parents (HCO). METHODS: Symptomatic (n:18, age: 13.8 ± 2.6 years, 44% female) and asymptomatic (n:12, age: 12.8 ± 3.0 years, 42% female) HRO and age- and sex-matched HCO (n:20, age: 13.3 ± 2.5 years, 45% female) performed an emotion-labeling task. Total number of errors, emotion category and intensity of emotion error scores were compared. Correlations between total error scores and symptom severity were also investigated. RESULTS: Compared to HCO, both HRO groups made more errors on the adult face task (pcor=0.014). The HRO group were 2.3 times [90%CI:0.9-6.3] more likely and 4.3 times [90%CI:1.3-14.3] more likely to make errors on sad and angry faces, respectively. With the exception of sad face type errors, we observed no significant differences in error patterns between symptomatic and asymptomatic HRO, and no correlations between symptom severity and total number of errors. LIMITATIONS: This study was cross-sectional in design, limiting our ability to infer trajectories or heritability of these deficits. CONCLUSIONS: This study provides further support for emotion labeling deficits as a candidate endophenotype for BD. Our study also suggests these deficits are not attributable to the presence of psychiatric symptoms.

Gray matter volumes in symptomatic and asymptomatic offspring of parents diagnosed with bipolar disorder.

Children of parents diagnosed with bipolar disorder (BD), termed high-risk offspring (HRO), are at greater risk of developing psychiatric disorders compared to healthy children of healthy parents (HCO). Gray matter volume (GMV) abnormalities have been observed in HRO, however, these reports are inconsistent. We posit that this variability may be attributed to differences in methodology among offspring studies; in particular, the presence of psychiatric symptoms in HRO. Here, we directly compared GMVs between symptomatic and asymptomatic HRO, and HCO. High-resolution T1-weighted MR images were collected from 31 HRO (18 symptomatic and 13 asymptomatic) and 20 age- and sex-matched HCO. HRO had at least one parent diagnosed with BD. Symptomatic HRO were defined as having a psychiatric diagnosis other than BD, while asymptomatic HRO were required to be free of any psychiatric diagnosis. Scans were processed using voxel-based morphometry methods and between group analyses were performed in SPM. Compared to HCO, the HRO group showed decreased GMV in the right inferior orbitofrontal, right middle frontal, and bilateral superior and middle temporal regions. Both symptomatic and asymptomatic HRO groups showed decreased GMV in these regions separately when compared to HCO. When comparing symptomatic and asymptomatic HRO, GMVs were comparable in all regions except the lateral occipital cortex. Our study compared symptomatic and asymptomatic HRO directly. In doing so, we provided further support for the presence of discrete GMV deficits in HRO, and confirmed that these deficits are present irrespective of the presence of symptoms in HRO.