Altered patterns of central executive, default mode and salience network activity and connectivity are associated with current and future depression risk in two independent young adult samples.

Neural markers of pathophysiological processes underlying the dimension of subsyndromal-syndromal-level depression severity can provide objective, biologically informed targets for novel interventions to help prevent the onset of depressive and other affective disorders in individuals with subsyndromal symptoms, and prevent worsening symptom severity in those with these disorders. Greater functional connectivity (FC) among the central executive network (CEN), supporting emotional regulation (ER) subcomponent processes such as working memory (WM), the default mode network (DMN), supporting self-related information processing, and the salience network (SN), is thought to interfere with cognitive functioning and predispose to depressive disorders. We examined in young adults (1) relationships among activity and FC in these networks and current depression severity, using a paradigm designed to examine WM and ER capacity in n = 90, age = 21.7 (2.0); (2) the extent to which these relationships were specific to depression versus mania/hypomania; (3) whether findings in a first, "discovery" sample could be replicated in a second, independent, "test" sample of young adults n = 96, age = 21.6 (2.1); and (4) whether such relationships also predicted depression at up to 12 months post scan and/or mania/hypomania severity in (n = 61, including participants from both samples, age = 21.6 (2.1)). We also examined the extent to which there were common depression- and anxiety-related findings, given that depression and anxiety are highly comorbid. In the discovery sample, current depression severity was robustly predicted by greater activity and greater positive functional connectivity among the CEN, DMN, and SN during working memory and emotional regulation tasks (all ps < 0.05 qFDR). These findings were specific to depression, replicated in the independent sample, and predicted future depression severity. Similar neural marker-anxiety relationships were shown, with robust DMN-SN FC relationships. These data help provide objective, neural marker targets to better guide and monitor early interventions in young adults at risk for, or those with established, depressive and other affective disorders.

A specific neural substrate predicting current and future impulsivity in young adults.

Impulsivity (rash action with deleterious outcomes) is common to many psychiatric disorders. While some studies indicate altered amygdala and prefrontal cortical (PFC) activity associated with impulsivity, it remains unclear whether these patterns of neural activity are specific to impulsivity or common to a range of affective and anxiety symptoms. To elucidate neural markers specific to impulsivity, we aimed to differentiate patterns of amygdala-PFC activity and functional connectivity associated with impulsivity from those associated with affective and anxiety symptoms, and identify measures of this circuitry predicting future worsening of impulsivity. Using a face emotion processing task that reliably activates amygdala-PFC circuitry, neural activity and connectivity were assessed in a transdiagnostically-recruited sample of young adults, including healthy (N = 47) and treatment-seeking individuals (N = 67). Relationships were examined between neural measures and impulsivity, anhedonia, and affective and anxiety symptoms at baseline (N = 114), and at 6 months post scan (N = 30). Impulsivity, particularly negative urgency and lack of perseverance, was related to greater amygdala activity (beta = 0.82, p = 0.003; beta = 0.68, p = 0.004; respectively) and lower amygdala-medial PFC functional connectivity (voxels = 60, tpeak = 4.45, pFWE = 0.017; voxels = 335, tpeak = 5.26, pFWE = 0.001; respectively) to facial fear. Left vlPFC, but not amygdala, activity to facial anger was inversely associated with mania/hypomania (beta = -2.08, p = 0.018). Impulsivity 6 months later was predicted by amygdala activity to facial sadness (beta = 0.50, p = 0.017). There were no other significant relationships between neural activity and 6-month anhedonia, affective, and anxiety symptoms. Our findings are the first to associate amygdala-PFC activity and functional connectivity with impulsivity in a large, transdiagnostic sample, providing neural targets for future interventions to reduce predisposition to impulsivity and related future mental health problems in young adults.

Distinguishing between depression in bipolar disorder and unipolar depression using magnetic resonance imaging: a systematic review.

OBJECTIVES: Magnetic resonance imaging (MRI) studies comparing bipolar and unipolar depression characterize pathophysiological differences between these conditions. However, it is difficult to interpret the current literature due to differences in MRI modalities, analysis methods, and study designs. METHODS: We conducted a systematic review of publications using MRI to compare individuals with bipolar and unipolar depression. We grouped studies according to MRI modality and task design. Within the discussion, we critically evaluated and summarized the functional MRI research and then further complemented these findings by reviewing the structural MRI literature. RESULTS: We identified 88 MRI publications comparing participants with bipolar depression and unipolar depressive disorder. Compared to individuals with unipolar depression, participants with bipolar disorder exhibited heightened function, increased within network connectivity, and reduced grey matter volume in salience and central executive network brain regions. Group differences in default mode network function were less consistent but more closely associated with depressive symptoms in participants with unipolar depression but distractibility in bipolar depression. CONCLUSIONS: When comparing mood disorder groups, the neuroimaging evidence suggests that individuals with bipolar disorder are more influenced by emotional and sensory processing when responding to their environment. In contrast, depressive symptoms and neurofunctional response to emotional stimuli were more closely associated with reduced central executive function and less adaptive cognitive control of emotionally oriented brain regions in unipolar depression. Researchers now need to replicate and refine network-level trends in these heterogeneous mood disorders and further characterize MRI markers associated with early disease onset, progression, and recovery.

Clinical, cortical thickness and neural activity predictors of future affective lability in youth at risk for bipolar disorder: initial discovery and independent sample replication.

We aimed to identify markers of future affective lability in youth at bipolar disorder risk from the Pittsburgh Bipolar Offspring Study (BIOS) (n = 41, age = 14, SD = 2.30), and validate these predictors in an independent sample from the Longitudinal Assessment of Manic Symptoms study (LAMS) (n = 55, age = 13.7, SD = 1.9). We included factors of mixed/mania, irritability, and anxiety/depression (29 months post MRI scan) in regularized regression models. Clinical and demographic variables, along with neural activity during reward and emotion processing and gray matter structure in all cortical regions at baseline, were used to predict future affective lability factor scores, using regularized regression. Future affective lability factor scores were predicted in both samples by unique combinations of baseline neural structure, function, and clinical characteristics. Lower bilateral parietal cortical thickness, greater left ventrolateral prefrontal cortex thickness, lower right transverse temporal cortex thickness, greater self-reported depression, mania severity, and age at scan predicted greater future mixed/mania factor score. Lower bilateral parietal cortical thickness, greater right entorhinal cortical thickness, greater right fusiform gyral activity during emotional face processing, diagnosis of major depressive disorder, and greater self-reported depression severity predicted greater irritability factor score. Greater self-reported depression severity predicted greater anxiety/depression factor score. Elucidating unique clinical and neural predictors of future-specific affective lability factors is a step toward identifying objective markers of bipolar disorder risk, to provide neural targets to better guide and monitor early interventions in bipolar disorder at-risk youth.

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.

Altered amygdala-prefrontal response to facial emotion in offspring of parents with bipolar disorder.

This study aimed to identify neuroimaging measures associated with risk for, or protection against, bipolar disorder by comparing youth offspring of parents with bipolar disorder versus youth offspring of non-bipolar parents versus offspring of healthy parents in (i) the magnitude of activation within emotional face processing circuitry; and (ii) functional connectivity between this circuitry and frontal emotion regulation regions. The study was conducted at the University of Pittsburgh Medical Centre. Participants included 29 offspring of parents with bipolar disorder (mean age = 13.8 years; 14 females), 29 offspring of non-bipolar parents (mean age = 13.8 years; 12 females) and 23 healthy controls (mean age = 13.7 years; 11 females). Participants were scanned during implicit processing of emerging happy, sad, fearful and angry faces and shapes. The activation analyses revealed greater right amygdala activation to emotional faces versus shapes in offspring of parents with bipolar disorder and offspring of non-bipolar parents than healthy controls. Given that abnormally increased amygdala activation during emotion processing characterized offspring of both patient groups, and that abnormally increased amygdala activation has often been reported in individuals with already developed bipolar disorder and those with major depressive disorder, these neuroimaging findings may represent markers of increased risk for affective disorders in general. The analysis of psychophysiological interaction revealed that offspring of parents with bipolar disorder showed significantly more negative right amygdala-anterior cingulate cortex functional connectivity to emotional faces versus shapes, but significantly more positive right amygdala-left ventrolateral prefrontal cortex functional connectivity to happy faces (all P-values corrected for multiple tests) than offspring of non-bipolar parents and healthy controls. Taken together with findings of increased amygdala-ventrolateral prefrontal cortex functional connectivity, and decreased amygdala-anterior cingulate cortex functional connectivity previously shown in individuals with bipolar disorder, these connectivity patterns in offspring of parents with bipolar disorder may be risk markers for, rather than markers conferring protection against, bipolar disorder in youth. The patterns of activation and functional connectivity remained unchanged after removing medicated participants and those with current psychopathology from analyses. This is the first study to demonstrate that abnormal functional connectivity patterns within face emotion processing circuitry distinguish offspring of parents with bipolar disorder from those of non-bipolar parents and healthy controls.

Identifying tripartite relationship among cortical thickness, neuroticism, and mood and anxiety disorders.

The number of young adults seeking help for emotional distress, subsyndromal-syndromal mood/anxiety symptoms, including those associated with neuroticism, is rising and can be an early manifestation of mood/anxiety disorders. Identification of gray matter (GM) thickness alterations and their relationship with neuroticism and mood/anxiety symptoms can aid in earlier diagnosis and prevention of risk for future mood and anxiety disorders. In a transdiagnostic sample of young adults (n = 252;177 females; age 21.7 ± 2), Hypothesis (H) 1:regularized regression followed by multiple regression examined relationships among GM cortical thickness and clinician-rated depression, anxiety, and mania/hypomania; H2:the neuroticism factor and its subfactors as measured by NEO Personality Inventory (NEO-PI-R) were tested as mediators. Analyses revealed positive relationships between left parsopercularis thickness and depression (B = 4.87, p = 0.002), anxiety (B = 4.68, p = 0.002), mania/hypomania (B = 6.08, p ≤ 0.001); negative relationships between left inferior temporal gyrus (ITG) thickness and depression (B = - 5.64, p ≤ 0.001), anxiety (B = - 6.77, p ≤ 0.001), mania/hypomania (B = - 6.47, p ≤ 0.001); and positive relationships between left isthmus cingulate thickness (B = 2.84, p = 0.011), and anxiety. NEO anger/hostility mediated the relationship between left ITG thickness and mania/hypomania; NEO vulnerability mediated the relationship between left ITG thickness and depression. Examining the interrelationships among cortical thickness, neuroticism and mood and anxiety symptoms enriches the potential for identifying markers conferring risk for mood and anxiety disorders and can provide targets for personalized intervention strategies for these disorders.

Patterns of Neural Network Functional Connectivity Associated With Mania/Hypomania and Depression Risk in 3 Independent Young Adult Samples.

Importance: Mania/hypomania is the pathognomonic feature of bipolar disorder (BD). Established, reliable neural markers denoting mania/hypomania risk to help with early risk detection and diagnosis and guide the targeting of pathophysiologically informed interventions are lacking. Objective: To identify patterns of neural responses associated with lifetime mania/hypomania risk, the specificity of such neural responses to mania/hypomania risk vs depression risk, and the extent of replication of findings in 2 independent test samples. Design, Setting, and Participants: This cross-sectional study included 3 independent samples of young adults aged 18 to 30 years without BD or active substance use disorder within the past 3 months who were recruited from the community through advertising. Of 603 approached, 299 were ultimately included and underwent functional magnetic resonance imaging at the University of Pittsburgh, Pittsburgh, Pennsylvania, from July 2014 to May 2023. Main Outcomes and Measures: Activity and functional connectivity to approach-related emotions were examined using a region-of-interest mask supporting emotion processing and emotional regulation. The Mood Spectrum Self-Report assessed lifetime mania/hypomania risk and depression risk. In the discovery sample, elastic net regression models identified neural variables associated with mania/hypomania and depression risk; multivariable regression models identified the extent to which selected variables were significantly associated with each risk measure. Multivariable regression models then determined whether associations in the discovery sample replicated in both test samples. Results: A total of 299 participants were included. The discovery sample included 114 individuals (mean [SD] age, 21.60 [1.91] years; 80 female and 34 male); test sample 1, 103 individuals (mean [SD] age, 21.57 [2.09] years; 30 male and 73 female); and test sample 2, 82 individuals (mean [SD] age, 23.43 [2.86] years; 48 female, 29 male, and 5 nonbinary). Associations between neuroimaging variables and Mood Spectrum Self-Report measures were consistent across all 3 samples. Bilateral amygdala-left amygdala functional connectivity and bilateral ventrolateral prefrontal cortex-right dorsolateral prefrontal cortex functional connectivity were positively associated with mania/hypomania risk: discovery omnibus χ2 = 1671.7 (P < .001); test sample 1 omnibus χ2 = 1790.6 (P < .001); test sample 2 omnibus χ2 = 632.7 (P < .001). Bilateral amygdala-left amygdala functional connectivity and right caudate activity were positively associated and negatively associated with depression risk, respectively: discovery omnibus χ2 = 2566.2 (P < .001); test sample 1 omnibus χ2 = 2935.9 (P < .001); test sample 2 omnibus χ2 = 1004.5 (P < .001). Conclusions and Relevance: In this study of young adults, greater interamygdala functional connectivity was associated with greater risk of both mania/hypomania and depression. By contrast, greater functional connectivity between ventral attention or salience and central executive networks and greater caudate deactivation were reliably associated with greater risk of mania/hypomania and depression, respectively. These replicated findings indicate promising neural markers distinguishing mania/hypomania-specific risk from depression-specific risk and may provide neural targets to guide and monitor interventions for mania/hypomania and depression in at-risk individuals.

Specific Patterns of Endogenous Functional Connectivity Are Associated With Harm Avoidance in Obsessive-Compulsive Disorder.

BACKGROUND: Individuals with obsessive-compulsive disorder (OCD) show persistent avoidance behaviors, often in the absence of actual threat. Quality-of-life costs and heterogeneity support the need for novel brain-behavior intervention targets. Informed by mechanistic and anatomical studies of persistent avoidance in rodents and nonhuman primates, our goal was to test whether connections within a hypothesized persistent avoidance-related network predicted OCD-related harm avoidance (HA), a trait measure of persistent avoidance. We hypothesized that 1) HA, not an OCD diagnosis, would be associated with altered endogenous connectivity in at least one connection in the network; 2) HA-specific findings would be robust to comorbid symptoms; and 3) reliable findings would replicate in a holdout testing subsample. METHODS: Using resting-state functional connectivity magnetic resonance imaging, cross-validated elastic net for feature selection, and Poisson generalized linear models, we tested which connections significantly predicted HA in our training subsample (n = 73; 71.8% female; healthy control group n = 36, OCD group n = 37); robustness to comorbidities; and replicability in a testing subsample (n = 30; 56.7% female; healthy control group n = 15, OCD group n = 15). RESULTS: Stronger inverse connectivity between the right dorsal anterior cingulate cortex and right basolateral amygdala and stronger positive connectivity between the right ventral anterior insula and left ventral striatum were associated with greater HA across groups. Network connections did not discriminate OCD diagnostic status or predict HA-correlated traits, suggesting sensitivity to trait HA. The dorsal anterior cingulate cortex-basolateral amygdala relationship was robust to controlling for comorbidities and medication in individuals with OCD and was also predictive of HA in our testing subsample. CONCLUSIONS: Stronger inverse dorsal anterior cingulate cortex-basolateral amygdala connectivity was robustly and reliably associated with HA across groups and in OCD. Results support the relevance of a cross-species persistent avoidance-related network to OCD, with implications for precision-based approaches and treatment.

Sex differences in neural responses to emotional facial expressions are associated with lifetime depression and mania risk.

INTRODUCTION: No studies systematically examined sex differences in neural mechanisms underlying depression and mania/hypomania risk. METHOD: 80 females and 35 males, n = 115(age21.6±1.90) were scanned using 3TfMRI during an implicit emotional-faces task. We examined neural activation to all emotional faces versus baseline, using an anatomical region-of-interest mask comprising regions supporting emotion and salience processing. Sex was a covariate. Extracted parameter estimates(FWE < 0.05,k > 15), age, IQ and their sex interactions were independent variables(IV) in two penalized regression models: dependent variable either MOODS-SR-lifetime, depressive or manic domain score as measures of mania and depression risk. Subsequent Poisson regression models included the non-zero variables identified in the penalized regression models. We tested each model in 2 independent samples. Test sample-I,n = 108(21.6 ± 2.09 years,males/females = 33/75); Test sample-II,n = 93(23.7 ± 2.9 years,males/females = 31/62). RESULTS: Poisson regression models yielded significant relationships with depression and mania risk: Positive correlations were found between right fusiform activity and depression(beta = 0.610) and mania(beta = 0.690) risk. There was a significant interaction between sex and right fusiform activity(beta = -0.609) related to depression risk, where females had a positive relationship than; and a significant interaction(beta = 0.743) between sex and left precuneus activity related to mania risk, with a more negative relationship in females than males. All findings were replicated in the test samples(qs < 0.05,FDR). LIMITATIONS: No longitudinal follow-up. CONCLUSION: Greater visual attention to emotional faces might underlie greater depression and mania risk, and confer greater vulnerability to depression in females, because of heightened visual attention to emotional faces. Females have a more negative relationship between mania risk and left precuneus activity, suggesting heightened empathy might be associated with reduced mania/hypomania risk in females more than males.

Neural markers of mania that distinguish inpatient adolescents with bipolar disorder from those with other psychopathology.

Pediatric bipolar disorder (BD) is difficult to distinguish from other psychiatric disorders, a challenge which can result in delayed or incorrect interventions. Using neuroimaging we aimed to identify neural measures differentiating a rarified sample of inpatient adolescents with BD from other inpatient psychopathology (OP) and healthy adolescents (HC) during a reward task. We hypothesized reduced subcortical and elevated cortical activation in BD relative to other groups, and that these markers will be related to self-reported mania scores. We examined inpatient adolescents with diagnosis of BD-I/II (n = 29), OP (n = 43), and HC (n = 20) from the Inpatient Child and Adolescent Bipolar Spectrum Imaging study. Inpatient adolescents with BD showed reduced activity in right thalamus, left thalamus, and left amygdala, relative to inpatient adolescents with OP and HC. This reduced neural function explained 21% of the variance in past month and 23% of the variance in lifetime mania scores. Lower activity in regions associated with the reward network, during reward processing, differentiates BD from OP in inpatient adolescents and explains >20% of the variance in mania scores. These findings highlight potential targets to aid earlier identification of, and guide new treatment developments for, pediatric BD.

Neural Network Functional Interactions Mediate or Suppress White Matter-Emotional Behavior Relationships in Infants.

BACKGROUND: Elucidating the neural basis of infant positive emotionality and negative emotionality can identify biomarkers of pathophysiological risk. Our goal was to determine how functional interactions among large-scale networks supporting emotional regulation influence white matter (WM) microstructural-emotional behavior relationships in 3-month-old infants. We hypothesized that microstructural-emotional behavior relationships would be differentially mediated or suppressed by underlying resting-state functional connectivity (rsFC), particularly between default mode network and central executive network structures. METHODS: The analytic sample comprised primary caregiver-infant dyads (52 infants [42% female, mean age at scan = 15.10 weeks]), with infant neuroimaging and emotional behavior assessments conducted at 3 months. Infant WM and rsFC were assessed by diffusion-weighted imaging/tractography and resting-state magnetic resonance imaging during natural, nonsedated sleep. The Infant Behavior Questionnaire-Revised provided measures of infant positive emotionality and negative emotionality. RESULTS: After significant WM-emotional behavior relationships were observed, multimodal analyses were performed using whole-brain voxelwise mediation. Results revealed that greater cingulum bundle volume was significantly associated with lower infant positive emotionality (ß = -0.263, p = .031); however, a pattern of lower rsFC between central executive network and default mode network structures suppressed this otherwise negative relationship. Greater uncinate fasciculus volume was significantly associated with lower infant negative emotionality (ß = -0.296, p = .022); however, lower orbitofrontal cortex-amygdala rsFC suppressed this otherwise negative relationship, while greater orbitofrontal cortex-central executive network rsFC mediated this relationship. CONCLUSIONS: Functional interactions among neural networks have an important influence on WM microstructural-emotional behavior relationships in infancy. These relationships can elucidate neural mechanisms that contribute to future behavioral and emotional problems in childhood.

White Matter Correlates of Early-Onset Bipolar Illness and Predictors of One-Year Recurrence of Depression in Adults with Bipolar Disorder.

Diffusion Magnetic Resonance Imaging (dMRI) studies have reported abnormalities in emotion regulation circuits in BD; however, no study has examined the contribution of previous illness on these mechanisms. Using global probabilistic tractography, we aimed to identify neural correlates of previous BD illness and the extent to which these can help predict one-year recurrence of depressive episodes. dMRI data were collected in 70 adults with early-onset BD who were clinically followed for up to 18 years and 39 healthy controls. Higher number of depressive episodes during childhood/adolescence and higher percentage of time with syndromic depression during longitudinal follow-up was associated with lower fractional anisotropy (FA) in focal regions of the forceps minor (left, F = 4.4, p = 0.003; right, F = 3.1, p = 0.021) and anterior cingulum bundle (left, F = 4.7, p = 0.002; right, F = 7.0, p < 0.001). Lower FA in these regions was also associated with higher depressive and anxiety symptoms at scan. Remarkably, those having higher FA in the right cluster of the forceps minor (AOR = 0.43, p = 0.017) and in a cluster of the posterior cingulum bundle (right, AOR = 0.50, p = 0.032) were protected against the recurrence of depressive episodes. Previous depressive symptomatology may cause neurodegenerative effects in the forceps minor that are associated with worsening of BD symptomatology in subsequent years. Abnormalities in the posterior cingulum may also play a role.

White matter predictors of worsening of subthreshold hypomania severity in non-bipolar young adults parallel abnormalities in individuals with bipolar disorder.

BACKGROUND: Identifying neural predictors of worsening subthreshold hypomania severity can help identify risk of progression to BD. While diffusion Magnetic Resonance Imaging (dMRI) studies reported white matter microstructural abnormalities in tracts supporting emotional regulation in individuals with BD, it remains unknown whether similar patterns of white matter microstructure predict worsening of subthreshold hypomania severity in non-BD individuals. METHODS: dMRI data were collected in: 81 non-BD individuals recruited across a range of subthreshold depression and hypomania, and followed for six months; and independent samples of 75 BD and 58 healthy individuals. All individuals were assessed using standardized diagnostic assessments, mood and anxiety symptom rating scales. Global probabilistic tractography and a tract-profile approach examined fractional anisotropy (FA), a measure of fiber collinearity, in tracts supporting emotional regulation shown to have abnormalities in BD: forceps minor (FMIN), anterior thalamic radiation (ATR), cingulum bundle (CB), and uncinate fasciculus (UF). RESULTS: Lower FA in left CB (middle, ß = -0.22, P = 0.022; posterior, ß = -0.32, P < 0.001), right CB (anterior, ß = -0.30, P = 0.003; posterior, ß = -0.27, P = 0.005), and right UF (frontal, ß = -0.29, P = 0.002; temporal, ß = -0.40, P < 0.001) predicted worsening of subthreshold hypomania severity in non-BD individuals. BD versus healthy individuals showed lower FA in several of these segments: middle left CB (F = 8.7, P = 0.004), anterior right CB (F = 9.8, P = 0.002), and frontal right UF (F = 7.0, P = 0.009). Non-BD individuals with worsening 6-month hypomania had lower FA in these three segments versus HC and non-BD individuals without worsening hypomania, but similar FA to BD individuals. LIMITATIONS: Relatively short follow-up. CONCLUSIONS: White matter predictors of worsening subthreshold hypomania in non-BD individuals parallel abnormalities in BD individuals, and can guide early risk identification and interventions.

Editorial: Moving From Innovation to Validation With Independent Sample Testing.

It is well established that family history is the most important known risk factor for the development of a mood disorder.1 Approximately 25% of at-risk offspring will develop a mood disorder1,2; yet, this is only slightly higher than the lifetime rate of a mood disorder overall of 21.4%.3 These statistics suggest heterogeneity within mood disorders generally and within people at familial risk. More information, particularly in the form of trait-level biomarkers, is sorely needed to accurately predict mood disorder risk and development. Trait-level biomarker identification may also help to decrease the well-known delay in accurately diagnosing bipolar disorders specifically,4 which could ultimately improve treatment and outcomes. Nimarko et al.5 aimed to identify trait-level biological markers of social reward-related neural vulnerability that distinguish youths genetically at risk for mood disorder. Nimarko and colleagues reported a well-designed study consisting of extremely well-matched youths who, by virtue of parentage, were at risk of bipolar disorder, were at risk of major depressive disorder, or were healthy (control group).5 The sample sizes reflected the challenges associated with doing this type of research with children, but the importance of the relationships was clear and strong. Specifically, the results showed reduced bilateral putamen activity (left: z = 4.39, p = .003; right: z = 4.56, p < .001) and reduced left putamen connectivity with right posterior cingulate cortex (z = 4.04, p < .01) and left anterior cingulate cortex (z > 3.64, p < .001) during an emotional face social reward task as potential trait markers that distinguished at-risk samples.5 In another study, similarly reduced reward-related connectivity in genetically at-risk youths for bipolar disorder relative to at-risk and healthy groups was shown to monetary reward and loss.6 Importantly, in both of these studies, reward-related connectivity group differences were observed before threshold symptoms developed, suggesting that early identification and intervention may be possible. In addition, this reduced reward-related connectivity was not related to subthreshold symptoms in either study. Taken together, these findings suggest that social reward and monetary reward and loss may be interconnected at a neural level in youths genetically at risk for bipolar disorder before symptom development. Exploratory analyses in Nimarko et al.5 also showed that reduced reward-related connectivity may be a trait-level biomarker of risk of future conversion to an Axis I disorder over time (bipolar disorder risk: hazard ratio = 8.28, p < .01); major depressive disorder risk: hazard ratio = 2.31, p = .02). Although Acuff et al.6 did not address the longitudinal question of conversion directly, the authors speculated that reduced reward-related connectivity was related to increased risk of future bipolar disorder. This serendipitous independent replication of reward-related connectivity is a promising lead, but repeated testing in independent samples is needed. However, direct independent sample testing is uncommon in psychiatry and in psychiatric neuroscience.7,8 This is partially due to factors such as time and money, but also to the value placed on innovation, which is prized by funding agencies, journal editors, and society. Independent sample testing is not, by definition, innovative, and while innovation is an important cornerstone of science and should be encouraged, we also need to test previously identified findings using independent samples.

Trauma Affects Prospective Relationships Between Reward-Related Ventral Striatal and Amygdala Activation and 1-Year Future Hypo/Mania Trajectories.

BACKGROUND: Trauma exposure is associated with a more severe, persistent course of affective and anxiety symptoms. Markers of reward neural circuitry function, specifically activation to reward prediction error (RPE), are impacted by trauma and predict the future course of affective symptoms. This study's purpose was to determine how lifetime trauma exposure influences relationships between reward neural circuitry function and the course of future affective and anxiety symptoms in a naturalistic, transdiagnostic observational context. METHODS: A total of 59 young adults aged 18-25 (48 female and 11 male participants, mean ± SD = 21.5 ± 2.0 years) experiencing psychological distress completed the study. Participants were evaluated at baseline, 6, and 12 months. At baseline, the participants reported lifetime trauma events and completed a monetary reward functional magnetic resonance imaging task. Affective and anxiety symptoms were reported at each visit, and trajectories were calculated using MPlus. Neural activation during RPE and other phases of reward processing were determined using SPM8. Trauma and reward neural activation were entered as predictors of symptom trajectories. RESULTS: Trauma exposure moderated prospective relationships between left ventral striatum (ß = -1.29, p = .02) and right amygdala (ß = 0.58, p = .04) activation to RPE and future hypo/mania severity trajectory: the interaction between greater trauma and greater left ventral striatum activation to RPE was associated with a shallower increase in hypo/mania severity, whereas the interaction between greater trauma and greater right amygdala activation to RPE was associated with increasing hypo/mania severity. CONCLUSIONS: Trauma exposure affects prospective relationships between markers of reward circuitry function and affective symptom trajectories. Evaluating trauma exposure is thus crucial in naturalistic and treatment studies aiming to identify neural predictors of future affective symptom course.

Differences in adolescent cerebral perfusion as a function of obesity: Results from the FLEX-Brain study.

OBJECTIVE: Children and adolescents have greater resting cerebral blood flow (rCBF) during periods of rapid brain growth. Overweight and obesity have a global impact on brain cerebrovascular health in adults, but whether these effects are discernable in adolescents with overweight and obesity remains unknown. This study examined differences in rCBF between adolescents with a healthy weight (HW) and adolescents with overweight or obesity (OW). METHODS: The current study focused on analyzing data from 58 participants (mean age = 15.43 [SD 1.37] years). Participants were classified into OW (n = 38) and HW groups (n = 20) according to the Centers for Disease Control and Prevention's guidelines for children. Voxelwise t tests between the HW and OW groups were conducted to test for regional group differences in rCBF, controlling for age and sex. Mean rCBF was extracted from a gray matter mask to compare global rCBF between the HW and OW groups. RESULTS: The HW group had greater rCBF compared with the OW group in five clusters, with peaks in the cerebellum, precentral gyrus, and supplementary motor area. No clusters survived correction for the OW > HW contrast. Global rCBF did not significantly differ between the groups (p = 0.09). CONCLUSIONS: These results suggest that overweight and obesity in adolescence are associated with discernable reductions in blood flow to specific brain regions rather than having a global impact on rCBF.

Differentiating white matter measures that protect against vs. predispose to bipolar disorder and other psychopathology in at-risk youth.

Bipolar disorder (BD) is highly heritable. Identifying objective biomarkers reflecting pathophysiological processes predisposing to, versus protecting against BD, can help identify BD risk in offspring of BD parents. We recruited 21 BD participants with a first-degree relative with BD, 25 offspring of BD parents, 27 offspring of comparison parents with non-BD psychiatric disorders, and 32 healthy offspring of healthy parents. In at-risk groups, 23 had non-BD diagnoses and 29, no Axis-I diagnoses(healthy). Five at-risk offspring who developed BD post scan(Converters) were included. Diffusion imaging(dMRI) analysis with tract segmentation identified between-group differences in the microstructure of prefrontal tracts supporting emotional regulation relevant to BD: forceps minor, anterior thalamic radiation(ATR), cingulum bundle(CB), and uncinate fasciculus(UF). BD participants showed lower fractional anisotropy (FA) in the right CB (anterior portion) than other groups (q < 0.05); and in bilateral ATR (posterior portion) versus at-risk groups (q < 0.001). Healthy, but not non-BD, at-risk participants showed significantly higher FA in bilateral ATR clusters than healthy controls (qs < 0.05). At-risk groups showed higher FA in these clusters than BD participants (qs < 0.05). Non-BD versus healthy at-risk participants, and Converters versus offspring of BD parents, showed lower FA in the right ATR cluster (qs < 0.05). Low anterior right CB FA in BD participants versus other groups might result from having BD. High bilateral ATR FA in at-risk groups, and in healthy at-risk participants, versus healthy controls might protect against BD/other psychiatric disorders. Absence of elevated right ATR FA in non-BD versus healthy at-risk participants, and in Converters versus non-converter offspring of BD parents, might lower protection against BD in at-risk groups.

Informing the study of suicidal thoughts and behaviors in distressed young adults: The use of a machine learning approach to identify neuroimaging, psychiatric, behavioral, and demographic correlates.

Young adults are at high risk for suicide, yet there is limited ability to predict suicidal thoughts and behaviors. Machine learning approaches are better able to examine a large number of variables simultaneously to identify combinations of factors associated with suicidal thoughts and behaviors. The current study used LASSO regression to investigate extent to which a number of demographic, psychiatric, behavioral, and functional neuroimaging variables are associated with suicidal thoughts and behaviors during young adulthood. 78 treatment seeking young adults (ages 18-25) completed demographic, psychiatric, behavioral, and suicidality measures. Participants also completed an implicit emotion regulation functional neuroimaging paradigm. Report of recent suicidal thoughts and behaviors served as the dependent variable. Five variables were identified by the LASSO regression: Two were demographic variables (age and level of education), two were psychiatric variables (depression and general psychiatric distress), and one was a neuroimaging variable (left amygdala activity during sad faces). Amygdala function was significantly associated with suicidal thoughts and behaviors above and beyond the other factors. Findings inform the study of suicidal thoughts and behaviors among treatment seeking young adults, and also highlight the importance of investigating neurobiological markers.

Neural function during emotion regulation and future depressive symptoms in youth at risk for affective disorders.

Affective disorders (AD, including bipolar disorder, BD, and major depressive disorder) are severe recurrent illnesses. Identifying neural markers of processes underlying AD development in at-risk youth can provide objective, "early-warning" signs that may predate onset or worsening of symptoms. Using data (n = 34) from the Bipolar Offspring Study, we examined relationships between neural response in regions supporting executive function, and those supporting self-monitoring, during an emotional n-back task (focusing on the 2-back face distractor versus the 0-back no-face control conditions) and future depressive and hypo/manic symptoms across two groups of youth at familial risk for AD: Offspring of parents with BD (n = 15, age = 14.15) and offspring of parents with non-BD psychopathology (n = 19, age = 13.62). Participants were scanned and assessed twice, approximately 4 years apart. Across groups, less deactivation in the mid-cingulate cortex during emotional regulation (Rate Ratio = 3.07(95% CI:1.09-8.66), χ2(1) = 4.48, p = 0.03) at Time-1, and increases in functional connectivity from Time-1 to 2 (Rate Ratio = 1.45(95% CI:1.15-1.84), χ2(1) = 8.69, p = 0.003) between regions that showed deactivation during emotional regulation and the right caudate, predicted higher depression severity at Time-2. Both effects were robust to sensitivity analyses controlling for clinical characteristics. Decreases in deactivation between Times 1 and 2 in the right putamen tail were associated with increases in hypo/mania at Time-2, but this effect was not robust to sensitivity analyses. Our findings reflect neural mechanisms of risk for worsening affective symptoms, particularly depression, in youth across a range of familial risk for affective disorders. They may serve as potential objective, early-warning signs of AD in youth.