Structure-function associations in hippocampus in bipolar disorder.

Hippocampus volume decreases and verbal memory deficits have been reported in bipolar disorder (BD) as independent observations. We investigated potential associations between these deficits in subjects with BD. Hippocampus volumes were measured on magnetic resonance images of 31 subjects with BD and 32 healthy comparison (HC) subjects. The California Verbal Learning Test-Second Edition (CVLT) assessed verbal memory function in these subjects. Compared to the HC group, the BD group showed both significantly smaller hippocampus volumes and impaired performance on CVLT tests of immediate, short delay and long delay cued and free recall. Further, smaller hippocampus volume correlated with impaired performance in BD. Post hoc analyses revealed a trend towards improved memory in BD subjects taking antidepressant medications. These results support associations between morphological changes in hippocampus structure in BD and verbal memory impairment. They provide preliminary evidence pharmacotherapy may reverse hippocampus-related memory deficits.

Childhood abuse and neglect and cognitive flexibility in adolescents.

Childhood maltreatment (CM) has been associated with diminished executive functioning in children and adults; however, there is a relative paucity of study of executive function in adolescents exposed to CM. Yet, executive dysfunction in adolescence may have important adverse consequences including increased vulnerability to risky behaviors and impaired school functioning. This study investigates the relationship between self-reported CM and an executive function, cognitive flexibility, in adolescents without identified psychiatric disorders. Effects of physical and emotional, abuse and neglect, maltreatment subtypes were explored. Thirty adolescents ages 12-17 years, 50% females, completed the retrospective self-report Childhood Trauma Questionnaire (CTQ) and were administered the Wisconsin Card Sorting Test (WCST). Correlational analyses assessed the relationship between WCST perseverative error scores norm-referenced for age and education with CTQ total scores. The relationship with nonperseverative errors, as well as with physical and emotional abuse and neglect CM subscores, were explored. Total CTQ scores showed significant associations with perseverative errors on the WCST, but not with nonperseverative errors. Significant associations with perseverative errors were seen for physical abuse and physical neglect among the CTQ subscales. The results suggest both physical abuse and physical neglect are associated with diminished cognitive flexibility in adolescents. These effects were detected in adolescents without identified psychiatric diagnoses suggesting the importance of considering executive dysfunction in adolescents exposed to CM who may not meet diagnostic criteria for an Axis I disorder and that tests of perseverative errors, such as those of the WCST, may be sensitive indicators of this dysfunction.

Lateral ventricle volume and psychotic features in adolescents and adults with bipolar disorder.

This magnetic resonance imaging study demonstrates increased lateral ventricle volume (LVV) in adolescents and adults with bipolar disorder (BD) with psychotic symptoms, but not without psychosis, compared to healthy adolescents and adults. This suggests LVV is a morphologic feature associated with psychosis in BD, present by adolescence.

Olfactocentric paralimbic cortex morphology in adolescents with bipolar disorder.

The olfactocentric paralimbic cortex plays a critical role in the regulation of emotional and neurovegetative functions that are disrupted in core features of bipolar disorder. Adolescence is thought to be a critical period in both the maturation of the olfactocentric paralimbic cortex and in the emergence of bipolar disorder pathology. Together, these factors implicate a central role for the olfactocentric paralimbic cortex in the development of bipolar disorder and suggest that abnormalities in this cortex may be expressed by adolescence in the disorder. We tested the hypothesis that differences in olfactocentric paralimbic cortex structure are a morphological feature in adolescents with bipolar disorder. Subjects included 118 adolescents (41 with bipolar disorder and 77 healthy controls). Cortical grey matter volume differences between adolescents with and without bipolar disorder were assessed with voxel-based morphometry analyses of high-resolution structural magnetic resonance imaging scans. Compared with healthy comparison adolescents, adolescents with bipolar disorder demonstrated significant volume decreases in olfactocentric paralimbic regions, including orbitofrontal, insular and temporopolar cortices. Findings in these regions survived small volume correction (P < 0.05, corrected). Volume decreases in adolescents with bipolar disorder were also noted in inferior prefrontal and superior temporal gyri and cerebellum. The findings suggest that abnormalities in the morphology of the olfactocentric paralimbic cortex may contribute to the bipolar disorder phenotype that emerges in adolescence. The morphological development of the olfactocentric paralimbic cortex has received little study. The importance of these cortices in emotional and social development, and support for a central role for these cortices in the development of bipolar disorder, suggest that study of the development of these cortices in health and in bipolar disorder is critically needed.

Impulsivity in Adolescent Bipolar Disorder.

OBJECTIVE: Increased impulsivity has been demonstrated to be a trait feature of adults with bipolar disorder (BD), yet impulsivity has received little study in adolescents with BD. Thus, it is unknown whether it is a trait feature that is present early in the course of the disorder. We tested the hypotheses that self-reported impulsiveness is increased in adolescents with BD, and that it is present during euthymia, supporting impulsiveness as an early trait feature of the disorder. METHODS: Impulsiveness was assessed in 23 adolescents with BD and 23 healthy comparison (HC) adolescents using the self-report measure of impulsivity, the Barratt Impulsiveness Scale (BIS), comprised by attentional, motor and nonplanning subscale scores. Effects of subscale scores and associations of scores with mood state and course features were explored. RESULTS: Total and subscale BIS scores were significantly higher in adolescents with BD than HC adolescents. Total, attentional and motor subscale BIS scores were also significantly higher in the subset of adolescents with BD who were euthymic, compared to HC adolescents. Adolescents with BD with rapid-cycling and chronic mood symptoms had significantly higher total and motor subscale BIS scores than adolescents with BD without these course features. CONCLUSION: These results suggest increased self-reported impulsiveness is a trait feature of adolescents with BD. Elevated impulsivity may be especially prominent in adolescents with rapid-cycling and chronic symptoms.

Sexually dimorphic features of vermis morphology in bipolar disorder.

OBJECTIVES: The cerebellar vermis is increasingly implicated in bipolar disorder (BD). In this study, we investigated vermis morphology in BD using a quantitative volumetric analysis. METHODS: Volumes for total vermis and vermis subregions V1 (lobules I-V), V2 (lobules VI-VII), and V3 (lobules VIII-X) were calculated using high-resolution structural magnetic resonance imaging obtained from 44 individuals with BD (25 females and 19 males) and 43 healthy comparison (HC) subjects (26 females and 17 males). Total vermis volumes were compared between the BD and HC groups. Potential effects of vermis subregions and clinical features were explored. RESULTS: Total vermis volumes were significantly larger in the BD group than in the HC group (p = 0.02). There was a significant group-by-sex interaction (p = 0.02). Total vermis volumes were significantly larger in males with BD than HC males (p = 0.004); vermis volumes did not differ significantly between females with and without BD (p = 0.95). Subregion analyses showed a trend-level interaction between diagnosis and subregion (p = 0.07) in which subregion V1 volumes were significantly larger in BD participants (p = 0.001), with differences primarily driven by males (p = 0.001). CONCLUSIONS: Our findings demonstrate increases in cerebellar vermis volumes in males with BD. These findings support the presence of structural alterations in the cerebellar vermis in BD and furthermore the influence of sex on such changes.

Preliminary evidence for progressive prefrontal abnormalities in adolescents and young adults with bipolar disorder.

Previous cross-sectional study of ventral prefrontal cortex (VPFC) implicated progressive volume abnormalities during adolescence in bipolar disorder (BD). In the present study, a within-subject, longitudinal design was implemented to examine brain volume changes during adolescence/young adulthood. We hypothesized that VPFC volume decreases over time would be greater in adolescents/young adults with BD than in healthy comparison adolescents/young adults. Eighteen adolescents/young adults (10 with BD I and 8 healthy comparison participants) underwent two high-resolution magnetic resonance imaging scans over approximately 2 years. Regional volume changes over time were measured. Adolescents/young adults with BD displayed significantly greater volume loss over time, compared to healthy comparison participants, in a region encompassing VPFC and rostral PFC and extending to rostral anterior cingulate cortex (p < .05). Additional areas where volume change differed between groups were observed. While data should be interpreted cautiously due to modest sample size, this study provides preliminary evidence to support the presence of accelerated loss in VPFC and rostral PFC volume in adolescents/young adults with BD.

Functional and structural connectivity between the perigenual anterior cingulate and amygdala in bipolar disorder.

OBJECTIVE: Abnormalities in the morphology and function of two gray matter structures central to emotional processing, the perigenual anterior cingulate cortex (pACC) and amygdala, have consistently been reported in bipolar disorder (BD). Evidence implicates abnormalities in their connectivity in BD. This study investigates the potential disruptions in pACC-amygdala functional connectivity and associated abnormalities in white matter that provides structural connections between the two brain regions in BD. METHODS: Thirty-three individuals with BD and 31 healthy comparison subjects (HC) participated in a scanning session during which functional magnetic resonance imaging (fMRI) during processing of face stimuli and diffusion tensor imaging (DTI) were performed. The strength of pACC-amygdala functional connections was compared between BD and HC groups, and associations between these functional connectivity measures from the fMRI scans and regional fractional anisotropy (FA) from the DTI scans were assessed. RESULTS: Functional connectivity was decreased between the pACC and amygdala in the BD group compared with HC group, during the processing of fearful and happy faces (p < .005). Moreover, a significant positive association between pACC-amygdala functional coupling and FA in ventrofrontal white matter, including the region of the uncinate fasciculus, was identified (p < .005). CONCLUSION: This study provides evidence for abnormalities in pACC-amygdala functional connectivity during emotional processing in BD. The significant association between pACC-amygdala functional connectivity and the structural integrity of white matter that contains pACC-amygdala connections suggest that disruptions in white matter connectivity may contribute to disturbances in the coordinated responses of the pACC and amygdala during emotional processing in BD.

Relation between amygdala structure and function in adolescents with bipolar disorder.

OBJECTIVE: Previous study supports the presence of reduced volume and elevated response to emotional stimuli in amygdala in adolescents with bipolar disorder (BD). In the present study, structural and functional magnetic resonance imaging scans were obtained during the same neuroimaging session to examine amygdala structure-function relations in adolescents with BD. We hypothesized that amygdala volume would be inversely associated with amygdala response to emotional stimuli, such that BD participants with the smallest amygdala volumes would exhibit the highest amygdala response. METHOD: Fifty-one adolescents (21 with BD I and 30 control adolescents, ages 10-18 years) underwent structural and functional magnetic resonance imaging scans. Amygdala volume (n = 49) and signal change (n = 44) during emotional face processing were compared between groups, and structure-function correlations were examined within the BD group (n = 16). RESULTS: Adolescents with BD showed decreased amygdala volume (p =.009) and increased amygdala response to emotional faces (p =.043). There was no significant interaction between diagnosis and emotion type. A significant inverse association between amygdala volume and activation during emotional face processing was observed (r = -0.54, p =.029). CONCLUSIONS: Decreased volume and increased response to emotional stimuli in the amygdala in adolescents with BD are consistent with previous reports. This study represents the first report, to our knowledge, of the two findings in the same adolescent BD sample and supports an amygdala structure-function relation characterized by an inverse association between volume and response to emotional stimuli. This preliminary finding requires replication and suggests a possible pathophysiological link between abnormalities in amygdala structure and response to emotional stimuli in BD.

Role of variation in the serotonin transporter protein gene (SLC6A4) in trait disturbances in the ventral anterior cingulate in bipolar disorder.

Bipolar disorder (BD) is associated with abnormalities of the ventral anterior cingulate cortex (vACC) and its connection sites, including the amygdala, which are key components of a corticolimbic neural system that subserves emotional regulation. Decreased functional connectivity from the vACC to the amygdala in healthy individuals is associated with the short 's' allele--as opposed to the long 'l' allele--of a well-known serotonin transporter promoter polymorphism (5-HTTLPR, locus SLC6A4), as are features of BD. This study tests the hypothesis that the s allele influences dysfunction in the vACC-amygdala neural system in BD. A total of 30 euthymic individuals with BD (20 s carriers, 10 ll) and 48 healthy comparison (HC) participants (34 s, 14 ll) participated in an event-related functional magnetic resonance imaging scan while processing fearful, happy, or neutral faces. During fear and happy face processing, vACC activation was significantly lower in the BD compared to the HC group, and in s carriers compared to ll individuals within both the HC and BD groups, such that BD s carriers exhibited the greatest magnitude of vACC dysfunction. No significant differences were detected in amygdala activation. The findings suggest that the 5-HTTLPR s allele may contribute to a trait-related, genetically derived, neurobiological subgroup within BD characterized by prominent vACC dysfunction. Future treatment may be optimized for this BD subgroup by targeting the serotonergic system and the vACC.

A Ventral Prefrontal-Amygdala Neural System in Bipolar Disorder: A View from Neuroimaging Research.

In the past decade, neuroimaging research has identified key components in the neural system that underlies bipolar disorder (BD). The ventral prefrontal cortex (VPFC) and amygdala are highly interconnected structures that jointly play a central role in emotional regulation. Numerous research groups have reported prominent structural and functional abnormalities within the VPFC and amygdala supporting their essential role in a neural system underlying the emotional dysregulation that is a core feature of BD. Findings in BD also include those in brain regions interconnected with the VPFC and amygdala, including the ventral striatum, hippocampus, and the cerebellum. Abnormalities in these regions may contribute to symptoms that reflect disruption in functions subserved by these structures, including motivational, mnemonic and psychomotor functions.This article will first review leads from behavioral neurology that implicated these neural system abnormalities in BD. It will then review findings from structural imaging and functional imaging studies to support the presence of abnormalities within these neural system components in BD. It will also review new findings from studies using diffusion tensor imaging (DTI) that provide increasing evidence of abnormalities in the connections between these neural system components in BD. Emerging data supporting differences in this neural system during adolescence, as well as potential beneficial effects of treatment on structure and function will also be presented. Finally, the article will discuss the implications for future investigations, including those for early identification and treatment of BD.

A ventral prefrontal-amygdala neural system in bipolar disorder: a view from neuroimaging research.

In the past decade, neuroimaging research has identified key components in the neural system that underlies bipolar disorder (BD). The ventral prefrontal cortex (VPFC) and amygdala are highly interconnected structures that jointly play a central role in emotional regulation. Numerous research groups have reported prominent structural and functional abnormalities within the VPFC and amygdala supporting their essential role in a neural system underlying the emotional dysregulation that is a core feature of BD. Findings in BD also include those in brain regions interconnected with the VPFC and amygdala, including the ventral striatum, hippocampus and the cerebellum. Abnormalities in these regions may contribute to symptoms that reflect disruption in functions sub-served by these structures, including motivational, mnemonic and psychomotor functions. This article will first review leads from behavioural neurology that implicated these neural system abnormalities in BD. It will then review findings from structural and functional imaging studies to support the presence of abnormalities within these neural system components in BD. It will also review new findings from studies using diffusion tensor imaging (DTI) that provide increasing evidence of abnormalities in the connections between these neural system components in BD. Emerging data supporting differences in this neural system during adolescence, as well as potential beneficial effects of treatment on structure and function will also be presented. Finally, the article will discuss the implications for future investigations, including those for early identification and treatment of BD.

Influence of vascular endothelial growth factor variation on human hippocampus morphology.

BACKGROUND: Morphological abnormalities in hippocampus have been implicated in neuropsychiatric disorders, including depression, schizophrenia, and dementia. Vascular endothelial growth factor (VEGF) has been demonstrated to have neurogenic effects in the hippocampus in rats. However, influence of VEGF variation on hippocampus morphology in humans has yet to be shown. Here, an integrated genetic and neuroimaging approach was used to investigate whether VEGF variation influences hippocampus morphology in humans. METHODS: High-resolution magnetic resonance imaging and voxel-based morphometry were used to identify the influence of genetic variation of VEGFA [rs833068 (SNP-1), rs833070 (SNP-2), rs2146323 (SNP-3) and rs3025020 (SNP-4)] on brain morphology in 47 healthy individuals. RESULTS: Variation in VEGFA SNP-2 and SNP-3 showed significant effects on hippocampus concentration. CONCLUSIONS: The findings suggest that effects of VEGF in hippocampus found in rats extend to humans; further understanding of effects of VEGFA variation might have important implications in identifying individuals more vulnerable to hippocampus pathology as well as those neuropsychiatric populations most likely to benefit from VEGF-mediated interventions.

Abnormal anterior cingulum integrity in bipolar disorder determined through diffusion tensor imaging.

BACKGROUND: Convergent evidence implicates white matter abnormalities in bipolar disorder. The cingulum is an important candidate structure for study in bipolar disorder as it provides substantial white matter connections within the corticolimbic neural system that subserves emotional regulation involved in the disorder. AIMS: To test the hypothesis that bipolar disorder is associated with abnormal white matter integrity in the cingulum. METHOD: Fractional anisotropy in the anterior and posterior cingulum was compared between 42 participants with bipolar disorder and 42 healthy participants using diffusion tensor imaging. RESULTS: Fractional anisotropy was significantly decreased in the anterior cingulum in the bipolar disorder group compared with the healthy group (P=0.003); however, fractional anisotropy in the posterior cingulum did not differ significantly between groups. CONCLUSIONS: Our findings demonstrate abnormalities in the structural integrity of the anterior cingulum in bipolar disorder. They extend evidence that supports involvement of the neural system comprising the anterior cingulate cortex and its corticolimbic gray matter connection sites in bipolar disorder to implicate abnormalities in the white matter connections within the system provided by the cingulum.

The relationship between cognitive deficits and everyday functional activities in multiple sclerosis.

Considerable evidence indicates that cognitive dysfunction and impairments in everyday life activities are common in multiple sclerosis (MS). However, the relationship between these cognitive and functional deficits has not been thoroughly investigated. The purpose of this study was to examine the role of cognitive dysfunction in the functional status of individuals with MS. Participants were 74 adults with MS and 35 healthy comparison participants (HCs) who underwent neuropsychological testing and completed the Executive Functions Performance Test (EFPT; Baum, Morrison, Hahn, & Edwards, 2003), an objective measure of everyday life activities. Between-groups comparisons and correlational analyses were conducted to examine the relationship between cognition and functional capacity. Significant differences in EFPT performance were revealed between individuals with MS with and without cognitive impairment and HCs. In individuals with MS, performance on cognitive constructs was related to performance on the EFPT. Furthermore, a linear regression model comprised of indices of cognitive functioning explained a significant portion of the variance in everyday life activities. Findings suggest that individuals with and without cognitive impairment differ in functional status and that aspects of cognition are predictive of functional status in MS.

Abnormal corpus callosum integrity in bipolar disorder: a diffusion tensor imaging study.

OBJECTIVE: Abnormalities in the anterior interhemispheric connections provided by the corpus callosum (CC) have long been implicated in bipolar disorder (BD). In this study, we used complementary diffusion tensor imaging methods to study the structural integrity of the CC and localization of potential abnormalities in BD. METHODS: Subjects included 33 participants with BD and 40 healthy comparison participants. Fractional anisotropy (FA) measures were compared between groups with region of interest (ROI) methods to investigate the anterior, middle, and posterior CC and voxel-based methods to further localize abnormalities. RESULTS: In ROI-based analyses, FA was significantly decreased in the anterior and middle CC in the BD group (p < .05). Voxel-based analyses similarly localized group differences to the genu, rostral body, and anterior midbody of CC (p < .05, corrected). CONCLUSION: The findings demonstrate abnormalities in the structural integrity of the anterior CC in BD that might contribute to altered interhemispheric connectivity in this disorder.

Elevated childhood serotonergic function protects against adolescent aggression in disruptive boys.

OBJECTIVE: This longitudinal study examined whether responsiveness of the neurotransmitter serotonin (5-HT) in childhood predicts adolescent aggression. METHOD: Boys (N = 33) with disruptive behavior disorders who received assessments of central 5-HT function via the prolactin response to fenfluramine between 1990 and 1994 when they were 7 to 11 years old were re-evaluated clinically on average 6.7 years later. RESULTS: After accounting for baseline aggression, early 5-HT function accounted for a significant proportion of variance in adolescent aggression. This prospective relationship of childhood 5-HT function with adolescent aggression (r = -0.71) and antisocial behavior (r = -0.59) was found primarily in adolescents who were aggressive during childhood. Irrespective of childhood aggression, no child with high 5-HT function was particularly aggressive at follow-up. CONCLUSIONS: Low childhood 5-HT function appears important, but not sufficient, for the emergence of adolescent aggression. However, early high 5-HT function may protect against adolescent violence and aggression.

Processing speed interacts with working memory efficiency in multiple sclerosis.

Information processing speed was assessed using the visual threshold serial addition test (VT-SAT), a computerized modification of the PASAT designed to assess processing speed by controlling for performance accuracy. Persons with MS (N=43) and healthy individuals (N=32) were administered the VT-SAT varying working memory loads (1-back versus 2-back). Results indicated that at the lower working memory load (1-back) all individuals with MS were able to achieve a working memory performance level equivalent to healthy individuals, but required significantly more processing time to do so. In contrast, at the higher working memory load (2-back), about 70% of MS participants were able to achieve a performance level equivalent to healthy individuals, but again required significantly more processing time. The results are discussed in the context of the dynamic nature of the relationship between processing speed and working memory performance, emphasizing the dependence of this relationship on other cognitive and disease-related factors.

Preliminary evidence for persistent abnormalities in amygdala volumes in adolescents and young adults with bipolar disorder.

OBJECTIVES: Abnormalities in volumes of the amygdala have been reported previously in adolescents and adults with bipolar disorder (BD). Several studies have reported reduced volumes in adolescents with BD; however, both decreases and increases in volumes have been reported in adults with BD. Understanding of potential developmental contributions to these disturbances in morphology of the amygdala has been limited by the absence of longitudinal data in persons with BD. Here we use a within-subject longitudinal design to investigate whether amygdala volume abnormalities persist in adolescents and young adults with BD over a time interval of approximately 2 years. METHODS: Participants included 18 adolescents and young adults: 10 participants with BD I and 8 healthy comparison participants. Amygdala volumes were measured on high-resolution magnetic resonance imaging scans acquired twice for each subject over intervals of approximately 2 years. Amygdala volumes were the dependent measures in a mixed-model statistical analysis to compare amygdala volumes between groups over time while covarying for total brain volume. RESULTS: Amygdala volumes were significantly smaller in adolescents and young adults with BD compared with healthy participants (p = 0.018). The effect of time was not significant. CONCLUSIONS: Although the sample size is modest, this study provides preliminary evidence to support the presence of decreased amygdala volumes in adolescents and young adults with BD that persist during this developmental epoch.

The effect of childhood conduct disorder and cognitive functioning on adolescent substance use.

OBJECTIVE: To assess the impact of childhood conduct disorder (CD) and intelligence quotient (IQ) on later substance use in adolescence. METHODS: Neuropsychological and structured diagnostic evaluations were initially administered to 32 children with disruptive behavior disorder when they were 7-11 years of age. They were then re-evaluated on average 6.7 years later using an array of interviews and rating scales with a focus on substance use. RESULTS: Early CD and IQ scores together accounted for a significant proportion of the variance in later substance use (R2=.248). In addition, there was a significant CD and Verbal IQ interaction (R2=.164) such that high Verbal IQ was linked to increased substance use in adolescents who had childhood CD. CONCLUSION: These data indicate that the presence of conduct disorder may interact with high Verbal IQ during childhood in such a way as to predict later adolescent substance use in disruptive behavior disorder populations.