Altered neural function in pediatric bipolar disorder during reversal learning

Dickstein DP, Finger EC, Skup M, Pine DS, Blair JR, Leibenluft E. Altered neural function in pediatric bipolar disorder during reversal learning.
Bipolar Disord 2010: 12: 707–719. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objective: Data documenting the functional impairment associated with the diagnosis of bipolar disorder (BD) in children and adolescents highlight the need for greater understanding of its pathophysiology. Toward that end, we demonstrated previously that BD youth have behavioral deficits on reversal learning tasks. On such tasks, participants must first acquire a stimulus/response relationship through trial‐and‐error learning, and then discern when the stimulus/reward relationship reverses. Here, we use event‐related functional magnetic resonance imaging (fMRI) to elucidate neural correlates of reversal learning deficits in euthymic BD youth compared to typically developing controls. Method: We compared euthymic pediatric BD participants (n = 16) versus age‐, sex‐, and IQ‐matched controls (n = 16). Our main outcome measure was blood oxygen level‐dependent (BOLD) signal measured with fMRI during an event‐related probabilistic reversal task. Results: Pediatric BD participants had significantly greater neural activity than controls in fronto‐parietal regions during the reversal phase, particularly in response to punished reversal errors (p < 0.05 corrected for multiple comparisons). Conclusions: Our current study suggests that during reversal learning, BD youths inefficiently recruit regions associated with processing response conflict and implementing alternative responses, including subdivisions of the frontal cortex and the parietal cortex. Such deficits are present in euthymic BD youth. Further work is necessary to evaluate the specificity of such alterations.     

Biological risk factors in pediatric bipolar disorder.

BACKGROUND: The current study attempted to determine whether neurodevelopmental and acquired brain abnormalities are more common in pediatric bipolar disorder (PBD). METHODS: The study sample consisted of 98 subjects with a mean age of 11.5 +/- 3.3 years comprising three demographically matched groups: healthy controls (HC, n = 28), subjects with bipolar disorder - Type I (PBD, n = 37), and bipolar disorder - Type I combined with attention deficit hyperactivity disorder (PBD+ADHD, n = 33). Family history of PBD was determined using the Family History Screen. Additional measures were administered to assess the history on perinatal risk, development milestones, serious physical illnesses, and head injury. RESULTS: Logistic regression showed that that family history and perinatal risk factors predicted the diagnosis of PBD. PBD diagnosis was 15 times higher among those with a family history of BD. Second, for every additional perinatal risk factor such as prenatal exposure to drugs or birth complications, the risk of having a PBD diagnosis increased more than six-fold. CONCLUSIONS: Having a positive familial history of BD in a first degree relative and perinatal insults may elevate the risk for developing PBD. Presence of these risk factors, especially in the context of clinical signs of affect dysregulation, should alert clinicians to screen for PBD.     

Impact of ADHD on the neurocognitive functioning of adolescents with bipolar disorder.

BACKGROUND: Pediatric Bipolar Disorder (BD) has been associated with a number of neurocognitive deficits not dissimilar to ADHD. This study compared neuropsychological profiles of 4 groups of adolescents (14-17 years): 41 Normal Controls (NC), 30 ADHD, 12 BD and 12 combined (BD+ADHD). METHODS: Participants were identified according to a standardized protocol (WASHU-KSADS mood section, K-SADS-PL and Conners Scales) and completed tests of processing speed, memory, executive functioning, set shifting, and inhibition. ADHD adolescents on stimulant medication did not take it on the day. RESULTS: After controlling for covariates, the ADHD-only and combined groups were most impaired, including processing and naming speed, working memory, and response inhibition. The ADHD-only group showed specific impairment in naming objects, numbers and letters than the NC and showed greater deficits than the BD-only group on tests of naming speed. The combined group showed greatest deficits in verbal memory and inhibitory control. Other than working memory, there were no differences between the BD-only and NC groups. Removal of BD-NOS did not impact on the results. CONCLUSIONS: This study failed to find broad neurocognitive deficits in BD-only adolescents. Only those with comorbid ADHD showed cognitive deficits, highlighting the impact ADHD may have on neurocognitive functioning of BD.     

Association of clinical symptoms and neurocognitive performance in bipolar disorder: a longitudinal study

Chaves OC, Lombardo LE, Bearden CE, Woolsey MD, Martinez DM, Barrett JA, Miller AL, Velligan DI, Glahn DC. Association of clinical symptoms and neurocognitive performance in bipolar disorder: a longitudinal study.
Bipolar Disord 2011: 13: 118–123. © 2011 The Authors. Journal compilation © 2011 John Wiley & Sons A/S. Objective: Despite evidence that individuals with bipolar disorder have neurocognitive impairment that persists during euthymia, the impact of changes in affective symptoms on cognitive function has not been well established. Here, we sought to determine whether specific neurocognitive functions are sensitive to mood changes in individuals with bipolar disorder assessed three months apart without changes in treatment regimen. Methods: A total of 29 individuals with DSM‐IV bipolar disorder and 30 healthy controls participated in the study. All participants received a comprehensive neuropsychological assessment and ratings of depressive [Hamilton Depression Rating Scale (HAMD)] and manic [Young Mania Rating Scale (YMRS)] symptoms at baseline and follow‐up. Changes in symptoms over time were calculated and were examined in relation to changes in neurocognitive performance. Results: At baseline, clinically stable but symptomatic patients were impaired on measures of speed of processing and attention. Over the three‐month follow‐up period, HAMD scores changed by 6 points on average [range: ?10 to +18] and YMRS scores changed by 5.31 points on average [range ?11 to +15]. Changes in depressive symptoms were correlated with poorer verbal fluency, while no relationship between manic symptoms and neuropsychological performance was detected. Conclusions: Individuals with bipolar disorder showed consistent impairment on speed of processing and attention over time, despite significant changes in mood.     

Neural activation during encoding of emotional faces in pediatric bipolar disorder

OBJECTIVE: Neurobiological understanding of bipolar disorder (BD) is limited by a paucity of functional magnetic resonance imaging (fMRI) research examining correlates of psychological processes. To begin to address these limitations, the current study tests the hypothesis that pediatric BD (PBD) subjects exhibit altered neural activation during encoding of emotional faces compared to typically developing controls. METHODS: Pediatric BD subjects (n=23; mean age=14.2+/-3.1 years) and controls (n=22; mean age=14.7+/-2.3 years) were matched on age, gender, and IQ. In this event-related fMRI study, subjects were scanned while viewing emotional faces and given a surprise recognition memory test 30 min postscan. Our main outcome measure was between-group differences in neural activation during successful versus unsuccessful face encoding. RESULTS: Pediatric BD youth exhibited reduced memory for emotional faces, relative to healthy comparisons, particularly on fearful faces. Event-related fMRI analyses controlling for this behavioral difference showed that PBD subjects, compared to controls, had increased neural activation in the striatum and anterior cingulate cortex when successfully encoding happy faces and in the orbitofrontal cortex when successfully encoding angry faces. There were no between-group differences in neural activation during fearful face encoding. CONCLUSIONS: Our results extend what is known about memory and face emotion processing impairments in PBD subjects by showing increased fronto-striatal activation during encoding of emotional faces. Further work is required to determine the impact of mood state, medication, and comorbid illnesses on these findings.     

Neuropsychological performance in pediatric bipolar disorder.

BACKGROUND: Growing awareness of childhood bipolar disorder necessitates further cognitive neuroscience research to determine unique developmental differences between pediatric and adult onset bipolar disorder. We sought to examine whether neuropsychological function in children with bipolar disorder resembles that in adults with the illness and to extend our knowledge about cognitive function in pediatric bipolar disorder. METHODS: We administered a computerized neuropsychological test battery known as the Cambridge Neuropsychological Test Automated Battery to a sample of 21 children and adolescents with bipolar disorder and compared them with 21 age- and gender-matched controls. RESULTS: In comparison to controls, children with bipolar disorder were impaired on measures of attentional set-shifting and visuospatial memory. Post hoc analyses in pediatric bipolar disorder subjects did not show significant associations between neuropsychological performance and manic symptomatology or attention-deficit/hyperactivity disorder comorbidity. CONCLUSIONS: Cambridge Neuropsychological Test Automated Battery data presented here in pediatric bipolar disorder fit well within the broader framework of known neurocognitive deficits in adult bipolar disorder. Our pediatric bipolar disorder subjects demonstrated selective deficiencies in attentional set-shifting and visuospatial memory. Our work suggests altered ventrolateral prefrontal cortex function, especially when linked to other lesion and neuroimaging studies.     

Researching the pathophysiology of pediatric bipolar disorder.

We suggest that the core feature of bipolar disorder (BPD) is marked state fluctuations. The pathophysiology of switches into depressed, irritable, and extreme positive valence states requires study, with the latter deserving particular focus because it represents a pathognomonic feature of BPD in both adults and children. Hypotheses regarding the pathophysiology of pediatric BPD must account for these marked state fluctuations as well as for specific developmental aspects of the illness. These developmental aspects include marked irritability (in addition to euphoria and depression) and very rapid cycles, along with high rates of attention-deficit/hyperactivity disorder. We review research on neural mechanisms underlying positive valence states and state regulation, focusing on those data relevant to BPD and to development. Researchers are beginning to explore the response of manic patients and control subjects to positive affective stimuli, and considerable research in both nonhuman primates and humans has focused on the cortico-limbic-striatal circuits mediating responses to rewarding stimuli. In control subjects, positive affect affects cognition, and data indicate that prefrontal electroencephalogram asymmetry may differ between control subjects with consistently positive affect and those with more negative affect; however, this latter generalization may not apply to adolescents. With regard to the pathophysiology of state switching in pediatric BPD, data in control subjects indicating that attention regulation plays a role in emotion regulation may be germane. In addition, research detailing physiologic and psychological responses to negative emotional stimuli in bipolar patients and control subjects may increase our understanding of the mechanisms underlying both irritability and rapid cycling seen in children with BPD. Potential foci for research on the pathophysiology of pediatric BPD include reactivity to standardized positive and negative emotional stimuli, and the interaction between emotion regulation and attentional processes.     

Comparing diagnostic checklists for pediatric bipolar disorder in academic and community mental health settings

OBJECTIVES: To compare six promising mania measures, the Parent Mood Disorder Questionnaire (P-MDQ), the Adolescent self-report MDQ, the 10-item short form of the Parent General Behavior Inventory (PGBI-SF10), the 28-item Adolescent General Behavior Inventory (AGBI), the Parent Young Mania Rating Scale (P-YMRS), and the adolescent YMRS, in a demographically diverse outpatient sample. METHODS: Participants were 262 outpatients (including 164 males and 131 African-Americans) presenting to either an academic medical center (n = 153) or a community mental health center (n = 109). Diagnoses were based on semi-structured interviews with the parent and then youth sequentially. RESULTS: Ninety youths (34%) met criteria for a bipolar spectrum disorder. Parent measures yielded Areas Under the Receiver Operating Curve (AUROC) values of 0.81 for the PGBI-SF10 to 0.66 for the P-YMRS. Adolescent report measures performed significantly less well, with AUROCs ranging from 0.65 to 0.50. There were no significant differences in the diagnostic performance of the measures across the sites or by racial groups, although the reliability of measures tended to be lower in the urban community mental health site. The PGBI-SF10 made a significant contribution to logistic regression models examining all combinations of the instruments. The P-MDQ added information in the younger age group, and no measure improved classification of bipolar cases after controlling for the PGBI-SF10 in the older age group. DISCUSSION: Results replicate previous findings that, in decreasing order of efficiency, the PGBI-SF10, P-MDQ, and P-YMRS significantly discriminate bipolar from non-bipolar cases in youths aged 5-18; and they appear robust in a demographically diverse community setting. Adolescent self-report measures are significantly less efficient, sometimes performing no better than chance at detecting bipolar cases.     

Cortical gray matter differences identified by structural magnetic resonance imaging in pediatric bipolar disorder

OBJECTIVE: Few magnetic resonance imaging (MRI) studies of bipolar disorder (BPD) have investigated the entire cerebral cortex. Cortical gray matter (GM) volume deficits have been reported in some studies of adults with BPD; this study assessed the presence of such deficits in children with BPD. METHODS: Thirty-two youths with DSM-IV BPD (mean age 11.2 +/- 2.8 years) and 15 healthy controls (HC) (11.2 +/- 3.0 years) had structured and clinical interviews, neurological examinations, neurocognitive testing, and MRI scanning on a 1.5 T GE Scanner. Image parcellation divided the neocortex into 48 gyral-based units per hemisphere, and these units were combined into frontal (FL), temporal (TL), parietal (PL), and occipital (OL) lobe volumes. Volumetric differences were examined using univariate linear regression models with alpha = 0.05. RESULTS: Relative to controls, the BPD youth had significantly smaller bilateral PL, and left TL. Analysis of PL and TL gyri showed significantly smaller volume in bilateral postcentral gyrus, and in left superior temporal and fusiform gyri, while the parahippocampal gyri were bilaterally increased in the BPD group. Although the FL overall did not differ between groups, an exploratory analysis showed that the right middle frontal gyrus was also significantly smaller in the BPD group. CONCLUSIONS: Children with BPD showed deficits in PL and TL cortical GM. Further analyses of the PL and TL found differences in areas involved in attentional control, facial recognition, and verbal and declarative memory. These cortical deficits may reflect early age of illness onset.     

Neuropsychological and electrophysiological indices of neurocognitive dysfunction in bipolar II disorder

Objectives: There are conflicting findings regarding the nature and degree of neurocognitive dysfunction in bipolar II disorder (BD II). The aim of this study was to describe different levels of neurocognitive functioning in BD II by combining behavior‐based methods (neuropsychological testing) and event‐related potentials (ERP). Methods: Twenty‐five consecutively referred outpatients fulfilling DSM‐IV criteria for BD II and 28 matched controls performed a neuropsychological test battery targeting working memory/attention, executive functions, verbal and visual memory, and psychomotor speed. In addition, ERPs for measuring early and controlled stages of information processing were recorded using a duration mismatch negativity (MMN) paradigm and a three‐tone auditory oddball paradigm. Results: Compared to controls, BD II patients’ performance was significantly impaired on all neuropsychological measures, except for phonemic verbal fluency, with moderate to strong effect sizes ranging from 0.62 to 1.34. The ERP results indicate dysfunctions in early stages of information processing, showing a significant MMN latency increase and attenuated frontal amplitudes in BD II patients. Female patients showed increased P3a latency compared to female controls, but no group differences were found for P3b latency or amplitude, the ERP component expressing controlled information processing. Conclusions: The functional significance of neuropsychological impairment is discussed. Differences regarding some aspects of executive function may be related to psychomotor speed, and not primarily to dysexecutive functioning. ERP results must be interpreted with caution, but the differences found in MMN latency and amplitudes may be related to fronto‐temporal circuitry underlying pre‐attentive stimulus change detection as measured by MMN, and are discussed in relation to previous research on MMN in other neuropsychiatric conditions.     

Theory of mind and neurocognitive functioning in patients with bipolar disorder

Wolf F, Brüne M, Assion H‐J. Theory of mind and neurocognitive functioning in patients with bipolar disorder. Bipolar Disord 2010: 12: 657–666. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objectives: Studies into social cognition in psychiatric disorders have recently been expanded to address the question of whether or not theory of mind (ToM), i.e., the ability to represent one’s own and others’ mental states, is impaired in bipolar affective disorder (BPD). Results have been mixed so far, mainly due to possible confounding effects of neurocognition, as well as clinical factors such as acuity and current mood. Here, we explored ToM and its associations with neurocognitive functioning in BPD. Methods: A total of 33 patients with bipolar I disorder (of whom 12 were currently depressed, 10 manic, and 11 remitted) and 29 healthy controls were assessed using a test battery that was identical to the one that was used in previous studies in schizophrenia, comprising diverse neurocognitive tasks, including measures of intelligence, executive functioning, and ToM tasks. Results: The bipolar disorder patient group as a whole and all three clinical subgroups were impaired on all measures of ToM relative to controls, but did not differ from each other in most ToM scores. Patients’ poorer performance on executive tasks did not fully explain ToM differences between patients and controls, suggesting a partially selective ToM deficit in BPD. Conclusions: Patients with BPD are impaired in ToM, partially independent of other cognitive dysfunctions and current mood.     

Neurocognitive profiles in bipolar I and bipolar II disorder: differences in pattern and magnitude of dysfunction

Objectives:  Studies on neurocognitive functioning in bipolar disorder, reporting deficits in memory, attention, and executive functioning, have primarily focused on bipolar I disorder. The aim of this study was to examine whether patients with bipolar I and bipolar II disorder have different neurocognitive profiles.
Methods:  Forty-two patients with bipolar I disorder, 31 patients with bipolar II and 124 healthy controls, from a large ongoing study on psychotic disorders, were included. Neurocognitive function was measured with a comprehensive neuropsychological test battery.
Results:  The bipolar I group performed significantly poorer than the healthy control group and the bipolar II group on all measures of memory. Compared with the control group, the bipolar I group also had significantly reduced performance on most measures of attention and executive functioning, while the bipolar II group only had a significantly reduced performance on a subset of these measures. On average, 24% of the bipolar I group had clinically significant cognitive impairment (≤1.5 SD below the control group mean) across measures, compared with 13% of the bipolar II group.
Conclusions:  Patients with bipolar I and bipolar II disorder in this study have different neurocognitive profiles. Bipolar I patients have more widespread cognitive dysfunction both in pattern and magnitude, and a higher proportion has clinically significant cognitive impairments compared with patients with bipolar II. This may suggest neurobiological differences between the two bipolar subgroups.     

伴轻度抑郁症状的双相障碍患者执行和注意功能对照研究

目的:探讨伴轻度抑郁症状的双相障碍患者执行功能、注意功能与健康对照者的差异。方法:40例伴轻度抑郁症状的双相障碍患者(研究组)和40名年龄、性别、受教育年限与研究组匹配的健康者(健康对照组)均采用威斯康星卡片分类测验(WCST)及持续操作测验(CPT)测试两组执行功能和注意功能。结果:两组WCST测试成绩除完成第1个分类所需应答数、非持续性错误数差异无统计学意义(P0.05)外,完成分类数、总应答数、正确应答数、错误应答数、持续性错误数、持续性错误率组间差异有统计学意义(t=-6.10~5.96,P均=0.000);CPT测验中正确数研究组明显低于健康对照组(t=-3.87,P=0.000);错误数明显高于健康对照组(t=5.21,P=0.000)。结论:伴轻度抑郁症状的双相障碍患者存在执行功能损害和注意功能损害。     

缓解期双相情感性精神障碍患者认知功能

目的:了解缓解期双相情感性精神障碍患者认知功能损害的特点。方法:采用逻辑记忆、视觉再生记忆、连线测验A和B、数字广度测验、威斯康星卡片分类测验(WCST)及字色混淆测验(stroop)对62例缓解期双相情感性精神障碍患者(患者组)和62名健康者(对照组)进行有关言语学习和记忆、非言语学习和记忆、注意以及执行功能的神经心理学评定,比较两组间认知功能的差异。结果:患者组在即刻逻辑记忆、延迟逻辑记忆、连线测验A和B、WCST正确应答数、完成分类数、持续性错误数以及Stroop C-W操作分上均显著低于对照组(P<0.05~0.01)。结论:双相情感性精神障碍患者的认知缺陷有其特点。     

A linkage and family-based association analysis of a potential neurocognitive endophenotype of bipolar disorder

The identification of the genetic variants underpinning bipolar disorder (BPD) has been impeded by a complex pattern of inheritance characterized by genetic and phenotypic heterogeneity, genetic epistasis, and gene-environment interactions. In this paper two strategies were used to ameliorate these confounding factors. A unique South African sample including 190 individuals of the relatively, reproductively isolated Afrikaner population was assessed with a battery of neuropsychological tests in an attempt to identify a BPD-associated quantitative trait or endophenotype. BPD individuals performed significantly worse than their unaffected relatives on visual and verbal memory tasks, a finding congruent with the literature. A focused linkage and family-based association study was carried out using this memory-related endophenotype. In the largest 77-strong Afrikaner pedigree significant evidence for linkage was detected on chromosome 22q11, a region previously implicated in BPD. The quantitative transmission disequilibrium tests-based association analysis suggested that functional variants of the DRD4 and MAO-A genes modulate memory-related cognition. We speculate that polymorphisms at these loci may predispose to a subtype of BPD characterized by memory-related deficits.     

How cardinal are cardinal symptoms in pediatric bipolar disorder? An examination of clinical correlates.

BACKGROUND: The main goal of this study was to test whether the hypothesized cardinal symptom of euphoria results in differences in clinical correlates in bipolar youth ascertained with no a priori assumptions about cardinal symptoms. METHODS: Subjects (n = 86) satisfying DSM-IV criteria for bipolar disorder with and without the proposed cardinal symptom of euphoria were compared in their bipolar symptom pattern, functioning and patterns of comorbidity. RESULTS: Among Criterion A (abnormal mood), we found that severe irritability was the predominant abnormal mood rather than euphoria (94% vs. 51%). We also found that among Criterion B items, grandiosity was not uniquely overrepresented in youth with mania, nor did the rate of grandiosity differ whether irritability or irritability and euphoria were the Criterion A mood symptom. Neither symptom profile, patterns of comorbidity nor measures of functioning differed related to the presence or absence of euphoria. CONCLUSIONS: These findings challenge the notion that euphoria represents a cardinal symptom of mania in children. Instead they support the clinical relevance of severe irritability as the most common presentation of mania in the young. They also support the use of unmodified DSM-IV criteria in establishing the diagnosis of mania in pediatric populations.