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.

Reward related ventral striatal activity and differential response to sertraline versus placebo in depressed individuals.

Medications to treat major depressive disorder (MDD) are not equally effective across patients. Given that neural response to rewards is altered in MDD and given that reward-related circuitry is modulated by dopamine and serotonin, we examined, for the first time, whether reward-related neural activity moderated response to sertraline, an antidepressant medication that targets these neurotransmitters. A total of 222 unmedicated adults with MDD randomized to receive sertraline (n = 110) or placebo (n = 112) in the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study completed demographic and clinical assessments, and pretreatment functional magnetic resonance imaging while performing a reward task. We tested whether an index of reward system function in the ventral striatum (VS), a key reward circuitry region, moderated differential response to sertraline versus placebo, assessed with the Hamilton Rating Scale for Depression (HSRD) over 8 weeks. We observed a significant moderation effect of the reward index, reflecting the temporal dynamics of VS activity, on week-8 depression levels (Fs ≥ 9.67, ps ≤ 0.002). Specifically, VS responses that were abnormal with respect to predictions from reinforcement learning theory were associated with lower week-8 depression symptoms in the sertraline versus placebo arms. Thus, a more abnormal pattern of pretreatment VS dynamic response to reward expectancy (expected outcome value) and prediction error (difference between expected and actual outcome), likely reflecting serotonergic and dopaminergic deficits, was associated with better response to sertraline than placebo. Pretreatment measures of reward-related VS activity may serve as objective neural markers to advance efforts to personalize interventions by guiding individual-level choice of antidepressant treatment.

Longitudinal changes in brain activation during anticipation of monetary loss in bipolar disorder.

BACKGROUND: Individuals with bipolar disorder (BD) show aberrant brain activation patterns during reward and loss anticipation. We examined for the first time longitudinal changes in brain activation during win and loss anticipation to identify trait markers of aberrant anticipatory processing in BD. METHODS: Thirty-four euthymic and depressed individuals with BD-I and 17 healthy controls (HC) were scanned using functional magnetic resonance imaging twice 6 months apart during a reward task. RESULTS: HC, but not individuals with BD, showed longitudinal reductions in the right lateral occipital cortex (RLOC) activation during processing of cues predicting possible money loss (p-corrected <0.05). This result was not affected by psychotropic medication, mood state or the changes in depression/mania severity between the two scans in BD. Elevated symptoms of subthreshold hypo/mania at baseline predicted more aberrant longitudinal patterns of RLOC activation explaining 12.5% of variance in individuals with BD. CONCLUSIONS: Increased activation in occipital cortex during negative outcome anticipation may be related to elevated negative emotional arousal during anticipatory cue processing. One interpretation is that, unlike HC, individuals with BD were not able to learn at baseline that monetary losses were smaller than monetary gains and were not able to reduce emotional arousal for negative cues 6 months later. Future research in BD should examine how modulating occipital cortical activation affects learning from experience in individuals with BD.

Anticipation-related brain connectivity in bipolar and unipolar depression: a graph theory approach.

Bipolar disorder is often misdiagnosed as major depressive disorder, which leads to inadequate treatment. Depressed individuals versus healthy control subjects, show increased expectation of negative outcomes. Due to increased impulsivity and risk for mania, however, depressed individuals with bipolar disorder may differ from those with major depressive disorder in neural mechanisms underlying anticipation processes. Graph theory methods for neuroimaging data analysis allow the identification of connectivity between multiple brain regions without prior model specification, and may help to identify neurobiological markers differentiating these disorders, thereby facilitating development of better therapeutic interventions. This study aimed to compare brain connectivity among regions involved in win/loss anticipation in depressed individuals with bipolar disorder (BDD) versus depressed individuals with major depressive disorder (MDD) versus healthy control subjects using graph theory methods. The study was conducted at the University of Pittsburgh Medical Center and included 31 BDD, 39 MDD, and 36 healthy control subjects. Participants were scanned while performing a number guessing reward task that included the periods of win and loss anticipation. We first identified the anticipatory network across all 106 participants by contrasting brain activation during all anticipation periods (win anticipation + loss anticipation) versus baseline, and win anticipation versus loss anticipation. Brain connectivity within the identified network was determined using the Independent Multiple sample Greedy Equivalence Search (IMaGES) and Linear non-Gaussian Orientation, Fixed Structure (LOFS) algorithms. Density of connections (the number of connections in the network), path length, and the global connectivity direction ('top-down' versus 'bottom-up') were compared across groups (BDD/MDD/healthy control subjects) and conditions (win/loss anticipation). These analyses showed that loss anticipation was characterized by denser top-down fronto-striatal and fronto-parietal connectivity in healthy control subjects, by bottom-up striatal-frontal connectivity in MDD, and by sparse connectivity lacking fronto-striatal connections in BDD. Win anticipation was characterized by dense connectivity of medial frontal with striatal and lateral frontal cortical regions in BDD, by sparser bottom-up striatum-medial frontal cortex connectivity in MDD, and by sparse connectivity in healthy control subjects. In summary, this is the first study to demonstrate that BDD and MDD with comparable levels of current depression differed from each other and healthy control subjects in density of connections, connectivity path length, and connectivity direction as a function of win or loss anticipation. These findings suggest that different neurobiological mechanisms may underlie aberrant anticipation processes in BDD and MDD, and that distinct therapeutic strategies may be required for these individuals to improve coping strategies during expectation of positive and negative outcomes.

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.

Early Infant Prefrontal Cortical Microstructure Predicts Present and Future Emotionality.

BACKGROUND: High levels of infant negative emotionality (NE) and low positive emotionality (PE) predict future emotional and behavioral problems. The prefrontal cortex (PFC) supports emotional regulation, with each PFC subregion specializing in specific emotional processes. Neurite orientation dispersion and density imaging estimates microstructural integrity and myelination via the neurite density index (NDI) and dispersion via the orientation dispersion index (ODI), with potential to more accurately evaluate microstructural alterations in the developing brain. Yet, no study has used these indices to examine associations between PFC microstructure and concurrent or developing infant emotionality. METHODS: We modeled PFC subregional NDI and ODI at 3 months with caregiver-reported infant NE and PE at 3 months (n = 61) and at 9 months (n = 50), using multivariable and subsequent bivariate regression models. RESULTS: The most robust statistically significant findings were positive associations among 3-month rostral anterior cingulate cortex (ACC) ODI and caudal ACC NDI and concurrent NE, a positive association between 3-month lateral orbitofrontal cortex ODI and prospective NE, and a negative association between 3-month dorsolateral PFC ODI and concurrent PE. Multivariate models also revealed that other PFC subregional microstructure measures, as well as infant and caregiver sociodemographic and clinical factors, predicted infant 3- and 9-month NE and PE. CONCLUSIONS: Greater NDI and ODI, reflecting greater microstructural complexity, in PFC regions supporting salience perception (rostral ACC), decision making (lateral orbitofrontal cortex), action selection (caudal ACC), and attentional processes (dorsolateral PFC) might result in greater integration of these subregions with other neural networks and greater attention to salient negative external cues, thus higher NE and/or lower PE. These findings provide potential infant cortical markers of future psychopathology risk.

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.

Impact of Sex and Pubertal Development on Anxiety in Adolescents After Concussion.

Concussion often results in psychological symptoms, including anxiety. Post-concussion anxiety has been well documented, although much of this research has focused on collegiate athletes. The purpose of this study was to compare (1) anxiety symptoms in concussed and healthy controls over time and (2) to explore sex differences in post-concussion anxiety within the context of pubertal development. Participants (N = 126, mean age = 15.1 years old), including concussed (n = 86) and healthy adolescents (n = 40), completed the Pubertal Development Scale (PDS) and the Screen for Child Anxiety and Related Disorders (SCARED-C). The concussed groups completed SCARED-C at three visits (<10 days, 4 weeks, 3 months). Results of an analysis of covariance (ANCOVA) and multi-variate analysis of covariance (MANCOVA) found concussed adolescents reported higher SCARED-C total, generalized, and panic anxiety scores than healthy controls, after controlling for sex, age, and PDS score (PDSS). A three-way mixed ANCOVA examined the effects of sex, PDSS, time, and their interaction on SCARED-C total score in concussed adolescents while controlling for age. There was a significant three-way interaction between sex, age, and PDSS on SCARED-C total score while controlling for age. Overall, we observed increased anxiety in concussed adolescents, compared with controls, as well as greater post-concussion anxiety reported by females compared with males, including within PDSS groups. Concussion providers should be prepared to receive training to administer well-validated measures of psychopathology and should consider that female adolescents, compared with males, regardless of pubertal development, may be at greater risk for post-concussion anxiety.

Early infant prefrontal gray matter volume is associated with concurrent and future infant emotionality.

High levels of infant negative emotionality (NE) are associated with emotional and behavioral problems later in childhood. Identifying neural markers of high NE as well as low positive emotionality (PE) in infancy can provide neural markers to aid early identification of vulnerability, and inform interventions to help delay or even prevent psychiatric disorders before the manifestation of symptoms. Prefrontal cortical (PFC) subregions support the regulation of NE and PE, with each PFC subregion differentially specializing in distinct emotional regulation processes. Gray matter (GM) volume measures show good test-retest reliability, and thus have potential use as neural markers of NE and PE. Yet, while studies showed PFC GM structural abnormalities in adolescents and young adults with affective disorders, few studies examined how PFC subregional GM measures are associated with NE and PE in infancy. We aimed to identify relationships among GM in prefrontal cortical subregions at 3 months and caregiver report of infant NE and PE, covarying for infant age and gender and caregiver sociodemographic and clinical variables, in two independent samples at 3 months (Primary: n = 75; Replication sample: n = 40) and at 9 months (Primary: n = 44; Replication sample: n = 40). In the primary sample, greater 3-month medial superior frontal cortical volume was associated with higher infant 3-month NE (p < 0.05); greater 3-month ventrolateral prefrontal cortical volume predicted lower infant 9-month PE (p < 0.05), even after controlling for 3-month NE and PE. GM volume in other PFC subregions also predicted infant 3- and 9-month NE and PE, together with infant demographic factors, caregiver age, and/or caregiver affective instability and anxiety. These findings were replicated in the independent sample. To our knowledge, this is the first study to determine in primary and replication samples associations among infant PFC GM volumes and concurrent and prospective NE and PE, and identify promising, early markers of future psychopathology risk.

Neurobehavioral Reward and Sleep-Circadian Profiles Predict Present and Next-Year Mania/Hypomania Symptoms.

BACKGROUND: Heightened reward sensitivity/impulsivity, related neural activity, and sleep-circadian disruption are important risk factors for bipolar spectrum disorders, the defining feature of which is mania/hypomania. Our goal was to identify neurobehavioral profiles based on reward and sleep-circadian features and examine their specificity to mania/hypomania versus depression vulnerability. METHODS: At baseline, a transdiagnostic sample of 324 adults (18-25 years) completed trait measures of reward sensitivity (Behavioral Activation Scale), impulsivity (UPPS-P-Negative Urgency), and a functional magnetic resonance imaging card-guessing reward task (left ventrolateral prefrontal activity to reward expectancy, a neural correlate of reward motivation and impulsivity, was extracted). At baseline, 6-month follow-up, and 12-month follow-up, the Mood Spectrum Self-Report Measure - Lifetime Version assessed lifetime predisposition to subthreshold-syndromal mania/hypomania, depression, and sleep-circadian disturbances (insomnia, sleepiness, reduced sleep need, rhythm disruption). Mixture models derived profiles from baseline reward, impulsivity, and sleep-circadian variables. RESULTS: Three profiles were identified: 1) healthy (no reward or sleep-circadian disruption; n = 162); 2) moderate-risk (moderate reward and sleep-circadian disruption; n = 109); and 3) high-risk (high impulsivity and sleep-circadian disruption; n = 53). At baseline, the high-risk group had significantly higher mania/hypomania scores than the other groups but did not differ from the moderate-risk group in depression scores. Over the follow-up period, the high-risk and moderate-risk groups exhibited elevated mania/hypomania scores, whereas depression scores increased at a faster rate in the healthy group than in the other groups. CONCLUSIONS: Cross-sectional and next-year predisposition to mania/hypomania is associated with a combination of heightened reward sensitivity and impulsivity, related reward circuitry activity, and sleep-circadian disturbances. These measures can be used to detect mania/hypomania risk and provide targets to guide and monitor interventions.

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.

Working memory updating in individuals with bipolar and unipolar depression: fMRI study.

Understanding neurobiological characteristics of cognitive dysfunction in distinct psychiatric disorders remains challenging. In this secondary data analysis, we examined neurobiological differences in brain response during working memory updating among individuals with bipolar disorder (BD), those with unipolar depression (UD), and healthy controls (HC). Individuals between 18-45 years of age with BD (n = 100), UD (n = 109), and HC (n = 172) were scanned using fMRI while performing 0-back (easy) and 2-back (difficult) tasks with letters as the stimuli and happy, fearful, or neutral faces as distractors. The 2(n-back) × 3(groups) × 3(distractors) ANCOVA examined reaction time (RT), accuracy, and brain activation during the task. HC showed more accurate and faster responses than individuals with BD and UD. Difficulty-related activation in the prefrontal, posterior parietal, paracingulate cortices, striatal, lateral occipital, precuneus, and thalamic regions differed among groups. Individuals with BD showed significantly lower difficulty-related activation differences in the left lateral occipital and the right paracingulate cortices than those with UD. In individuals with BD, greater difficulty-related worsening in accuracy was associated with smaller activity changes in the right precuneus, while greater difficulty-related slowing in RT was associated with smaller activity changes in the prefrontal, frontal opercular, paracingulate, posterior parietal, and lateral occipital cortices. Measures of current depression and mania did not correlate with the difficulty-related brain activation differences in either group. Our findings suggest that the alterations in the working memory circuitry may be a trait characteristic of reduced working memory capacity in mood disorders. Aberrant patterns of activation in the left lateral occipital and paracingulate cortices may be specific to BD.

Vestibular/ocular motor symptoms in concussed adolescents are linked to retrosplenial activation.

Following concussion, adolescents often experience vestibular and ocular motor symptoms as well as working memory deficits that may affect their cognitive, academic and social well-being. Complex visual environments including school activities, playing sports, or socializing with friends may be overwhelming for concussed adolescents suffering from headache, dizziness, nausea and fogginess, thus imposing heightened requirements on working memory to adequately function in such environments. While understanding the relationship between working memory and vestibular/ocular motor symptoms is critically important, no previous study has examined how an increase in working memory task difficulty affects the relationship between severity of vestibular/ocular motor symptoms and brain and behavioural responses in a working memory task. To address this question, we examined 80 adolescents (53 concussed, 27 non-concussed) using functional MRI while performing a 1-back (easy) and 2-back (difficult) working memory tasks with angry, happy, neutral and sad face distractors. Concussed adolescents completed the vestibular/ocular motor screening and were scanned within 10 days of injury. We found that all participants showed lower accuracy and slower reaction time on difficult (2-back) versus easy (1-back) tasks (P-values < 0.05). Concussed adolescents were significantly slower than controls across all conditions (P < 0.05). In concussed adolescents, higher vestibular/ocular motor screening total scores were associated with significantly greater differences in reaction time between 1-back and 2-back across all distractor conditions and significantly greater differences in retrosplenial cortex activation for the 1-back versus 2-back condition with neutral face distractors (P-values < 0.05). Our findings suggest that processing of emotionally ambiguous information (e.g. neutral faces) additionally increases the task difficulty for concussed adolescents. Post-concussion vestibular/ocular motor symptoms may reduce the ability to inhibit emotionally ambiguous information during working memory tasks, potentially affecting cognitive, academic and social functioning in concussed adolescents.

Resting State Functional Connectivity between Dorsal Attentional Network and Right Inferior Frontal Gyrus in Concussed and Control Adolescents.

Concussion among adolescents continues to be a public health concern. Yet, the differences in brain function between adolescents with a recent concussion and adolescents with no history of concussion are not well understood. Although resting state functional magnetic resonance imaging (fMRI) can be a useful tool in examining these differences, few studies have used this technique to examine concussion in adolescents. Here, we investigate the differences in the resting state functional connectivity of 52 adolescents, 38 with a concussion in the previous 10 days (mean age = 15.6; female = 36.8%), and 14 controls with no concussion history (mean age = 15.1; female = 57.1%). Independent component analysis and dual regression revealed that control adolescents had significantly greater functional connectivity between the dorsal attention network (DAN) and right inferior frontal gyrus (RIFG) compared to concussed adolescents (p-corrected < 0.001). Specifically, there was a positive DAN-RIFG connectivity in control, but not concussed, adolescents. Our findings indicate that concussion is associated with disrupted DAN-RIFG connectivity, which may reflect a general, nonspecific response to injury.

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.

The Role of Puberty and Sex on Brain Structure in Adolescents With Anxiety Following Concussion.

BACKGROUND: Adolescence represents a window of vulnerability for developing psychological symptoms following concussion, especially in girls. Concussion-related lesions in emotion regulation circuits may help explain these symptoms. However, the contribution of sex and pubertal maturation remains unclear. Using the neurite density index (NDI) in emotion regulation tracts (left/right cingulum bundle [CB], forceps minor [FMIN], and left/right uncinate fasciculus), we sought to elucidate these relationships. METHODS: No adolescent had a history of anxiety and/or depression. The Screen for Child Anxiety Related Emotional Disorders and Children's Depression Rating Scale were used at scan to assess anxiety and depressive symptoms in 55 concussed adolescents (41.8% girls) and 50 control adolescents with no current/history of concussion (44% girls). We evaluated if a mediation-moderation model including the NDI (mediation) and sex or pubertal status (moderation) could help explain this relationship. RESULTS: Relative to control adolescents, concussed adolescents showed higher anxiety (p = .003) and lower NDI, with those at more advanced pubertal maturation showing greater abnormalities in 4 clusters: the left CB frontal (p = .002), right CB frontal (p = .011), FMIN left-sided (p = .003), and FMIN right-sided (p = .003). Across all concussed adolescents, lower NDI in the left CB frontal and FMIN left-sided clusters partially mediated the association between concussion and anxiety, with the CB being specific to female adolescents. These effects did not explain depressive symptoms. CONCLUSIONS: Our findings indicate that lower NDI in the CB and FMIN may help explain anxiety following concussion and that adolescents at more advanced (vs less advanced) status of pubertal maturation may be more vulnerable to concussion-related injuries, especially in girls.

The role of sleep quality on white matter integrity and concussion symptom severity in adolescents.

BACKGROUND: Sleep problems are common after concussion; yet, to date, no study has evaluated the relationship between sleep, white matter integrity, and post-concussion symptoms in adolescents. Using self-reported quality of sleep measures within the first 10 days of injury, we aimed to determine if quality of sleep exerts a main effect on white matter integrity in major tracts, as measured by diffusion Magnetic Resonance Imaging (dMRI), and further examine whether this effect can help explain the variance in post-concussion symptom severity in 12- to 17.9-year-old adolescents. METHODS: dMRI data were collected in 57 concussed adolescents (mean age[SD] = 15.4[1.5] years; 41.2 % female) with no history of major psychiatric diagnoses. Severity of post-concussion symptoms was assessed at study entry (mean days[SD] = 3.7[2.5] days since injury). Using the Pittsburgh Sleep Quality Index (PSQI), concussed adolescents were divided into two groups based on their quality of sleep in the days between injury and scan: good sleepers (PSQI global score ≤ 5; N = 33) and poor sleepers (PSQI global score > 5; N = 24). Neurite Orientation Dispersion and Dispersion Index (NODDI), specifically the Neurite Density Index (NDI), was used to quantify microstructural properties in major tracts, including 18 bilateral and one interhemispheric tract, and identify whether dMRI differences existed in good vs poor sleepers. Since the interval between concussion and neuroimaging acquisition varied among concussed adolescents, this interval was included in the analysis along with an interaction term with sleep groups. Regularized regression was used to identify if quality of sleep-related dMRI measures correlated with post-concussion symptom severity. Due to higher reported concussion symptom severity in females, interaction terms between dMRI and sex were included in the regularized regression model. Data collected in 33 sex- and age-matched non-concussed controls (mean age[SD] = 15.2[1.5]; 45.5 % female) served as healthy reference and sex and age were covariates in all analyses. RESULTS: Relative to good sleepers, poor sleepers demonstrated widespread lower NDI (18 of the 19 tracts; FDR corrected P < 0.048). This group effect was only significant with at least seven days between concussion and neuroimaging acquisition. Post-concussion symptoms severity was negatively correlated with NDI in four of these tracts: cingulum bundle, optic radiation, striato-fronto-orbital tract, and superior longitudinal fasciculus I. The multiple linear regression model combining sex and NDI of these four tracts was able to explain 33.2 % of the variability in symptom severity (F[7,49] = 4.9, P < 0.001, Adjusted R2 = 0.332). Relative to non-concussed controls, poor sleepers demonstrated lower NDI in the cingulum bundle, optic radiation, and superior longitudinal fasciculus I (FDR corrected P < 0.040). CONCLUSIONS: Poor quality of sleep following concussion is associated with widespread lower integrity of major white matter tracts, that in turn helped to explain post-concussion symptom severity in 12-17.9-year-old adolescents. The effect of sleep on white matter integrity following concussion was significant after one week, suggesting that acute sleep interventions may need this time to begin to take effect. Our findings may suggest an important relationship between good quality of sleep in the days following concussion and integrity of major white matter tracts. Moving forward, researchers should evaluate the effectiveness of sleep interventions on white matter integrity and clinical outcomes following concussion.

Patterns of Infant Amygdala Connectivity Mediate the Impact of High Caregiver Affect on Reducing Infant Smiling: Discovery and Replication.

BACKGROUND: Behavioral research indicates that caregiver mood disorders and emotional instability in the early months following childbirth are associated with lower positive emotionality and higher negative emotionality in infants, but the neural mechanisms remain understudied. METHODS: Using resting-state functional connectivity as a measure of the functional architecture of the early infant brain, we aimed to determine the extent to which connectivity between the amygdala, a key region supporting emotional learning and perception, and large-scale neural networks mediated the association between caregiver affect and anxiety and early infant negative emotionality and positive emotionality. Two samples of infants (first sample: n = 58; second sample: n = 31) 3 months of age underwent magnetic resonance imaging during natural sleep. RESULTS: During infancy, greater resting-state functional connectivity between the amygdala and the salience network and, to a lesser extent, lower amygdala and executive control network resting-state functional connectivity mediated the effect of greater caregiver postpartum depression and trait anxiety on reducing infant smiling (familywise error-corrected p < .05). Furthermore, results from the first sample were replicated in the second, independent sample, to a greater extent for caregiver depression than for caregiver anxiety. CONCLUSIONS: We provide evidence of early objective neural markers that can help identify infants who are more likely to be at risk from, versus those who might be protected against, the deleterious effects of caregiver depression and anxiety and reduced positive emotionality.