Pediatric Bipolar Disorder Patients Research Articles

Lower N-Acetyl-Aspartate Levels in Prefrontal Cortices in Pediatric Bipolar Disorder: A 1H Magnetic Resonance Spectroscopy Study

The few studies applying single-voxel ¹H spectroscopy in children and adolescents with bipolar disorder (BD) have reported low N-acetyl-aspartate (NAA) levels in the dorsolateral prefrontal cortex (DLPFC), and high myo-inositol / phosphocreatine plus creatine (PCr+Cr) ratios in the anterior cingulate. The aim of this study was to evaluate NAA, glycerophosphocholine plus phosphocholine (GPC+PC) and PCr+Cr in various frontal cortical areas in children and adolescents with BD. We hypothesized that NAA levels within the prefrontal cortex are lower in BD patients than in healthy controls, indicating neurodevelopmental alterations in the former. We studied 43 pediatric patients with DSM-IV BD (19 female, mean age 13.2 ± 2.9 years) and 38 healthy controls (19 female, mean age 13.9 ± 2.7 years). We conducted multivoxel in vivo ¹H spectroscopy measurements at 1.5 Tesla using a long echo time of 272 ms to obtain bilateral metabolite levels from the medial prefrontal cortex (MPFC), DLPFC (white and gray matter), cingulate (anterior and posterior), and occipital lobes. We used the nonparametric Mann-Whitney U test to compare neurochemical levels between groups. In pediatric BD patients, NAA and GPC+PC levels in the bilateral MPFC, and PCr+Cr levels in the left MPFC were lower than those seen in the controls. In the left DLPFC white matter, levels of NAA and PCr+Cr were also lower in BD patients than in controls. Lower NAA and PCr+Cr levels in the PFC of children and adolescents with BD may be indicative of abnormal dendritic arborization and neuropil, suggesting neurodevelopmental abnormalities.

A Pharmacological Functional Magnetic Resonance Imaging Study Probing the Interface of Cognitive and Emotional Brain Systems in Pediatric Bipolar Disorder

This functional magnetic resonance imaging (fMRI) study investigated the effects of pharmacotherapy on brain function underlying affect dysregulation and cognitive function in pediatric bipolar disorder (PBD). Healthy controls (HC) (n=14; mean age =14.1 ± 2.4 years) and unmedicated PBD patients with manic or hypomanic episodes (n=17; mean age =14.3 ± 1.1 years) were matched on intelligence quotient (IQ) and demographic factors. The fMRI studies were performed at baseline and after 14 weeks, during which PBD patients were treated initially with second-generation antipsychotics (SGAs) followed by lamotrigine monotherapy. The pediatric affective color-matching task was used where subjects matched the color of a positive, negative, or neutral word with one of the two colored circles below in each of the trials. There were five blocks of each emotional word type, with 10 trials per block. Behavioral data showed that the PBD group was modestly slower and less accurate than the HC, regardless of condition or treatment status. The blood oxygen level-dependent (BOLD) signal activity was reduced with treatment in the PBD group relative to the HC group during the negative versus neutral condition in bilateral dorsolateral prefrontal cortex (DLPFC), right posterior cingulate gyrus, parahippocampal gyrus, and inferior parietal lobule, but increased in left ventromedial prefrontal cortex (VMPFC). Similarly, during the positive versus neutral condition, the PBD group, relative to HC, showed reduced activity in right DLPFC, precuneus, and inferior parietal lobule and increased activity in the right VMPFC. However, within the PBD group, there was treatment related decrease in VMPFC and DLPFC. Improvement on Young Mania Rating Scale (YMRS) score significantly correlated with the decreased activity in VMPFC within the patient group. Pharmacotherapy in PBD patients led to differential effort with persistently increased activity in the affective regions and decreased activity in the cognitive regions relative to HC, demonstrating altered mechanisms of affective and cognitive systems of brain function, regardless of symptom response.

Emotion Processing Influences Working Memory Circuits in Pediatric Bipolar Disorder and Attention-Deficit/Hyperactivity Disorder

This functional magnetic resonance imaging (fMRI) study examined how working memory circuits are affected by face emotion processing in pediatric bipolar disorder (PBD) and attention-deficit/hyperactivity disorder (ADHD). A total of 23 patients with PBD, 14 patients with ADHD, and 19 healthy control (HC) subjects (mean age, 13.36 ± 2.55 years) underwent an affective, two-back fMRI task with blocks of happy, angry, and neutral faces. For angry versus neutral faces PBD patients, relative to ADHD patients, exhibited increased activation in the subgenual anterior cingulate cortex (ACC) and orbitofrontal cortex, and reduced activation in the dorsolateral prefrontal cortex (DLPFC) and premotor cortex. Relative to the HC group, the PBD group showed no increased activation and reduced activation at the junction of DLPFC and ventrolateral prefrontal cortex (VLPFC). Relative to HC, the ADHD patients exhibited greater activation in the DLPFC and reduced activation in the ventral and medial PFC, pregenual ACC, striatum, and temporo-parietal regions. For happy versus neutral faces, relative to the ADHD group, the PBD group exhibited greater activation in the bilateral caudate, and relative to the HC group the ADHD group showed increased activation in the DLPFC, striatal, and parietal regions, and no reduced activation. The ADHD group, compared with the HC group, showed no reduced activation and increased activation in regions that were underactive for the angry face condition. Relative to the ADHD group, the PBD group exhibited greater deployment of the emotion-processing circuitry and reduced deployment of working memory circuitry. Commonalities across PBD and ADHD patients, relative to the HC individuals, entailed cortico-subcortical activity that was reduced under negative emotional challenge and increased under positive emotional challenge.

Enhanced working and verbal memory after lamotrigine treatment in pediatric bipolar disorder

To examine the treatment impact of lamotrigine on the neurocognitive profile of patients with pediatric bipolar disorder (PBD). Healthy controls (HC) (n = 24; mean age = 12.4 +/- 3.3 years) and unmedicated PBD patients with manic, mixed, or hypomanic episodes (n = 34; mean age = 13 +/- 3.1 years) were matched for IQ, age, sex, race, and socioeconomic status. A neurocognitive battery was administered at baseline and again after 14 weeks, during which PBD patients were treated with lamotrigine. Clinical symptoms improved with treatment in the patient group with significant change from baseline to follow-up on the Young Mania Rating Scale (p < 0.001) and the Children's Depression Rating Scale-Revised (p < 0.001). Global neurocognitive function improved with lamotrigine in PBD patients over time relative to that in HC, although overall performance remained impaired. Working memory and verbal memory significantly improved with treatment in patients, and deficits in these domains were no longer significantly impaired relative to HC at follow-up. Executive function significantly improved with treatment in the patient group but still lagged behind HC at follow-up. Performance on attention tests did not improve with treatment. There appears to be significant improvement in cognitive abilities in PBD patients treated with lamotrigine that is most prominent in the areas of working memory and verbal memory and that occurs along with mood stabilization.

Neural correlates of response inhibition in pediatric bipolar disorder and attention deficit hyperactivity disorder

Impulsivity, inattention and poor behavioral inhibition are common deficits in pediatric bipolar disorder (PBD) and attention deficit hyperactivity disorder (ADHD). This study aimed to identify similarities and differences in the neural substrate of response inhibition deficits that are associated with these disorders. A functional magnetic resonance imaging (fMRI) study was conducted on 15 unmedicated PBD patients (Type I, manic/mixed), 11 unmedicated ADHD patients, and 15 healthy controls (HC) (mean age = 13.5 years; S.D. = 3.5). A response inhibition task examined the ability to inhibit a motor response to a target when a stop cue appeared shortly after. The PBD and ADHD groups did not differ on behavioral performance, although both groups were less accurate than the HC group. fMRI findings showed that for trials requiring response inhibition, the ADHD group, relative to the PBD and HC groups, demonstrated reduced activation in both ventrolateral (VLPFC) and dorsolateral (DLPFC) prefrontal cortex, and increased bilateral caudate activation compared with HC. The PBD group, relative to HC, showed decreased activation in the left VLPFC, at the junction of the inferior and middle frontal gyri, and in the right anterior cingulate cortex (ACC). Prefrontal dysfunction was observed in both the ADHD and PBD groups relative to HC, although it was more extensive and accompanied by subcortical overactivity in ADHD.

Differential engagement of cognitive and affective neural systems in pediatric bipolar disorder and attention deficit hyperactivity disorder

This fMRI study investigates the neural bases of cognitive control of emotion processing in pediatric bipolar disorder (PBD) and attention deficit hyperactivity disorder (ADHD). Seventeen un-medicated PBD patients, 15 un-medicated ADHD patients, and 14 healthy controls (HC) (mean age = 13.78 +/- 2.47) performed an emotional valence Stroop Task, requiring them to match the color of an emotionally valenced word to the color of either of two adjacent circles. Both patient groups responded significantly slower than HC, but there were no group differences in accuracy. A voxel-wise analysis of variance on brain activation revealed a significant interaction of group by word valence [F(2,41) = 4.44; p = .02]. Similar group differences were found for negative and positive words. For negative versus neutral words, both patient groups exhibited greater activation in dorsolateral prefrontal cortex (DLPFC) and parietal cortex relative to HC. The PBD group exhibited greater activation in ventrolateral prefrontal cortex (VLPFC) and anterior cingulate cortex (ACC) relative to HC. The ADHD group exhibited decreased VLPFC activation relative to HC and the PBD group. During cognitive control of emotion processing, PBD patients deployed the VLPFC to a greater extent than HC. The ADHD patients showed decreased VLPFC engagement relative to both HC and PBD patients.

Facial emotion recognition in bipolar disorder: a critical review

Literature review of the controlled studies in the last 18 years in emotion recognition deficits in bipolar disorder. A bibliographical research of controlled studies with samples larger than 10 participants from 1990 to June 2008 was completed in Medline, Lilacs, PubMed and ISI. Thirty-two papers were evaluated. Euthymic bipolar disorder presented impairment in recognizing disgust and fear. Manic BD showed difficult to recognize fearful and sad faces. Pediatric bipolar disorder patients and children at risk presented impairment in their capacity to recognize emotions in adults and children faces. Bipolar disorder patients were more accurate in recognizing facial emotions than schizophrenic patients. Bipolar disorder patients present impaired recognition of disgust, fear and sadness that can be partially attributed to mood-state. In mania, they have difficult to recognize fear and disgust. Bipolar disorder patients were more accurate in recognizing emotions than depressive and schizophrenic patients. Bipolar disorder children present a tendency to misjudge extreme facial expressions as being moderate or mild in intensity. Affective and cognitive deficits in bipolar disorder vary according to the mood states. Follow-up studies re-testing bipolar disorder patients after recovery are needed in order to investigate if these abnormalities reflect a state or trait marker and can be considered an endophenotype. Future studies should aim at standardizing task and designs.

Neural bases of emotional processing in pediatric bipolar disorder

Pediatric bipolar disorder (PBD) presents with severe affect dysregulation characterized by elated mood, irritability and depressive symptoms, often in the form of a mixed episode. Early recognition of the external clinical features and the underlying emotional processing circuitry will help us understand the neurobiological underpinnings of this disorder and offer innovative ideas for early intervention. Methods: A 5-year review was conducted in structural and functional imaging studies in PBD that are potentially relevant to the emotional processing in PBD. Results: The ventral frontolimbic circuitry and the dorsal frontostriatal circuitry appear to be involved in affect regulation, with the ventral circuitry being more directly involved in emotion processing. The associated and interlinked circuits include the facial emotion-processing circuit and the association circuit between the occipital and the limbic regions responsible for automatic processing of emotions. Conclusion: While we are at a preliminary stage in understanding the neural circuitry behind emotional processing, there appears to be a top-down regulation of affect with prefrontal systems modulating subcortical structures such as the amygdala and the ventral striatum. Structural and connectivity studies support the functional studies findings, providing a cogent model for understanding emotion-processing circuits involving corticosubcortical neural systems. Functional studies with PBD patients are beginning to demonstrate the dysfunction in the affective and cognitive circuits that work in concert.

An fMRI study of the interface between affective and cognitive neural circuitry in pediatric bipolar disorder

The pathophysiology of pediatric bipolar disorder (PBD) impacts both affective and cognitive brain systems. Understanding disturbances in the neural circuits subserving these abilities is critical for characterizing developmental aberrations associated with the disorder and developing improved treatments. Our objective is to use functional neuroimaging with pediatric bipolar disorder patients employing a task that probes the functional integrity of attentional control and affect processing. Ten euthymic unmedicated pediatric bipolar patients and healthy controls matched for age, sex, race, socioeconomic status, and IQ were scanned using functional magnetic resonance imaging. In a pediatric color word matching paradigm, subjects were asked to match the color of a word with one of two colored circles below. Words had a positive, negative or neutral emotional valence, and were presented in 30-s blocks. In the negative affect condition, relative to the neutral condition, patients with bipolar disorder demonstrated greater activation of bilateral pregenual anterior cingulate cortex and left amygdala, and less activation in right rostral ventrolateral prefrontal cortex (PFC) and dorsolateral PFC at the junction of the middle frontal and inferior frontal gyri. In the positive affect condition, there was no reduced activation of PFC or increased amygdala activation. The pattern of reduced activation of ventrolateral PFC and greater amygdala activation in bipolar children in response to negative stimuli suggests both disinhibition of emotional reactivity in the limbic system and reduced function in PFC systems that regulate those responses. Higher cortical cognitive areas such as the dorsolateral PFC may also be adversely affected by exaggerated emotional responsivity to negative emotions. This pattern of functional alteration in affective and cognitive circuitry may contribute to the reduced capacity for affect regulation and behavioral self-control in pediatric bipolar disorder.

Theory of mind and social inference in children and adolescents with bipolar disorder

Deficits in theory of mind (ToM), or the ability to infer what another person is thinking or feeling, have been reported in manic and euthymic adults with bipolar disorder. To date, there have been no investigations of ToM in pediatric bipolar disorder (PBD). The aim of the current study was to investigate this ability in PBD patients and healthy controls. PBD patients (n=26) and intellectually and demographically similar healthy comparison subjects (n=20) were administered two ToM tasks. In the Affective Story Task, subjects were read positive-, negative- and neutral-valenced stories, and were assessed on their ability to recognize that a misleading series of events could lead one character to develop a false belief about another character. On the Hinting Task, subjects were required to infer the real intentions behind subtle hints. The PBD group performed significantly more poorly than controls on the Hinting Task and the positive and negative conditions of the Affective Story Task. In the PBD group only, younger age, earlier illness onset and manic symptoms were associated with poorer ToM performance. Consistent with past findings in adult bipolar disorder (BD), PBD youth performed more poorly than controls on ToM tasks. Data suggest that ToM ability may be more impaired in affectively charged contexts. Additionally, an earlier onset of illness among PBD youth may interfere with the development of social-cognitive skills. ToM disturbances may be a useful treatment target in PBD, with the aim of facilitating more accurate assessment of social cues and better interpersonal functioning.

Facial Emotion Processing in Acutely Ill and Euthymic Patients With Pediatric Bipolar Disorder

Past investigations indicate facial emotion-processing abnormalities in pediatric bipolar disorder (PBD) subjects. However, the extent to which these deficits represent state- and trait-related factors is unclear. We investigated facial affect processing in acutely ill and clinically stabilized children with PBD and matched healthy subjects. Subjects (N = 86) consisted of unmedicated/acutely ill (n = 29) and medicated/clinically stabilized (n = 29) PBD youths and matched healthy subjects (n = 28) who completed tasks of facial affect identification and differentiation. Subjects with PBD, regardless of clinical and treatment status, showed marked impairments in the ability to correctly identify emotionally intense happy and sad facial expressions, with both groups tending to misjudge extreme facial expressions as being moderate to mild in intensity. However, when differentiating subtle variations of happy or sad expressions, only unmedicated/acutely ill PBD patients performed more poorly than healthy subjects. Younger age at onset was associated with more impaired emotion processing only in the PBD sample. PBD subjects with comorbid attention-deficit/hyperactivity disorder (ADHD) performed more poorly than subjects without ADHD when processing sad facial expressions, but not happy ones. This study found evidence of both state-of-illness and trait-related deficits in emotion processing in PBD. Treatments are needed to better reduce this impairment and to reduce its developmental impact on interpersonal functioning.

Anterior cingulate volume in pediatric bipolar disorder and autism

Background An increasing number of studies indicate the anterior cingulate gyrus (ACG) may play a role in the attention deficits associated with pediatric bipolar disorder (BD). Age, medications, and intelligence quotient (IQ) may affect ACG volume; few studies have controlled for these effects. Methods We recruited 16 children with BD and 24 children with autism spectrum disorder (ASD); 15 children with no psychiatric diagnosis (NP) were also included. All participants were evaluated with the K-SADS and a DSM-IV Autism/Asperger's Checklist; the ADI-R was also administered to ASD participants shortly after the study began. The participants completed a brain MRI scan on a 1.5Tesla Signa GE scanner. We segmented the ACG and compared left and right ACG volumes between groups. The influence of medications on the ACG volume was assessed while controlling for the effects of age and IQ. Results The left ACG volume was significantly smaller in the BD group compared to the NP ( p = 0.004) and ASD ( p = 0.006) groups. No significant differences were found in the right ACG volume. These differences do not appear to be attributable to medication use or IQ. Conclusions Pediatric BD patients have a smaller left ACG volume compared to NP children and children diagnosed with ASD. This replication and extension of previous studies suggest that the ACG volume abnormality may be a biomarker for BD.

Decreased protein kinase C (PKC) in platelets of pediatric bipolar patients: Effect of treatment with mood stabilizing drugs

Pediatric bipolar disorder (PBD) is a major public health concern, however, its neurobiology is poorly understood. We, therefore, studied the role of protein kinase C (PKC) in the pathophysiology of bipolar illness. We determined PKC activity and immunolabeling of various PKC isozymes (i.e., PKC α, PKC βI, PKC βII, and PKC δ) in the cytosol and membrane fractions of platelets obtained from PBD patients and normal control subjects. PKC activity and PKC isozymes were also determined after 8 weeks of pharmacotherapy of PBD patients ( n = 16) with mood stabilizers. PKC activity and the protein expression of PKC βI and βII, but not PKC α or PKC δ, were significantly decreased in both membrane as well as cytosol fractions of platelets obtained from medication-free PBD patients compared with normal control subjects. Eight weeks of pharmacotherapy resulted in significantly increased PKC activity but no significant changes in any of the PKC isozymes in PBD patients. These results indicate that decreases of specific PKC isozymes and decreased PKC activity may be associated with the pathophysiology of PBD and that pharmacotherapy with mood stabilizing drugs results in an increase and normalization of PKC activity along with improvement in clinical symptoms.

P.1.e.017 Hippocampal volume in post traumatic stress disorder: effects of traumatic event and sertraline treatment

Previous studies have reported abnormalities of white-matter diffusivity in pediatric bipolar disorder. However, it has not been established whether these abnormalities are able to distinguish individual subjects with pediatric bipolar disorder from healthy controls with a high specificity and sensitivity. Diffusion-weighted imaging scans were acquired from 16 youths diagnosed with DSM-IV bipolar disorder and 16 demographically matched healthy controls. Regional white matter tissue microstructural measurements such as fractional anisotropy, axial diffusivity and radial diffusivity were computed using an atlas-based approach. These measurements were used to ‘train’ a support vector machine (SVM) algorithm to predict new or ‘unseen’ subjects’ diagnostic labels. The SVM algorithm predicted individual subjects with specificity=87.5%, sensitivity=68.75%, accuracy=78.12%, positive predictive value=84.62%, negative predictive value=73.68%, area under receiver operating characteristic curve (AUROC)=0.7812 and chi-square p-value=0.0012. A pattern of reduced regional white matter fractional anisotropy was observed in pediatric bipolar disorder patients. These results suggest that atlas-based diffusion weighted imaging measurements can distinguish individual pediatric bipolar disorder patients from healthy controls. Notably, from a clinical perspective these findings will contribute to the pathophysiological understanding of pediatric bipolar disorder.

Deficits in Social Cognition and Response Flexibility in Pediatric Bipolar Disorder

Little is known about neuropsychological and social-cognitive function in patients with pediatric bipolar disorder. Identification of specific deficits and strengths that characterize pediatric bipolar disorder would facilitate advances in diagnosis, treatment, and research on pathophysiology. The purpose of this study was to test the hypothesis that youths with bipolar disorder would perform more poorly than matched healthy comparison subjects on measures of social cognition, motor inhibition, and response flexibility. Forty outpatients with pediatric bipolar disorder and 22 comparison subjects (no differences in age, gender, and IQ) completed measures of social cognition (the pragmatic judgment subtest of the Comprehensive Assessment of Spoken Language, facial expression recognition subtests of the Diagnostic Analysis of Nonverbal Accuracy Scale, the oral expression subtest of the Test of Language Competence), inhibition and response flexibility (stop and stop-change tasks), and motor inhibition (continuous performance tasks). Pediatric bipolar disorder patients performed more poorly than comparison subjects on social-cognitive measures (pragmatic judgment of language, facial expression recognition) and on a task requiring response flexibility. These deficits were present in euthymic patients. Differences between patients and comparison subjects could not be attributed to comorbid attention deficit hyperactivity disorder. Findings of impaired social cognition and response flexibility in youths with pediatric bipolar disorder suggest continuity between pediatric bipolar disorder and adult bipolar disorder. These findings provide a foundation for neurocognitive research designed to identify the neural mechanisms underlying these deficits.

Fronto-Limbic Brain Abnormalities in Juvenile Onset Bipolar Disorder

Advances in brain imaging techniques and cognitive neuropsychology have brought new possibilities for the in vivo study of the pathophysiology of neuropsychiatric disorders, including bipolar disorder (BD). Recently, such studies have been extended to the pediatric age range. Here we review the neuroimaging and neuropsychological studies conducted in BD children and adolescents. A review of the peer-reviewed published literature was conducted in Medline for the period of 1966 to April 2005. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) studies suggest abnormalities in fronto-limbic structures in pediatric BD patients, similar to those found in adults. A notable exception in pediatric BD patients is smaller amygdala volumes compared to healthy controls, contrary to what has been reported in most adult studies. Further research evaluating children and adolescents is needed to study the normal neurodevelopmental process and to answer how and when the illness processes that result in bipolar disorder exert their effects on the developing brain.