Development of a Korean Version of the Child Mania Rating Scale: Korean Validity and Reliability Study.

OBJECTIVE: Clinical rating scales are essential in psychiatry. The Young Mania Rating Scale is the gold standard for assessing mania. However, increased attention to pediatric bipolar disorder has led to the development of the Child Mania Rating Scale (CMRS), which is a parent-reported rating scale designed to assess mania in children and adolescents. This study aimed to translate the CMRS into Korean and assess the validity and reliability of the Korean version of the CMRS (K-CMRS). METHODS: The original English version of the CMRS has been translated into Korean. We enrolled 33 patients with bipolar disorder and 26 patients with attention-deficit hyperactivity disorder (ADHD). All participants were evaluated using the translated K-CMRS, Mood Disorder Questionnaire (MDQ), and ADHD Rating Scale. RESULTS: The Cronbach's α was 0.907. Correlation analyses between K-CMRS and MDQ scores yielded significant positive correlations (r=0.529, p=0.009). However, the factor analysis was unsuccessful. The total K-CMRS scores of bipolar disorder and ADHD patients were compared. However, the differences were not statistically significant. CONCLUSION: The K-CMRS showed good internal consistency and reliability. The correlation between the K-CMRS and MDQ scores verifies its validity. The K-CMRS was designed to assess and score manic symptoms in children and adolescents but had difficulties in differentiating between bipolar disorder and ADHD. It is a valuable tool for evaluating the presence and severity of manic symptoms in pediatric patients with bipolar disorder.

Individuals with the post-traumatic stress disorder process emotions in subcortical regions irrespective of cognitive engagement: a meta-analysis of cognitive and emotional interface.

Post-traumatic stress disorder (PTSD) manifests as emotional suffering and problem-solving impairments under extreme stress. This meta-analysis aimed to pool the findings from all the studies examining emotion and cognition in individuals with PTSD to develop a robust mechanistic understanding of the related brain dysfunction. We identified primary studies through a comprehensive literature search of the MEDLINE and PsychINFO databases. The GingerALE software (version 2.3.6) from the BrainMap Project was used to conduct activation likelihood estimation meta-analyses of the eligible studies for cognition, emotion and interface of both. Relative to the non-clinical (NC) group, the PTSD group showed greater activation during emotional tasks in the amygdala and parahippocampal gyrus. In contrast, the NC group showed significantly greater activation in the bilateral anterior cingulate cortex (ACC) than did the PTSD group in the emotional tasks. When both emotional and cognitive processing were evaluated, the PTSD group showed significantly greater activation in the striatum than did the NC group. No differences in activation between the PTSD and NC groups were noted when only the cognitive systems were examined. Individuals with PTSD exhibited overactivity in the subcortical regions, i.e., amygdala and striatum, when processing emotions. Underactivity in the emotional and cognitive processing intermediary cortex, i.e., the ACC, was especially prominent in individuals with PTSD relative to the NC population following exposure to emotional stimuli. These findings may explain the trauma-related fear, irritability, and negative effects as well as the concentration difficulties during cognitive distress associated with emotional arousal, that are commonly observed in individuals with PTSD.

Resting-state functional connectivity in medication-naïve adolescents with major depressive disorder.

Adolescence is a vulnerable period for major depressive disorder (MDD). The aim of our study was to investigate resting-state functional connectivity (RSFC) in first-episode, medication-naïve adolescent MDD patients. Twenty-three drug-naïve adolescents diagnosed with first-episode MDD and 27 healthy participants were enrolled. Seed-to-voxel RSFC analyses were performed. The frontolimbic circuit regions of interest included the amygdala, anterior cingulate cortex, insula, and hippocampus. A correlation analysis between the RSFC and Children's Depression Inventory, Hamilton depression rating scale, and duration of episodes was performed. The adolescents with MDD exhibited the following characteristics: a lower RSFC between the right amygdala and right superior frontal gyrus; a lower RSFC between the right hippocampus and clusters including the right insula and right middle frontal gyrus; a higher RSFC between the left insula and clusters including the bilateral middle frontal gyrus, right superior frontal gyrus, and right frontal pole; and a higher RSFC between the left dorsal anterior cingulate cortex and a cluster including the left insula. Medication-naïve adolescents with depression display lower connectivity of several brain regions implicated in processing, regulation, and memory of emotions. Higher connectivity was observed in brain regions that potentially explain rumination, impaired concentration, and physiological arousal.

Lithium for the Maintenance Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled Discontinuation Study.

OBJECTIVE: This study examined the role of lithium in the maintenance treatment of pediatric patients with bipolar I disorder (BP-I). METHOD: Participants aged 7 to 17 years who presented with a manic or mixed episode received 24 weeks of lithium treatment in one of two multiphase studies, the Collaborative Lithium Trials (CoLT 1 and CoLT 2). Responders were randomized to continue lithium or to be cross-titrated to placebo for up to 28 weeks. The primary outcome measure was relative risk of study discontinuation for any reason. RESULTS: A Cox regression analysis found that those who continued treatment with lithium (n = 17) had a lower hazard ratio compared to those who received placebo (n = 14) (p = .015)]. The vast majority of discontinuations were due to mood symptom exacerbations, with most of these occurring in the placebo-treated group. Discontinuation for other reasons occurred at similarly low rates across both group. Most adverse events were mild to moderate in severity, and only one study participant was discontinued from the trial owing to a serious adverse event (aggression). There was no statistically significant difference with respect to weight gain in participants receiving lithium compared to those receiving placebo. CONCLUSION: This randomized, double-blind, placebo-controlled Discontinuation Trial builds support for the role of lithium as a maintenance treatment in pediatric patients with bipolar disorder and for the safety and tolerability of 28 weeks of maintenance lithium treatment. CLINICAL TRIAL REGISTRATION INFORMATION: Lithium for the Treatment of Pediatric Mania; https://clinicaltrials.gov/; NCT00442039 (CoLT 1). Safety and Efficacy Study of Lithium for the Treatment of Pediatric Mania; https://clinicaltrials.gov/; NCT01166425 (CoLT 2).

Attentional engagement increases inferior frontal gyrus activity and mutes limbic activity in pediatric bipolar disorder: Meta-analyses of fMRI studies.

OBJECTIVES: Attention deficit has been shown to exist in adult and pediatric bipolar disorder across the life span. Given that emotion dysregulation is central to bipolar disorder, this study hypothesizes that emotional circuitry regions are altered along with anomalies in the attentional systems during cognitive deployment in bipolar disorder. METHODS: An activation likelihood estimation meta-analysis of attentional activities using GingerALE software was completed for adult and pediatric bipolar disorder populations in all published studies till December 2017. The meta-analysis of all fMRI studies included a total of ten pediatric studies (comprised of pediatric bipolar disorder (PBD) and typically developing (TD) groups) and nine adult patient studies (comprised of adult bipolar disorder (ABD) and healthy control (HC) groups). RESULTS: While engaged in attentional tasks, increased activation was seen in inferior frontal gyrus with decreased activation in limbic regions in subjects with PBD, relative to TD. Differential patterns of underactivity were also noted in the dorsal attentional system i.e., frontostriatal circuit (dorsolateral prefrontal cortex, anterior cingulate cortex, right lentiform nucleus and right globus pallidus) in PBD patients relative to the TD. However, we did not see any significant differences between the adult groups i.e., ABD vs. HC. CONCLUSIONS: In PBD, deploying attentional system potentially improves the fronto-limbic affective circuitry function, despite impaired dorsal attentional system i.e., fronto-striatal circuitry. In contrast, these neural correlates underlying attentional engagement appeared to be not significant in adult BD. LIMITATIONS: We examined the PBD vs. TD and the ABD vs. HC separately instead of four-way contrast (dual meta-analytic study). Also, attentional tasks were not unidimensional and tend to capture selective and sustained attention along with response inhibition, thereby recruiting multiple brain circuits.

Lithium in the Acute Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled Study.

BACKGROUND: Lithium is a benchmark treatment for bipolar disorder in adults. Definitive studies of lithium in pediatric bipolar I disorder (BP-I) are lacking. METHODS: This multicenter, randomized, double-blind, placebo-controlled study of pediatric participants (ages 7-17 years) with BP-I/manic or mixed episodes compared lithium (n = 53) versus placebo (n = 28) for up to 8 weeks. The a priori primary efficacy measure was change from baseline to the end of study (week 8/ET) in the Young Mania Rating Scale (YMRS) score, based on last-observation-carried-forward analysis. RESULTS: The change in YMRS score was significantly larger in lithium-treated participants (5.51 [95% confidence interval: 0.51 to 10.50]) after adjustment for baseline YMRS score, age group, weight group, gender, and study site (P = .03). Overall Clinical Global Impression-Improvement scores favored lithium (n = 25; 47% very much/much improved) compared with placebo (n = 6; 21% very much/much improved) at week 8/ET (P = .03). A statistically significant increase in thyrotropin concentration was seen with lithium (3.0 ± 3.1 mIU/L) compared with placebo (-0.1 ± 0.9 mIU/L; P < .001). There was no statistically significant between-group difference with respect to weight gain. CONCLUSIONS: Lithium was superior to placebo in reducing manic symptoms in pediatric patients treated for BP-I in this clinical trial. Lithium was generally well tolerated in this patient population and was not associated with weight gain, distinguishing it from other agents commonly used to treat youth with bipolar disorder.

VAP-1 blockade prevents subarachnoid hemorrhage-associated cerebrovascular dilating dysfunction via repression of a neutrophil recruitment-related mechanism.

Our previous findings indicated that in rats subjected to subarachnoid hemorrhage (SAH), suppression of post-SAH neuroinflammation via vascular adhesion protein-1 (VAP-1) blockade provides significant neuroprotection. We and others have reported that neuroinflammation contributes to cerebral microvascular impairment. Thus, in the present study, we tested the hypotheses that: (1) treatment with LJP-1586, a selective VAP-1 blocker, prevents SAH-associated pial arteriolar dilating dysfunction; and (2) the vasculoprotective effect of LJP-1586 arises from inhibiting SAH-elicited neutrophil recruitment. We utilized an endovascular perforation model of SAH. Rats subjected to SAH were either treated with LJP-1586 or rendered neutropenic via anti-neutrophil-antibody treatment. Findings from these groups were compared to their respective control groups. At 48 h post-SAH, rats were evaluated for neurobehavioral function, pial venular leukocyte trafficking, and pial arteriolar reactivity to topically-applied acetylcholine (ACh) and S-nitroso-N-acetyl penicillamine (SNAP). Pial arteriolar responses decreased at 48 h post-SAH. However, in the presence of LJP-1586, those responses were significantly preserved. Neutrophil-depletion yielded a substantial suppression of SAH-associated leukocyte adhesion and infiltration. This was accompanied by a significant preservation of pial arteriolar dilating function, suggesting a direct link between neutrophil recruitment and the loss of cerebral microvascular reactivity. Moreover, neutrophil depletion also was associated with significant protection of neurobehavioral function. The present findings suggest that attenuating SAH-linked elevation in neutrophil trafficking will protect against the development of microvascular dysfunction and subsequent neurological impairment.

Child- and family-focused cognitive-behavioral therapy for pediatric bipolar disorder: a randomized clinical trial.

OBJECTIVE: Previous studies have found that family-based psychosocial treatments are effective adjuncts to pharmacotherapy among adults and adolescents with bipolar disorder (BD). The objective of this study was to compare the efficacy of adjunctive child- and family-focused cognitive-behavioral therapy (CFF-CBT) to psychotherapy as usual (control) for mood symptom severity and global functioning in children with BD. METHOD: Sixty-nine youth, aged 7 to 13 years (mean = 9.19, SD = 1.61) with DSM-IV-TR bipolar I, II, or not otherwise specified (NOS) disorder were randomly assigned to CFF-CBT or control groups. Both treatments consisted of 12 weekly sessions followed by 6 monthly booster sessions delivered over a total of 9 months. Independent evaluators assessed participants at baseline, week 4, week 8, week 12 (posttreatment), and week 39 (6-month follow-up). RESULTS: Participants in CFF-CBT attended more sessions, were less likely to drop out, and reported greater satisfaction with treatment than controls. CFF-CBT demonstrated efficacy compared to the control treatment in reducing parent-reported mania at posttreatment and depression symptoms at posttreatment and follow-up. Global functioning did not differ at posttreatment but was higher among CFF-CBT participants at follow-up. CONCLUSION: CFF-CBT may be efficacious in reducing acute mood symptoms and improving long-term psychosocial functioning among children with BD.

Meta-analyses of developing brain function in high-risk and emerged bipolar disorder.

OBJECTIVES: Identifying early markers of brain function among those at high risk (HR) for pediatric bipolar disorder (PBD) could serve as a screening measure when children and adolescents present with subsyndromal clinical symptoms prior to the conversion to bipolar disorder. Studies on the offspring of patients with bipolar disorder who are genetically at HR have each been limited in establishing a biomarker, while an analytic review in summarizing the findings offers an improvised opportunity toward that goal. METHODS: An activation likelihood estimation (ALE) meta-analysis of mixed cognitive and emotional activities using the GingerALE software from the BrainMap Project was completed. The meta-analysis of all fMRI studies contained a total of 29 reports and included PBD, HR, and typically developing (TD) groups. RESULTS: The HR group showed significantly greater activation relative to the TD group in the right DLPFC-insular-parietal-cerebellar regions. Similarly, the HR group exhibited greater activity in the right DLPFC and insula as well as the left cerebellum compared to patients with PBD. Patients with PBD, relative to TD, showed greater activation in regions of the right amygdala, parahippocampal gyrus, medial PFC, left ventral striatum, and cerebellum and lower activation in the right VLPFC and the DLPFC. CONCLUSION: The HR population showed increased activity, presumably indicating greater compensatory deployment, in relation to both the TD and the PBD, in the key cognition and emotion-processing regions, such as the DLPFC, insula, and parietal cortex. In contrast, patients with PBD, relative to HR and TD, showed decreased activity, which could indicate a decreased effort in multiple PFC regions in addition to widespread subcortical abnormalities, which are suggestive of a more entrenched disease process.

Type and duration of subsyndromal symptoms in youth with bipolar I disorder prior to their first manic episode.

OBJECTIVES: The aim of the present study was to systematically evaluate the prodrome to mania in youth. METHODS: New-onset/worsening symptoms/signs of ≥ moderate severity preceding first mania were systematically assessed in 52 youth (16.2 ± 2.8 years) with a research diagnosis of bipolar I disorder (BD-I). Youth and/or caregivers underwent semi-structured interviews, using the Bipolar Prodrome Symptom Scale-Retrospective. RESULTS: The mania prodrome was reported to start gradually in most youth (88.5%), with either slow (59.6%) or rapid (28.8%) deterioration, while a rapid-onset-and-deterioration prodrome was rare (11.5%). The manic prodrome, conservatively defined as requiring ≥ 3 symptoms, lasted 10.3 ± 14.4 months [95% confidence interval (CI): 6.3-14.4], being present for ≥ 4 months in 65.4% of subjects. Among prodromal symptoms reported in ≥ 50% of youth, three were subthreshold manic in nature (irritability: 61.5%, racing thoughts: 59.6%, increased energy/activity: 50.0%), two were nonspecific (decreased school/work functioning: 65.4%, mood swings/lability: 57.7%), and one each was depressive (depressed mood: 53.8%) or subthreshold manic/depressive (inattention: 51.9%). A decreasing number of youth had ≥ 1 (84.6%), ≥ 2 (48.1%), or ≥ 3 (26.9%) 'specific' subthreshold mania symptoms (i.e., elation, grandiosity, decreased need for sleep, racing thoughts, or hypersexuality), lasting 9.5 ± 14.9 months (95% CI: 5.0-14.0), 3.5 ± 3.5 months (95% CI: 2.0-4.9), and 3.0 ± 3.2 months (95% CI: 1.0-5.0) for ≥ 1, ≥ 2, or ≥ 3 specific symptoms, respectively. CONCLUSIONS: In youth with BD-I, a relatively long, predominantly slow-onset mania prodrome appears to be common, including subthreshold manic and depressive psychopathology symptoms. This suggests that early clinical identification and intervention may be feasible in bipolar disorder. Identifying biological markers associated with clinical symptoms of impending mania may help to increase chances for early detection and prevention before full mania.

Trials and tribulations of conducting medication trials: pediatric bipolar disorder as prototype.

"In reality, it is the interpretation of symptomatology that leads to accurate diagnosis, rather than the short-term training and inter-rater reliability attained by conducting semi-structured research diagnostic interviews."

Development of superficial white matter and its structural interplay with cortical gray matter in children and adolescents.

Healthy human brain undergoes significant changes during development. The developmental trajectory of superficial white matter (SWM) is less understood relative to cortical gray matter (GM) and deep white matter. In this study, a multimodal imaging strategy was applied to vertexwise map SWM microstructure and cortical thickness to characterize their developmental pattern and elucidate SWM-GM associations in children and adolescents. Microscopic changes in SWM were evaluated with water diffusion parameters including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) in 133 healthy subjects aged 10-18 years. Results demonstrated distinct maturational patterns in SWM and GM. SWM showed increasing FA and decreasing MD and RD underneath bilateral motor sensory cortices and superior temporal auditory cortex, suggesting increasing myelination. A second developmental pattern in SWM was increasing FA and AD in bilateral orbitofrontal regions and insula, suggesting improved axonal coherence. These SWM patterns diverge from the more widespread GM maturation, suggesting that cortical thickness changes in adolescence are not explained by the encroachment of SWM myelin into the GM-WM boundary. Interestingly, age-independent intrinsic association between SWM and cortical GM seems to follow functional organization of polymodal and unimodal brain regions. Unimodal sensory areas showed positive correlation between GM thickness and FA whereas polymodal regions showed negative correlation. Axonal coherence and differences in interstitial neuron composition between unimodal and polymodal regions may account for these SWM-GM association patterns. Intrinsic SWM-GM relationships unveiled by neuroimaging in vivo can be useful for examining psychiatric disorders with known WM/GM disturbances.

Psychosocial intervention for pediatric bipolar disorder: current and future directions.

Pediatric bipolar disorder (PBD) affects approximately 2% of the population and disrupts mood regulation, psychosocial functioning and quality of life among affected youths and families. Given the significant psychosocial impairment and poor long-term prognosis associated with PBD, psychosocial intervention is considered to be an essential component of a multimodal treatment approach. This relatively young field of research has witnessed significant growth in the evidence base for psychosocial treatments targeting youths in the past decade, particularly family-based interventions grounded in a biopsychosocial framework. This article reviews existing empirically supported interventions for children and adolescents with PBD. Common elements of successful interventions are identified, and future research directions to address current limitations in the field and advance understanding of treatment for PBD are discussed.

Altered affective, executive and sensorimotor resting state networks in patients with pediatric mania.

BACKGROUND: The aim of the present study was to map the pathophysiology of resting state functional connectivity accompanying structural and functional abnormalities in children with bipolar disorder. METHODS: Children with bipolar disorder and demographically matched healthy controls underwent resting-state functional magnetic resonance imaging. A model-free independent component analysis was performed to identify intrinsically interconnected networks. RESULTS: We included 34 children with bipolar disorder and 40 controls in our analysis. Three distinct resting state networks corresponding to affective, executive and sensorimotor functions emerged as being significantly different between the pediatric bipolar disorder (PBD) and control groups. All 3 networks showed hyperconnectivity in the PBD relative to the control group. Specifically, the connectivity of the dorsal anterior cingulate cortex (ACC) differentiated the PBD from the control group in both the affective and the executive networks. Exploratory analysis suggests that greater connectivity of the right amygdala within the affective network is associated with better executive function in children with bipolar disorder, but not in controls. LIMITATIONS: Unique clinical characteristics of the study sample allowed us to evaluate the pathophysiology of resting state connectivity at an early state of PBD, which led to the lack of generalizability in terms of comorbid disorders existing in a typical PBD population. CONCLUSION: Abnormally engaged resting state affective, executive and sensorimotor networks observed in children with bipolar disorder may reflect a biological context in which abnormal task-based brain activity can occur. Dual engagement of the dorsal ACC in affective and executive networks supports the neuroanatomical interface of these networks, and the amygdala's engagement in moderating executive function illustrates the intricate interplay of these neural operations at rest.