Risk of teenage pregnancy among adolescents with bipolar disorder: a cohort study of 35,398 adolescent girls.

Teenage pregnancy is a major public health concern. However, few studies have investigated the relationship between pediatric bipolar disorder and early pregnancy, and whether bipolar disorder medications reduce the risk of early pregnancy remains unknown. In total, 3218 adolescent girls with bipolar disorder and 32,180 controls matched for age, family income, residence, and time of enrollment were enrolled in this study from 2001 to 2009. Early pregnancy, defined as pregnancy occurring in patients younger than 20 years old, was identified during the follow-up period from enrollment until the end of 2011. After adjustment for demographic data, psychiatric comorbidities, and bipolar disorder medications, adolescent girls with bipolar disorder had 20 times the risk of early pregnancy (hazard ratio [HR] = 20.63, 95% confidence interval [CI] [15.68, 27.16]) and about 25 times the risk of repeated early pregnancy (HR = 24.59, 95% CI [15.20, 39.78]) compared with those without bipolar disorder. Long-term use of both mood stabilizers (HR = 0.34, 95% CI [0.23, 0.52]) and atypical antipsychotics (HR = 0.32, 95% CI [0.20, 0.51]) was associated with a reduced risk of early pregnancy. Bipolar disorder was associated with an increased risk of early pregnancy in adolescent girls. Bipolar disorder medications reduced this risk. The results suggest that interventions targeting the vulnerable population of adolescent girls with bipolar disorder are warranted to prevent early pregnancies.

Pediatric Bipolar Disorder: A Practical Guide for Clinicians.

Pediatric bipolar disorder (PBD) is a controversial clinical entity and it still needs to be satisfactorily defined. Having a polymorphous presentation and associated with numerous symptoms of comorbid psychiatric illnesses often diagnosed during childhood and adolescence, including attention deficit hyperactivity disorder, its symptoms do not completely parallel those of bipolar disorder in adults. The clinician must be able to reach a diagnosis of PBD in the presence of fluctuating and atypical symptoms, especially in children, who tend to experience mixed episodes and very rapid cycles. Historically a key symptom for diagnosing PBD is episodic irritability. Proper diagnosis is critical due to the gravity of its prognosis. Clinicians may find supporting evidence for a diagnosis through careful study of the medical and developmental history of the young patient in addition to psychometric data. Treatment prioritizes psychotherapeutic intervention and assigns important roles to family involvement and a healthy lifestyle.

Decreasing rate of inpatient pediatric bipolar disorder diagnosis in the US between 2004 and 2010.

OBJECTIVES: Diagnosis of bipolar disorder (BD) increased substantially among youth between the mid-1990s and mid-2000s in the United States. This dramatic increase in diagnosis resulted in concern regarding the potential for misdiagnosis of BD among youth. However, the rate of BD diagnosis in the United States had not been evaluated nationally since the mid-2000s. It was unclear whether changes in diagnostic rates continued to occur. Therefore, the present study aimed to assess the pattern of longitudinal trends in the rate of national inpatient BD diagnosis subsequent to 2004. METHODS: Data included a nationally representative dataset of inpatient hospitalizations between 1996 and 2010. De-identified data were obtained from the National Hospital Discharge Survey (NHDS) conducted annually by the National Center for Health Statistics. RESULTS: The proportion of BD diagnoses relative to all psychiatric diagnoses increased between 1996 and 2004 among children and adolescents. The proportion of BD diagnoses then decreased between 2004 and 2010 among children but continued to increase for adolescents. However, population-adjusted rates of BD diagnosis per 10,000 individuals in the general population initially increased until the mid-2000s and then decreased until 2010 for both children and adolescents. CONCLUSIONS: Rates of BD diagnosis substantially decreased for youth between the mid-2000s and 2010. This decline coincided with recommendations for more conservative diagnostic practices due to concerns about overdiagnosis and increasing awareness of the side effects of front-line medications used to treat BD in youth. Findings provide insight into changing trends in inpatient service utilization for BD in the United States.

Alterations in plasma kynurenine pathway metabolites in children and adolescents with bipolar disorder and unaffected offspring of bipolar parents: A preliminary study.

BACKGROUND: There has been growing scientific evidence in recent years that bipolar disorder (BD) is associated with alterations in the kynurenine (KYN) pathway. However, many of these studies have been limited by their focus on adults. Thus, this preliminary study investigated differences in the peripheral levels of KYN metabolites in children and adolescents with BD, unaffected offspring of parents with BD, and healthy controls (HCs). METHODS: Plasma samples were collected from 49 youths with BD, 19 bipolar offspring, and 31 HCs. Tryptophan (TRP), KYN, and kynurenic acid (KYNA) were separated using electrospray ionization. RESULTS: One-Way ANCOVA after controlling for age, gender, race, BMI-for-age, and smoking status showed that BD had lower levels of KYN, while unaffected high-risk offspring subjects had lower levels of TRP, KYN, and KYNA when compared to HCs. Moreover, we found that KYN, KYN/TRP, and KYNA/KYN levels predicted the severity of depressive symptoms, while the YMRS score was not associated with any metabolite. CONCLUSIONS: In summary, this preliminary study has shown that KYN metabolites are decreased in both affected and unaffected subjects, strengthening the idea that the KYN pathway might underlie the familial risk of BD shown by high-risk offspring individuals. However, longitudinal studies are needed to examine whether the alterations observed in this study represent early markers of risk for later developing BD.

Altered spatiotemporal consistency in pediatric bipolar disorder patients with and without psychotic symptoms.

OBJECTIVE: Psychotic symptoms are quite common in patients with pediatric bipolar disorder (PBD) and may affect the symptom severity and prognosis of PBD. However, the potential mechanisms are less well elucidated until now. Thus, the purpose of this study was to investigate the brain functional differences between PBD patients with and without psychotic symptoms. METHOD: A total of 71 individuals including: 27 psychotic PBD (P-PBD), 25 nonpsychotic PBD (NP-PBD), and 19 healthy controls were recruited in the present study. Each subject underwent 3.0 Tesla functional magnetic resonance imaging scan. Four-dimensional (spatiotemporal) Consistency of local neural Activities (FOCA) was employed to detect the local brain activity changes. Analyses of variance (ANOVA) were used to reveal brain regions with significant differences among three groups groups of individuals, and inter-group comparisons were assessed using post hoc tests. RESULTS: The ANOVA obtained significant among-group FOCA differences in the left triangular inferior frontal gyrus, left supplementary motor area, left precentral gyrus, right postcentral gyrus, right superior occipital gyrus, and right superior frontal gyrus. Compared with the control group, the P-PBD group showed decreased FOCA in the left supplementary motor area and bilateral superior frontal gyrus and showed increased FOCA in the left triangular inferior frontal gyrus. In contrast, the NP-PBD group exhibited decreased FOCA in the right superior occipital gyrus and right postcentral gyrus and showed increased FOCA in the left orbital inferior frontal gyrus. Compared to the NP-PBD group, the P-PBD group showed decreased FOCA in the right superior frontal gyrus. CONCLUSION: The present findings demonstrated that the two groups of PBD patients exhibited segregated brain functional patterns, providing empirical evidence for the biological basis of different clinical outcomes between PBD patients with and without psychotic symptoms.

Similar familial underpinnings for full and subsyndromal pediatric bipolar disorder: A familial risk analysis.

OBJECTIVES: To examine the validity of subthreshold pediatric bipolar I disorder (BP-I), we compared the familial risk for BP-I in the child probands who had either full BP-I, subthreshold BP-I, ADHD, or were controls that neither had ADHD nor bipolar disorder. METHODS: BP-I probands were youth aged 6-17 years meeting criteria for BP-I, full (N=239) or subthreshold (N=43), and also included were their first-degree relatives (N=687 and N=120, respectively). Comparators were youth with ADHD (N=162), controls without ADHD or bipolar disorder (N=136), and their first-degree relatives (N=511 and N=411, respectively). We randomly selected 162 non-bipolar ADHD probands and 136 non-bipolar, non-ADHD control probands of similar age and sex distribution to the BP-I probands from our case-control ADHD family studies. Psychiatric assessments were made by trained psychometricians using the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children Epidemiological Version (KSADS-E) and Structured Clinical Interview for DSM-IV (SCID) structured diagnostic interviews. We analyzed rates of bipolar disorder using multinomial logistic regression. RESULTS: Rates of full BP-I significantly differed between the four groups (χ23 =32.72, P<.001): relatives of full BP-I probands and relatives of subthreshold BP-I probands had significantly higher rates of full BP-I than relatives of ADHD probands and relatives of control probands. Relatives of full BP-I, subthreshold BP-I, and ADHD probands also had significantly higher rates of major depressive disorder compared to relatives of control probands. CONCLUSIONS: Our results showed that youth with subthreshold BP-I had similarly elevated risk for BP-I and major depressive disorder in first-degree relatives as youth with full BP-I. These findings support the diagnostic continuity between subsyndromal and fully syndromatic states of pediatric BP-I disorder.

Treatments and Services Provided to Children Diagnosed with Bipolar Disorder.

To better understand the types and quantity of mental health services and medication usage for youth diagnosed with bipolar disorder (BD) within an integrated healthcare system, medical records were reviewed from 2000 to 2011. Eighty-five youth diagnosed with BD were identified and healthcare services (medication and psychotherapy follow-up appointments, emergency room (ER) visits, admissions, phone contacts) and visit-related details (medication usage) were abstracted for 2 years after initial BD diagnosis. Despite complex medication regimens (91.7 and 81.2 % received mood stabilizers and antipsychotic agents, respectively), medication appointments were infrequent, averaging 1 visit every 2 months. Only 36 (42 %) of 85 youth were noted to receive psychotherapy services following BD diagnosis, also averaging 1 visit every 2 months. Most (58.8 %) patients needed one or more hospitalizations during the follow-up period; nearly half (48.2 %) had psychiatric ER visits. The relative lack of psychotherapy and infrequent follow-up visits suggests need for improvement to optimize healthcare delivery.

Prediction of pediatric bipolar disorder using neuroanatomical signatures of the amygdala.

OBJECTIVES: Pediatric bipolar disorder is currently diagnosed based on signs and symptoms, and without objective diagnostic biomarkers. In the present study, we investigated the utility of structural neuroanatomical signatures of the amygdala to objectively differentiate individual subjects with pediatric bipolar disorder from matched healthy controls. METHODS: Structural T1 -weighted neuroimaging scans were obtained from 16 children and adolescents with unmedicated DSM-IV bipolar disorder (11 males, five females) and 16 matched healthy controls (11 males, five females). Voxel-based gray matter morphometric features extracted from a bilateral region-of-interest within the amygdala were used to develop a multivariate pattern analysis model which was utilized in predicting novel or 'unseen' individual subjects as either bipolar disorder or healthy controls. RESULTS: The model assigned 25 out of 32 subjects the correct label (bipolar disorder/healthy) translating to a 78.12% diagnostic accuracy, 81.25% sensitivity, 75.00% specificity, 76.47% positive predictive value, and 80.00% negative predictive value and an area under the receiver operating characteristic curve (ROC) of 0.81. The predictions were significant at p = 0.0014 (χ(2) test p-value). CONCLUSIONS: These results reaffirm previous reports on the existence of neuroanatomical abnormalities in the amygdala of pediatric patients with bipolar disorder. Remarkably, the present study also demonstrates that neuroanatomical signatures of the amygdala can predict individual subjects with bipolar disorder with a relatively high specificity and sensitivity. To the best of our knowledge, this is the first study to present a proof-of-concept diagnostic marker of pediatric bipolar disorder based on structural neuroimaging scans of largely medication-naïve patients.

Comparative effectiveness of monotherapy with mood stabilizers versus second generation (atypical) antipsychotics for the treatment of bipolar disorder in children and adolescents.

OBJECTIVE: This study compared the effectiveness and safety of second generation (atypical) antipsychotic (SGA) versus traditional mood stabilizers (MS) in children and adolescents with bipolar disorder. METHODS: The study was a retrospective cohort study on 5 years (2003-2007) of Medicaid claims data from four geographically diversified states. Children and adolescents aged 6-18 years who initiated a new treatment episode for bipolar disorder on either an SGA or an MS were followed for 12 months to compare the effectiveness and safety between the two therapeutic categories for pediatric bipolar disorder (PBD). The outcome measures were psychiatric hospital admission, all cause medication discontinuation and treatment augmentation. Potential selection bias caused by unobserved confounding was addressed with instrumental variable methods, using physician prescribing preference and year of cohort entry as the instruments. Sensitivity analysis was conducted to test the robustness of findings against the uncertainties on PBD diagnosis. RESULTS: Of the 7423 bipolar children and adolescents identified, 66.60% started treatment on SGA, whereas 33.40% initiated on MS. Patients who initiated on MS and SGA had comparable risk of psychiatric hospital admission (HR=1.172, 95%CI: 0.827-1.660). However, as compared with those who initiated on MS, patients who initiated on SGA were less likely to discontinue the treatment (HR=0.634, 95%CI: 0.419-0.961) and less likely to receive treatment augmentation (HR=0.223, 95%CI: 0.103-0.484). CONCLUSION: As compared with MS monotherapy, SGA monotherapy could be a more effective and safer treatment option for PBD.

Risk of Pediatric Bipolar Disorder After General Anesthesia in Infants and Toddlers: A Propensity Score-Matched Population-Based Cohort Study.

BACKGROUND AND HYPOTHESIS: The potential role of anesthesia as an independent risk factor for childhood bipolar disorder (BD) remains unclear. To address this, we conducted a population-based cohort study employing propensity score matching to compare BD incidence between pediatric patients undergoing surgery with and without general anesthesia. STUDY DESIGN: Our study included patients aged 0-3 years who received at least 1 episode of general anesthesia and were hospitalized for over 1 day in Taiwan between January 2004 and December 2014. They were matched 1:1 with a population not receiving general anesthesia to assess pediatric BD incidence. STUDY RESULTS: The study cohort comprised 15 070 patients, equally distributed between the general anesthesia and nongeneral anesthesia groups (7535 each). Multivariate Cox regression analysis revealed adjusted hazard ratios (aHRs; 95% CIs) for pediatric BD in the general anesthesia group as 1.26 (1.04-1.54; P = .021) compared to the nongeneral anesthesia group. Moreover, the incidence rate ratio (95% CI) for the general anesthesia group was 1.26 (1.03-1.53) compared to the nongeneral anesthesia group. CONCLUSIONS: Early childhood exposure to general anesthesia is significantly associated with an increased risk of pediatric BD. This expands understanding of pediatric BD's complex development, informing preventive strategies, and enhancing mental health outcomes for vulnerable young patients and global pediatric healthcare.

Structural and functional disruption of subcortical limbic structures related with executive function in pediatric bipolar disorder.

BACKGROUND: Impaired cognition has been demonstrated in pediatric bipolar disorder (PBD). The subcortical limbic structures play a key role in PBD. However, alternations of anatomical and functional characteristics of subcortical limbic structures and their relationship with neurocognition of PBD remain unclear. METHODS: Thirty-six PBD type I (PBD-I) (15.36 ± 0.32 years old), twenty PBD type II (PBD-II) (14.80 ± 0.32 years old) and nineteen age-gender matched healthy controls (HCs) (14.16 ± 0.36 years old) were enlisted. Primarily, the volumes of the subcortical limbic structures were obtained and differences in the volumes were evaluated. Then, these structures served as seeds of regions of interest to calculate the voxel-wised functional connectivity (FC). After that, correlation analysis was completed between volumes and FC of brain regions showing significant differences and neuropsychological tests. RESULTS: Compared to HCs, both PBD-I and PBD-II patients showed a decrease in the Stroop color word test (SCWT) and digit span backward test scores. Compared with HCs, PBD-II patients exhibited a significantly increased volume of right septal nuclei, and PBD-I patients presented increased FC of right nucleus accumbens and bilateral pallidum, of right basal forebrain with right putamen and left pallidum. Both the significantly altered volumes and FC were negatively correlated with SCWT scores. SIGNIFICANCE: The study revealed the role of subcortical limbic structural and functional abnormalities on cognitive impairments in PBD patients. These may have far-reaching significance for the etiology of PBD and provide neuroimaging clues for the differential diagnosis of PBD subtypes. CONCLUSIONS: Distinctive features of neural structure and function in PBD subtypes may contribute to better comprehending the potential mechanisms of PBD.

Abnormal functional connectivity of the intrinsic networks in adolescent bipolar I versus bipolar II disorder.

BACKGROUND: The symptoms of pediatric bipolar disorder (PBD)-I and PBD-II differ, but accurate identification at an early stage is difficult and may prevent effective treatment of this disorder. Therefore, it is urgent to elucidate a biological marker based on objective imaging indicators to help distinguish the two. Therefore, this research aims to compare the functional connectivity between PBD-I patient and PBD-II patient in different brain networks. METHODS: Our study enrolled 31 PBD-I and 23 PBD-II patients from 12 to 17 years of age. They were analyzed by resting state-functional connectivity through Independent component analysis (ICA). RESULTS: We found differences between PBD-I and PBD-II in functional connectivity of the default network, frontoparietal network, salience network and limbic system. In addition, the clinical features, cognitive functions are associated with the functional connectivity of the intrinsic networks in PBD-I and PBD-II separately. CONCLUSION: This research is the first to find differences in functional connectivity between PBD-I and PBD-II, suggesting that abnormality of the functional connectivity within large networks may be biomarkers that help differentiate PBD-I from PBD-II in the future.

Deformations of amygdala morphology in familial pediatric bipolar disorder.

OBJECTIVE: Smaller amygdalar volumes have been consistently observed in pediatric bipolar disorder subjects compared to healthy control subjects. Whether smaller amygdalar volume is a consequence or antecedent of the first episode of mania is not known. Additionally, smaller volume has not been localized to specific amygdala subregions. METHODS: We compared surface contour maps of the amygdala between 22 youths at high risk for bipolar disorder, 26 youths meeting full diagnostic criteria for pediatric familial bipolar disorder, and 24 healthy control subjects matched for age, gender, and intelligence quotient. Amygdalae were manually delineated on three-dimensional spoiled gradient echo images by a blinded rater using established tracing protocols. Statistical surface mesh modeling algorithms supported by permutation statistics were used to identify regional surface differences between the groups. RESULTS: When compared to high-risk subjects and controls, youth with bipolar disorder showed surface deformations in specific amygdalar subregions, suggesting smaller volume of the basolateral nuclei. The high-risk subjects did not differ from controls in any subregion. CONCLUSIONS: These findings support previous reports of smaller amygdala volume in pediatric bipolar disorder and map the location of abnormality to specific amygdala subregions. These subregions have been associated with fear conditioning and emotion-enhanced memory. The absence of amygdala size abnormalities in youth at high risk for bipolar disorder suggests that reductions might occur after the onset of mania.

Behavioral self-regulation in pediatric bipolar disorder and healthy offspring of bipolar patients.

OBJECTIVES: This study investigated behavioral self-regulation problems using the Children's Hostility Inventory (CHI) in pediatric bipolar disorder (PBD), healthy offspring of bipolar disorder patients (HOBD), and healthy controls (HC) without previous history of psychiatric disorders. METHODS: The CHI was administered to 41 consecutive children and adolescents diagnosed with PBD, to 16 HOBD, and to 22 HC. The inventory assessed irritability, expression, hostility, and aggression and was completed by the children with the help of their mothers. Adolescents and their respective parents were interviewed separately using the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL). RESULTS: All subscales of the CHI presented statistically significant differences, except for the subscale assessing feelings of suspicion. Pairwise comparisons revealed consistently significant differences between the PBD group and controls, indicating more self-regulation difficulties in the PBD group, represented by high levels of hostility and aggressive behavior. There were no significant differences between the PBD and HOBD groups. CONCLUSIONS: Future studies should further investigate if such behavior is state-dependent or a trait of bipolar juvenile expression. Expression of hostility and irritability should be considered relevant targets in psychosocial approaches addressing this population.

The disruption of functional connectome gradient revealing networks imbalance in pediatric bipolar disorder.

OBJECTIVE: Pediatric bipolar disorder (PBD) is a psychiatric disorder marked by alteration of brain networks. However, the understanding of these alterations in topological organization still unclear. This study aims to leverage the functional connectome gradient to examine changes in functional network hierarchy in PBD. METHOD: Connectome gradients were used to scrutinize the differences between functional gradient map in PBD patients (n = 68, aged 11 to 18) and healthy controls (HC, n = 37, aged 11 to 18). The association between regional altered gradient scores and clinical factors was examined. We further used Neurosynth to determine the correlation of the cognitive terms with the PBD principal gradient changes. RESULTS: Global topographic alterations were exhibited in the connectome gradient in PBD patients, involving gradient variance, explanation ratio, gradient range, and gradient dispersion in the principal gradient. Regionally, PBD patients revealed that the default mode network (DMN) held the most majority of the brain areas with higher gradient scores, whereas a higher proportion of brain regions with lower gradient scores in the sensorimotor network (SMN). These regional gradient differences exhibited significant correlation with clinical features and meta-analysis terms including cognitive behavior and sensory processing. CONCLUSION: Functional connectome gradient presents a thorough investigation of large-scale networks hierarchy in PBD patients. This exhibited excessive segregation between DMN and SMN supports the theory of imbalance in top-down control and bottom-up in PBD and provides a possible biomarker for diagnostic assessment.

Self-regulation in youth with bipolar disorder.

OBJECTIVES: To examine the composition of self-regulation in pediatric bipolar disorder (PBD) through the relationship between executive functions, emotion processing, and family environmental factors. METHODS: 58 participants (36 with PBD and 22 controls), ages 12-17, were assessed using the Barratt Impulsiveness Scale (BIS), Conners' Continuous Performance Test (CPT-II), Wisconsin Cards Sorting Test (WCST), Computerized Neurocognitive Battery Emotion Recognition Test-Facial Emotion Recognition Test (PENNCNB ER-40), and Expressed Emotion Adjective Checklist Questionnaire (EEAC). RESULTS: Adolescents with PBD displayed significant deficits in all three spheres when compared to the control group. Emotion processing correlated negatively with inhibition and attention, and correlated positively with mental flexibility/working memory. Family environmental factors correlated negatively with mental flexibility/working memory and emotion processing, and positively with attention and inhibition. These correlations indicate that better inhibitory control, attention, and mental flexibility/working memory are associated with greater emotion processing and a fitter family environment. CONCLUSION: This study is the first to investigate all of the components of self-regulation deficits simultaneously in patients with PBD. Results suggest that self-regulation is essential for a comprehensive perspective of PBD and should be assessed in an integrative and multifaceted way. Understanding that self-regulation is impacted by the abovementioned factors should influence treatment and improve the functional impairments of daily life observed in this population.

Fourteen-year trends in the prescribing patterns of pediatric bipolar patients discharged from two public mental hospitals in Taiwan.

INTRODUCTION: The management of pediatric bipolar disorder (PBD) requires pharmacotherapy to control acute symptoms, reduce relapse, prevent suicide, and improve psychosocial functioning. The purpose of this study was to investigate prescribing patterns among PBD patients discharged from two public mental hospitals in Taiwan, from 2006 to 2019. METHODS: PBD patients discharged from the two study hospitals, from 1 January 2006 to 31 December 2019 (n = 420), were included in the analysis. Prescribed drugs at discharge, including mood stabilizers (i.e., lithium, valproate, carbamazepine, and lamotrigine), antipsychotics (i.e., second- and first-generation antipsychotics, SGAs and FGAs), and antidepressants, were explored. Complex polypharmacy was defined as the use of 3 or more agents among the prescribed drugs. Time trends of each prescribing pattern were analyzed using the Cochran-Armitage Trend test. RESULTS: The most commonly prescribed psychotropic agents were SGAs (76.0%), followed by valproate (65.7%) and FGAs (24.8%). The prescription rates of SGAs, antidepressants, antidepressant plus antipsychotic, and antidepressant without mood stabilizer significantly increased over time, whereas the prescription rates of mood stabilizers, lithium, and FGAs significantly decreased. DISCUSSIONS: Prescribing patterns changed greatly for PBD patients over time. However, much more evidence supporting the effectiveness of psychotropic agents in PBD patients is required.

The Different Impact of Depressive or Manic First-episode on Pediatric Bipolar Disorder Patients: Evidence From Resting-state fMRI.

Bipolar disorder may begin as depression or mania, which can affect the treatment and prognosis of bipolar disorder. However, the physiological and pathological differences of pediatric bipolar disorder (PBD) patients with different onset symptoms are not clear. The purpose of this study was to investigate the differences of clinical, cognitive function and intrinsic brain networks in PBD patients with first-episode depression and first-episode mania. A total of 63 participants, including 43 patients and 20 healthy controls, underwent resting-state fMRI scans. PBD patients were classified as first-episode depressive and first-episode manic based on their first-episode symptoms. Cognitive tests were used to measure attention and memory of all participants. Independent component analysis (ICA) was used to extract the salience network (SN), default-mode network (DMN), central executive network (ECN) and limbic network (LN) for each participant. Spearman rank correlation analysis was performed between abnormal activation and clinical and cognitive measures. The results showed that there were differences in cognitive functions such as attention and visual memory between first-episode depression and mania, as well as differences activation in anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), precuneus, inferior parietal cortex and parahippocampus. And significant associations of brain activity with clinical assessments or cognition were found in different patients. In conclusion, we found differential impairments in cognitive and brain network activation in first-episode depressive and first-episode manic PBD patients, and correlations were found between these impairments. These evidences may shed light on the different developmental paths of bipolar disorder.

Neurocognitive Correlates of Cerebellar Volumetric Alterations in Youth with Pediatric Bipolar Spectrum Disorders and Bipolar Offspring.

BACKGROUND: Emerging evidence points towards the involvement of the cerebellum in the processing of emotions and pathophysiology of mood disorders. However, cerebellar and related cognitive alterations in youth with pediatric bipolar disorder (PBD) and those at high risk to develop the disorder, such as bipolar offspring (BD-OFF) are not clearly defined. OBJECTIVE: To investigate cerebellar gray and white matter volumes, cognition, and their relationship in youth with PBD and BD-OFF. METHODS: Thirty youth (7 to 17 years, inclusive) with PBD, 30 BD-OFF and 40 healthy controls (HC) were recruited. Study participants underwent a computer-based cognitive battery assessing affective processing, executive function, attention, psychomotor speed, and learning. Three-tesla MRI scan was performed to assess cerebellar white and gray matter volumes. Cerebellar segmentation was performed with FreeSurfer. Statistical analyses include between-group differences in cognitive domains, cerebellar gray, and white matter volumes. Relationships between cerebellar volumes and cognitive domains were examined. RESULTS: Youth with PBD showed greater cerebellar gray matter volumes than both BD-OFF and HC, whereas no differences were present between BD-OFF and HC. Both youth with PBD and BD-OFF showed altered processing of negative emotions and a bias towards positive emotions. In youth with PBD and BD-OFF, greater impairment in the processing of emotions correlated with greater cerebellar gray matter volumes. CONCLUSION: The present findings corroborate hypotheses on cerebellar involvement in the processing of emotions and the pathophysiology of PBD. The presence of cerebellar dysfunction in BD-OFF is unclear.

Does the Brain Matter? Cortical Alterations in Pediatric Bipolar Disorder: A Critical Review of Structural and Functional Magnetic Resonance Studies.

Pediatric bipolar disorder (PBD) is associated with significant psychosocial impairment, high use of mental health services and a high number of relapses and hospitalization. Neuroimaging techniques provide the opportunity to study the neurodevelopmental processes underlying PBD, helping to identify the endophenotypic markers of illness and early biological markers of PBD. The aim of the study is to review available studies assessing structural and functional brain correlates associated with PBD. PubMed, ISI Web of Knowledge and PsychINFO databases have been searched. Studies were included if they enrolled patients aged 0-18 years with a main diagnosis of PBD according to ICD or DSM made by a mental health professional, adopted structural and/or functional magnetic resonance as the main neuroimaging method, were written in English and included a comparison with healthy subjects. Of the 400 identified articles, 46 papers were included. Patients with PBD present functional and anatomic alterations in structures normally affecting regulations and cognition. Structural neuroimaging revealed a significant reduction in gray matter, with cortical thinning in bilateral frontal, parietal and occipital cortices. Functional neuroimaging studies reported a reduced engagement of the frontolimbic and hyperactivation of the frontostriatal circuitry. Available studies on brain connectivity in PBD patients potentially indicate less efficient connections between regions involved in cognitive and emotional functions. A greater functional definition of alteration in brain functioning of PBD patients will be useful to set up a developmentally sensitive targeted pharmacological and nonpharmacological intervention.