Aberrant intrinsic functional connectivity within and between corticostriatal and temporal-parietal networks in adults and youth with bipolar disorder.

BACKGROUND: Major questions remain regarding the dysfunctional neural circuitry underlying the pathophysiology of bipolar disorder (BD) in both youths and adults. In both age groups, studies implicate abnormal intrinsic functional connectivity among prefrontal, limbic and striatal areas. METHOD: We collected resting-state functional magnetic resonance imaging (fMRI) data from youths and adults (ages 10-50 years) with BD (n = 39) and healthy volunteers (HV; n = 78). We identified brain regions with aberrant intrinsic functional connectivity in BD by first comparing voxel-wise mean global connectivity and then conducting correlation analyses. We used k-means clustering and multidimensional scaling to organize all detected regions into networks. RESULTS: Across the brain, we detected areas of dysconnectivity in both youths and adults with BD relative to HV. There were no significant age-group × diagnosis interactions. When organized by interregional connectivity, the areas of dysconnectivity in patients with BD comprised two networks: one of temporal and parietal areas involved in late stages of visual processing, and one of corticostriatal areas involved in attention, cognitive control and response generation. CONCLUSIONS: These data suggest that two networks show abnormal intrinsic functional connectivity in BD. Regions in these networks have been implicated previously in BD. We observed similar dysconnectivity in youths and adults with BD. These findings provide guidance for refining models of network-based dysfunction in BD.

DSM-5 disruptive mood dysregulation disorder: correlates and predictors in young children.

BACKGROUND: Despite the inclusion of disruptive mood dysregulation disorder (DMDD) in DSM-5, little empirical data exist on the disorder. We estimated rates, co-morbidity, correlates and early childhood predictors of DMDD in a community sample of 6-year-olds. METHOD: DMDD was assessed in 6-year-old children (n = 462) using a parent-reported structured clinical interview. Age 6 years correlates and age 3 years predictors were drawn from six domains: demographics; child psychopathology, functioning, and temperament; parental psychopathology; and the psychosocial environment. RESULTS: The 3-month prevalence rate for DMDD was 8.2% (n = 38). DMDD occurred with an emotional or behavioral disorder in 60.5% of these children. At age 6 years, concurrent bivariate analyses revealed associations between DMDD and depression, oppositional defiant disorder, the Child Behavior Checklist - Dysregulation Profile, functional impairment, poorer peer functioning, child temperament (higher surgency and negative emotional intensity and lower effortful control), and lower parental support and marital satisfaction. The age 3 years predictors of DMDD at age 6 years included child attention deficit hyperactivity disorder, oppositional defiant disorder, the Child Behavior Checklist - Dysregulation Profile, poorer peer functioning, child temperament (higher child surgency and negative emotional intensity and lower effortful control), parental lifetime substance use disorder and higher parental hostility. CONCLUSIONS: A number of children met DSM-5 criteria for DMDD, and the diagnosis was associated with numerous concurrent and predictive indicators of emotional and behavioral dysregulation and poor functioning.

Fronto-limbic-striatal dysfunction in pediatric and adult patients with bipolar disorder: impact of face emotion and attentional demands.

BACKGROUND: Research in bipolar disorder (BD) implicates fronto-limbic-striatal dysfunction during face emotion processing but it is unknown how such dysfunction varies by task demands, face emotion and patient age. METHOD: During functional magnetic resonance imaging (fMRI), 181 participants, including 62 BD (36 children and 26 adults) and 119 healthy comparison (HC) subjects (57 children and 62 adults), engaged in constrained and unconstrained processing of emotional (angry, fearful, happy) and non-emotional (neutral) faces. During constrained processing, subjects answered questions focusing their attention on the face; this was processed either implicitly (nose width rating) or explicitly (hostility; subjective fear ratings). Unconstrained processing consisted of passive viewing. RESULTS: Pediatric BD rated neutral faces as more hostile than did other groups. In BD patients, family-wise error (FWE)-corrected region of interest (ROI) analyses revealed dysfunction in the amygdala, inferior frontal gyrus (IFG), anterior cingulate cortex (ACC) and putamen. Patients with BD showed amygdala hyperactivation during explicit processing (hostility ratings) of fearful faces and passive viewing of angry and neutral faces but IFG hypoactivation during implicit processing of neutral and happy faces. In the ACC and striatum, the direction of dysfunction varied by task demand: BD demonstrated hyperactivation during unconstrained processing of angry or neutral faces but hypoactivation during constrained processing (implicit or explicit) of angry, neutral or happy faces. CONCLUSIONS: Findings suggest amygdala hyperactivation in BD while processing negatively valenced and neutral faces, regardless of attentional condition, and BD IFG hypoactivation during implicit processing. In the cognitive control circuit involving the ACC and putamen, BD neural dysfunction was sensitive to task demands.

Threat bias in attention orienting: evidence of specificity in a large community-based study.

BACKGROUND: Preliminary research implicates threat-related attention biases in paediatric anxiety disorders. However, major questions exist concerning diagnostic specificity, effects of symptom-severity levels, and threat-stimulus exposure durations in attention paradigms. This study examines these issues in a large, community school-based sample. Method A total of 2046 children (ages 6-12 years) were assessed using the Development and Well Being Assessment (DAWBA), Childhood Behavior Checklist (CBCL) and dot-probe tasks. Children were classified based on presence or absence of 'fear-related' disorders, 'distress-related' disorders, and behavioural disorders. Two dot-probe tasks, which differed in stimulus exposure, assessed attention biases for happy-face and threat-face cues. The main analysis included 1774 children. RESULTS: For attention bias scores, a three-way interaction emerged among face-cue emotional valence, diagnostic group, and internalizing symptom severity (F = 2.87, p < 0.05). This interaction reflected different associations between internalizing symptom severity and threat-related attention bias across diagnostic groups. In children with no diagnosis (n = 1411, mean difference = 11.03, s.e. = 3.47, df = 1, p < 0.001) and those with distress-related disorders (n = 66, mean difference = 10.63, s.e. = 5.24, df = 1, p < 0.05), high internalizing symptoms predicted vigilance towards threat. However, in children with fear-related disorders (n = 86, mean difference = -11.90, s.e. = 5.94, df = 1, p < 0.05), high internalizing symptoms predicted an opposite tendency, manifesting as greater bias away from threat. These associations did not emerge in the behaviour-disorder group (n = 211). CONCLUSIONS: The association between internalizing symptoms and biased orienting varies with the nature of developmental psychopathology. Both the form and severity of psychopathology moderates threat-related attention biases in children.

Differential associations of conduct disorder, callous-unemotional traits and irritability with outcome expectations and values regarding the consequences of aggression.

BACKGROUND: Previous work has examined the association of aggression levels and callous-unemotional traits with outcome expectations and values regarding the consequences of aggression. Less work has examined the outcome expectations and values regarding the consequences of aggression of adolescents with Conduct Disorder (CD). Also, no studies have examined links between irritability (a second socio-affective trait associated with CD) and these social cognitive processes despite the core function of anger in retaliatory aggression and establishing dominance. METHOD: The current study, investigating these issues, involved 193 adolescents (typically developing [TD; N = 106], 87 cases with CD [N = 87]). Participants completed an adaptation of the Outcomes Expectations and Values Questionnaire and were assessed for CU traits and irritability via the Inventory of Callous-Unemotional traits and the Affective Reactivity Index. RESULTS: While CD was associated with atypical outcome expectations this was not seen within statistical models including CU traits and irritability. CU traits were associated with decreased expectation that aggression would result in feelings of remorse and victim suffering, as well as decreased concern that aggressive acts would result in punishment and victim suffering. Irritability was associated with increased expectations and concern that aggression would result in dominance and forced respect. CONCLUSIONS: The results suggest that CU traits and irritability, often present in youth with CD, are associated with different forms of maladaptive outcome expectations and values regarding the consequences of aggression. This suggests that the atypical social cognitive processes underlying aggressive behavior among youth exhibiting CU traits may differ from those exhibiting problems regulating anger.

Impaired probabilistic reversal learning in youths with mood and anxiety disorders.

BACKGROUND: From an affective neuroscience perspective, our understanding of psychiatric illness may be advanced by neuropsychological test paradigms probing emotional processes. Reversal learning is one such process, whereby subjects must first acquire stimulus/reward and stimulus/punishment associations through trial and error and then reverse them. We sought to determine the specificity of previously demonstrated reversal learning impairments in youths with bipolar disorder (BD) by now comparing BD youths to those with severe mood dysregulation (SMD), major depressive disorder (MDD), anxiety (ANX), and healthy controls. METHOD: We administered the probabilistic response reversal (PRR) task to 165 pediatric participants aged 7-17 years with BD (n=35), SMD (n=35), ANX (n=42), MDD (n=18) and normal controls (NC; n=35). Our primary analysis compared PRR performance across all five groups matched for age, sex and IQ. RESULTS: Compared to typically developing controls, probabilistic reversal learning was impaired in BD youths, with a trend in those with MDD (p=0.07). CONCLUSIONS: Our results suggest that reversal learning deficits are present in youths with BD and possibly those with MDD. Further work is necessary to elucidate the specificity of neural mechanisms underlying such behavioral deficits.

Social anxiety and age are associated with neural response to social evaluation during adolescence.

Adolescence is a sensitive period for the development of adaptive social behaviors and social anxiety, possibly due to aspects of brain development. However, research is needed to examine interactions among age, social anxiety, and social dynamics previously shown to influence neural responding. The current functional magnetic resonance imaging (fMRI) study examines brain function in 8-18 year-olds with varying levels of social anxiety. Interactions are examined among age, social anxiety, and two key task factors: valence and predictability of social interactions. Results demonstrate age, social anxiety severity, and each of the two key task-based factors interact to predict neural response in the caudate, middle and superior temporal gyri. In particular, among adolescents less-than 13 years of age, higher social anxiety predicted greater responding to unpredictable negative evaluations. However, in this same age group, the opposite pattern emerged during receipt of unpredictable positive evaluations, with less neural response in more anxious youth. Adolescents aged 13 and older overall showed less robust effects. We discuss these findings in terms of age- and anxiety-related differences in socioemotional processing.

Frontal alpha asymmetry moderates the relations between behavioral inhibition and social-effect ERN.

Behavioral inhibition (BI) is an early temperamental precursor of anxiety disorders, characterized by withdrawal from novel situations. Some but not all young children with BI go on to display anxiety disorders. Neural correlates, such as frontal alpha asymmetry or event-related negativity (ERN), could moderate the relations between early BI and later anxiety. The goal of this longitudinal study was to test frontal alpha asymmetry as a potential moderator of the relation between BI and later anxiety, and of the relation between BI and the social-effect ERN. 100 children were assessed for BI at ages 2 and 3, and we collected EEG during resting state and the social Flanker task at age 12. Frontal alpha asymmetry did not correlate with BI or anxiety, nor did it moderate the relation between early BI and later anxiety. However, frontal alpha asymmetry did moderate the relation between BI and the social-effect ERN. This suggests that, in adolescents who previously manifested BI, a pattern of resting EEG associated with avoidance predicts hypersensitivity to errors in a social context.

Early-childhood social reticence predicts SCR-BOLD coupling during fear extinction recall in preadolescent youth.

Social Reticence (SR) is a temperament construct identified in early childhood that is expressed as shy, anxiously avoidant behavior and, particularly when stable, robustly associated with risk for anxiety disorders. Threat circuit function may develop differently for children high on SR than low on SR. We compared brain function and behavior during extinction recall in a sample of 11-to-15-year-old children characterized in early childhood on a continuum of SR. Three weeks after undergoing fear conditioning and extinction, participants completed a functional magnetic resonance imaging extinction recall task assessing memory and threat differentiation for conditioned stimuli. Whereas self-report and psychophysiological measures of differential conditioning, extinction, and extinction recall were largely similar across participants, SR-related differences in brain function emerged during extinction recall. Specifically, childhood SR was associated with a distinct pattern of hemodynamic-autonomic covariation in the brain when recalling extinguished threat and safety cues. SR and attention focus impacted associations between trial-by-trial variation in autonomic responding and in brain activation. These interactions occurred in three main brain areas: the anterior insular cortex (AIC), the anterior subdivision of the medial cingulate cortex (aMCC), and the dorsolateral prefrontal cortex (dlPFC). This pattern of SCR-BOLD coupling may reflect selective difficulty tracking safety in a temperamentally at-risk population.

Investigating the genetic underpinnings of early-life irritability.

Severe irritability is one of the commonest reasons prompting referral to mental health services. It is frequently seen in neurodevelopmental disorders that manifest early in development, especially attention-deficit/hyperactivity disorder (ADHD). However, irritability can also be conceptualized as a mood problem because of its links with anxiety/depressive disorders; notably DSM-5 currently classifies severe, childhood-onset irritability as a mood disorder. Investigations into the genetic nature of irritability are lacking although twin studies suggest it shares genetic risks with both ADHD and depression. We investigated the genetic underpinnings of irritability using a molecular genetic approach, testing the hypothesis that early irritability (in childhood/adolescence) is associated with genetic risk for ADHD, as indexed by polygenic risk scores (PRS). As a secondary aim we investigated associations between irritability and PRS for major depressive disorder (MDD). Three UK samples were utilized: two longitudinal population-based cohorts with irritability data from childhood (7 years) to adolescence (15-16 years), and one ADHD patient sample (6-18 years). Irritability was defined using parent reports. PRS were derived from large genome-wide association meta-analyses. We observed associations between ADHD PRS and early irritability in our clinical ADHD sample and one of the population samples. This suggests that early irritability traits share genetic risk with ADHD in the general population and are a marker of higher genetic loading in individuals with an ADHD diagnosis. Associations with MDD PRS were not observed. This suggests that early-onset irritability could be conceptualized as a neurodevelopmental difficulty, behaving more like disorders such as ADHD than mood disorders.

Effects of the menstrual cycle on dependent variables in mood disorder research.

The purpose of this article is to review the literature on the effects of the menstrual cycle on dependent variables in mood disorder research to inform investigators which physiological measures are likely to be significantly affected by menstrual cycle fluctuations and precisely how they might be affected. The following variables are discussed: prolactin; growth hormone; the hypothalamic-pituitary-thyroid axis (including thyrotropin, triiodothyronine, and thyroxine); the hypothalamic-pituitary-adrenal axis (cortisol, corticotropin, and beta-endorphin); melatonin; sleep; body temperature; and neurotransmitter activity (serotonergic and adrenergic systems). Body temperature and plasma and urinary norepinephrine vary predictably over the menstrual cycle. Prolactin and beta-endorphin may have peaks in the periovulatory phase, whereas serotonin levels in platelet-poor plasma may reach a nadir at that time. Triiodothyronine, thyroxine, cortisol, and melatonin do not appear to vary systematically over the course of the menstrual cycle, whereas the data for growth hormone, thyrotropin, corticotropin, and sleep are inconclusive.

Sex differences in rank attainment and research activities among academic psychiatrists.

Data from a survey distributed to all full-time faculty in academic departments of psychiatry were used to examine possible sex differences in research activities and rank attainment among psychiatrists. A total of 1923 psychiatrists responded, 1564 men (81.3%) and 359 women (18.7%). Continuous dependent variables were analyzed by using analyses of covariance with the year graduated from medical school as a covariate. For categorical dependent variables, the sample was divided into four 10-year cohorts based on the year graduated from medical school, and differences between men and women were analyzed with chi 2 tests. Over the entire sample, men were more likely than women to have had research training, to have ever been principal investigators on peer-reviewed grants, to mentor research trainees, to be currently involved in research activities, and to meet defined criteria as a "researcher." Many gender differences remained significant after controlling for seniority and research training. In every cohort, the men had attained higher academic rank than the women. In general, differences in research activity and productivity were most marked in the youngest cohort. To ensure a rich talent pool for psychiatric research, efforts must be made to recruit and support researchers from among the increased number of women in psychiatry.

An fMRI study of emotional face encoding in youth at risk for bipolar disorder.

Face memory deficits may be a bipolar disorder (BD) endophenotype. BD (n=27) and unaffected youth at risk (n=13) exhibited middle frontal gyrus hypoactivation during successful vs. unsuccessful encoding. Parahippocampal gyrus dysfunction was found in BD and at-risk youth (vs. low-risk, n=37). Middle occipital gyrus hypoactivation was only present in BD.

Effects of leuprolide-induced hypogonadism and testosterone replacement on sleep, melatonin, and prolactin secretion in men.

The possible role of gonadal steroids in regulating sleep and circadian rhythms in humans has received relatively little attention despite the importance of the topic to several clinical syndromes. Pharmacologically induced hypogonadism, with and without gonadal steroid replacement, provides an opportunity to examine these questions within a controlled experimental design. We used leuprolide acetate, with and without testosterone replacement, to study the role of testosterone in the regulation of sleep and of melatonin, PRL, and TSH secretion in men. Results from 10 men revealed significant decreases in 24-h PRL levels and in the percentage and time of stage 4 sleep in the hypogonadal state compared with testosterone replacement. There were no differences in melatonin or TSH secretion or in the timing or duration of sleep between the two hormonal conditions. These results indicate that testosterone has relatively specific and discrete effects on sleep and hormonal rhythms in men.

Lack of relationship between menstrual cycle phase and mood in a sample of women with rapid cycling bipolar disorder.

BACKGROUND: Women are overrepresented in samples of patients with rapid cycling bipolar disorder (RCBD). To explore whether menstrually related mood changes might account for this gender difference, we studied the relationship between menstrual cycle phase and mood in a sample of premenopausal women with rapid cycling bipolar disorder (RCBD). METHODS: Twenty-five women with RCBD completed daily self-rating forms indicating their mood and days of menstruation for a minimum of three months. The data were analyzed for each individual and for the group as a whole, categorically (depression, euthymia, and hypomania) and ordinally (0-100, with 0 being "most depressed ever felt" and 100 being "most manic"), with and without normalization of the menstrual cycle to a 28-day cycle. RESULTS: None of the group analyses showed a significant effect of menstrual cycle on mood. Although some women did exhibit significant relationships between menstrual cycle phase and categorical mood state, there was no consistent pattern to the relationship. CONCLUSIONS: There was no systematic relationship between menstrual cycle and mood in a sample of women with RCBD.

Salivary and plasma measures of dim light melatonin onset (DLMO) in patients with rapid cycling bipolar disorder.

A number of researchers have suggested that the phase (timing) of circadian rhythms in depressed patients is abnormal. Longitudinal studies could help to elucidate the relationship between circadian phase and mood. Such studies would be facilitated by the development of a noninvasive method for measuring circadian phase. In normal volunteers, the concentration of salivary melatonin measurements has been shown to be significantly correlated with those obtained in plasma; however, it is unknown whether salivary melatonin measurements can reliably detect the unmasked time of onset of nocturnal melatonin secretion (a measure of circadian phase). In addition, the relationship between salivary and plasma melatonin measurements in medicated psychiatric patients is unknown. We measured plasma and salivary melatonin simultaneously in a sample of 12 medicated patients with rapid cycling bipolar disorder. The intraclass correlation coefficient between plasma and salivary measures of the dim light melatonin onset (DLMO) was 0.93. We therefore conclude that salivary melatonin can be used to determine the time of the DLMO in this population.

Treatment of rapidly cycling bipolar patient by using extended bed rest and darkness to stabilize the timing and duration of sleep.

BACKGROUND: The modern practice of using artificial light to extend waking activities into the nighttime hours might be expected to precipitate or exacerbate bipolar illness, because it has been shown that modifying the timing and duration of sleep can induce mania in susceptible individuals. With this possibility in mind, we treated a patient with rapidly cycling bipolar illness by creating an environment that was likely to increase and to stabilize the number of hours that he slept each night. METHODS: We asked the patient to remain at bed rest in the dark for 14 hours each night (later this was gradually reduced to 10 hours). Over a period of several years, his clinical state was assessed with twice-daily self-ratings, once-weekly observer ratings, and continuous wrist motor activity recordings. Times of sleeping and waking were recorded with sleep logs, polygraphic recordings, and computer-based event recordings. RESULTS: The patient cycled rapidly between depression and mania and experienced marked fluctuations in the timing and duration of sleep when he slept according to his usual routine, but his sleep and mood stabilized when he adhered to a regimen of long nightly periods of enforced bed rest in the dark. CONCLUSIONS: Fostering sleep and stabilizing its timing by scheduling regular nightly periods of enforced bed rest in the dark may help to prevent mania and rapid cycling in bipolar patients.

Women with bipolar illness: clinical and research issues.

OBJECTIVE: The purpose of this article is to review the literature concerning gender differences in the course of bipolar illness and discuss issues relevant to the treatment of women with the illness. METHOD: The literature concerning the following topics is reviewed: gender differences in the course of bipolar illness; effects of the female reproductive cycle on the course of bipolar illness; special considerations in the treatment of bipolar women (focusing on the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-thyroid axes); and hypotheses to explain the greater prevalence of rapid cycling among bipolar women than among bipolar men. RESULTS: Data clearly indicate that rapid cycling is more common among bipolar women. Data also suggest that bipolar women may have more depressive episodes (and fewer manic episodes) and may be more likely to suffer from mixed (as opposed to pure) mania than bipolar men. While it is clear that bipolar women are at high risk for postpartum episodes, the effects of other reproductive system events (i.e., puberty, menstrual cycle, pregnancy, menopause, use of oral contraceptives or hormone replacement therapy) on the course or treatment of bipolar illness have received little systematic study. It is unclear whether women are at higher risk than men for developing lithium-induced hypothyroidism. Higher rates of hypothyroidism, greater use of antidepressants, and gonadal steroid effects are possible explanations for the greater prevalence of rapid cycling among bipolar women. CONCLUSIONS: Gender differences in bipolar illness and the effects of the female reproductive system on the course and treatment of the illness deserve more study. The importance of a longitudinal approach to these questions is emphasized.

Reimbursement for partial hospitalization: a survey and policy implications.

Lack of third-party reimbursement is frequently cited as a cause of underutilization of partial hospitalization. The authors contacted a sample of health maintenance organizations (HMOs) and public and private payers to obtain information about their payment policies. They conclude that in the private sector, reimbursement barriers are diminishing but that clinicians frequently must obtain an extracontractual agreement for coverage. Partial hospitalization is particularly attractive to HMOs and others that pay on a capitated basis and can strictly control utilization. A recent clarification of Medicare guidelines may facilitate reimbursement for hospital-based programs, but there remain significant disincentives under the Medicare statute for widespread utilization of partial hospitalization.