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1.  Microstructural abnormalities of white matter differentiate pediatric and adult onset bipolar disorder 
Bipolar disorders  2012;14(6):597-606.
White matter microstructure, known to undergo significant developmental transformation, is abnormal in bipolar disorder (BD). Available evidence suggests that white matter deviation may be more pronounced in pediatric than adult onset BD. This study aimed to examine how white matter microstructure deviates from a typical maturational trajectory in BD.
Fractional anisotropy (FA) was measured in 35 individuals presenting with first episode BD (type I) and 46 healthy controls (HC) (aged 9–42) using diffusion tensor imaging (DTI). Patients were medication free and close to illness onset at the time of DTI scans. Tract based spatial statistics were used to examine the center of white matter tracts, and FA was extracted from nine tracts of interest. Axial, radial, and mean diffusivity were examined in post-hoc analyses.
The left anterior limb of the internal capsule (ALIC) showed significantly lower FA in pediatric than adult onset BD. The lower FA in BD was due primarily to greater radial rather than a decrease in axial diffusivity.
ALIC connects the frontal lobes with archistriatum, thalamus, and medial temporal regions, and alteration in these pathways may contribute to mood dysregulation in BD. Abnormalities in this pathway appear to be associated with an earlier onset of illness and thus may reflect a greater liability for illness.
PMCID: PMC3612992  PMID: 22882719
diffusion tensor imaging; development; limbic system; anterior limb of internal capsule; affect network
2.  White matter microstructure in untreated first episode bipolar disorder with psychosis: comparison with schizophrenia 
Bipolar disorders  2011;13(0):604-613.
White matter abnormalities have been reported in bipolar disorder. The present study aimed to investigate white matter integrity in untreated first episode patients with psychotic bipolar disorder using diffusion tensor imaging, and to compare observations with those from untreated first episode schizophrenia patients.
Fractional anisotropy and mean diffusivity were measured in first episode psychotic patients with bipolar disorder (n = 13) or schizophrenia (n = 21) and healthy individuals (n = 18). Group differences were evaluated using voxel based morphometry. Axial and radial diffusivity were examined in regions with altered fractional anisotropy in post-hoc analyses.
Patients with bipolar disorder showed lower fractional anisotropy than healthy controls in several white matter tracts. Compared with schizophrenia patients, bipolar disorder patients showed lower fractional anisotropy in the cingulum, internal capsule, posterior corpus callosum, tapetum, and occipital white matter including posterior thalamic radiation and inferior longitudinal fasciculus/inferior fronto-occipital fasciculus. Lower fractional anisotropy in bipolar disorder was characterized by increased radial diffusion rather than axial diffusion along the orientation of fiber tracts. Across several white matter tracts, both patient groups showed greater mean diffusivity than healthy individuals.
Selectively increased radial diffusivity in bipolar disorder patients suggests structural disorganization in fiber tract coherence of neurodevelopmental origin or alterations in myelin sheaths along fiber tracts. In contrast, increased isotropic diffusion along white matter tracts in schizophrenia patients with alterations in both radial and axial diffusivity suggests increased water content outside of axonal space. Thus, the present results suggest that different pathophysiological mechanisms may underlie white matter microstructural abnormalities in bipolar disorder and schizophrenia.
PMCID: PMC3612986  PMID: 22085473
diffusion tensor imaging; first episode psychosis; radial diffusivity; fractional anisotropy; mean diffusivity
3.  Time Course of Recovery Showing Initial Prefrontal Cortex Changes at 16 weeks, Extended to Subcortical Changes by Three years in Pediatric Bipolar Disorder 
Journal of affective disorders  2013;150(2):571-577.
Developmental changes at the interface of affective and cognitive systems are examined over a three year period in pediatric bipolar disorder (PBD).
Thirteen participants with PBD and 10 healthy controls (HC) matched on demographics and IQ were scanned at baseline, 16 weeks, and after three years. All patients received pharmacotherapy based on a medication algorithm. A pediatric affective color matching paradigm was used to probe cognitive processing under emotional challenge.
Behavioral data illustrated that patients in PBD group were slower in response time at baseline, but normalized by three years. On fMRI analyses at baseline, in response to emotional vs. neutral words, patients with PBD showed greater activation, relative to HC, in the right dorsal lateral prefrontal cortex (DLPFC) and amygdala, ventral lateral prefrontal cortex (VLPFC), bilateral anterior cingulate cortex (ACC), and ventral striatum. The increased activation in cortical areas in the PBD group normalized with no differences from HC by 16 weeks. By three years, normalization was observed in not only the cortical, but also the subcortical regions such as amygdala and striatum.
These preliminary findings need to be replicated with a larger sample, although it can be challenging to obtain large samples for longitudinal studies.
Greater activation in fronto-striatal and fronto-limbic circuits were observed in unmedicated patients with PBD. With systematic pharmacotherapy for patients with PBD, the time course of recovery was characterized by initial prefrontal changes at 16 weeks, which extended to subcortical normalization at three years. These preliminary findings illustrated that, following appropriate treatment coupled with normal brain development, patients with PBD showed normalization in brain function.
PMCID: PMC3745513  PMID: 23517886
Pediatric bipolar disorder; Functional magnetic resonance imaging (fMRI); Emotion; treatment effects
4.  Altered affective, executive and sensorimotor resting state networks in patients with pediatric mania 
The aim of the present study was to map the pathophysiology of resting state functional connectivity accompanying structural and functional abnormalities in children with bipolar disorder.
Children with bipolar disorder and demographically matched healthy controls underwent resting-state functional magnetic resonance imaging. A model-free independent component analysis was performed to identify intrinsically interconnected networks.
We included 34 children with bipolar disorder and 40 controls in our analysis. Three distinct resting state networks corresponding to affective, executive and sensorimotor functions emerged as being significantly different between the pediatric bipolar disorder (PBD) and control groups. All 3 networks showed hyperconnectivity in the PBD relative to the control group. Specifically, the connectivity of the dorsal anterior cingulate cortex (ACC) differentiated the PBD from the control group in both the affective and the executive networks. Exploratory analysis suggests that greater connectivity of the right amygdala within the affective network is associated with better executive function in children with bipolar disorder, but not in controls.
Unique clinical characteristics of the study sample allowed us to evaluate the pathophysiology of resting state connectivity at an early state of PBD, which led to the lack of generalizability in terms of comorbid disorders existing in a typical PBD population.
Abnormally engaged resting state affective, executive and sensorimotor networks observed in children with bipolar disorder may reflect a biological context in which abnormal task-based brain activity can occur. Dual engagement of the dorsal ACC in affective and executive networks supports the neuroanatomical interface of these networks, and the amygdala’s engagement in moderating executive function illustrates the intricate interplay of these neural operations at rest.
PMCID: PMC3692720  PMID: 23735583
5.  Mapping White Matter Integrity and Neurobehavioral Correlates in Children with Fetal Alcohol Spectrum Disorders 
Brain structural abnormalities and neurocognitive dysfunction have been observed in individuals with fetal alcohol spectrum disorders (FASDs). Little is known about how white matter integrity is related to these functional and morphological deficits. We used a combination of diffusion tensor and T1-weighted magnetic resonance imaging to evaluate white matter integrity in individuals with FASDs and related these findings to neurocognitive deficits. Seventeen children and adolescents with FASDs were compared with 19 typically developing age-and gender-matched controls. Lower fractional anisotropy (FA) was observed in individuals with FASDs relative to controls in the right lateral temporal lobe and bilaterally in the lateral aspects of the splenium of the corpus callosum. White matter density was also lower in some, but not all regions in which FA was lower. FA abnormalities were confirmed to be in areas of white matter in post hoc region of interest analyses, further supporting that less myelin or disorganized fiber tracts are associated with heavy prenatal alcohol exposure. Significant correlations between performance on a test of visuomotor integration and FA in bilateral splenium, but not temporal regions were observed within the FASD group. Correlations between the visuomotor task and FA within the splenium were not significant with in the control group, and were not significant for measures of reading ability. This suggests that this region of white matter is particularly susceptible to damage from prenatal alcohol exposure and that disruption of splenial fibers in this group is associated with poorer visuomotor integration.
PMCID: PMC3567846  PMID: 18256251
FAS; FASDs; DTI; VBM; corpus callosum; visuomotor integration
6.  Double-blind randomized trial of risperidone versus divalproex in pediatric bipolar disorder: fMRI outcomes 
Psychiatry research  2011;193(1):28-37.
To determine the relative effects of risperidone and divalproex on brain function in pediatric mania. This is a double-blind 6-week fMRI trial with 24 unmedicated manic patients randomized to risperidone or divalproex, and 14 healthy controls (HC) matched for IQ and demographic factors (mean age: 13.1±3.3 years). A pediatric affective color matching task, in which subjects matched the color of a positive, negative or neutral word with one of two colored circles, was administered. The primary clinical measure was the Young Mania Rating Scale (YMRS). The risperidone group, relative to HC, showed an increase in activation from pre- to post-treatment in right pregenual and subgenual anterior cingulate cortex and decreased activation in bilateral middle frontal gyrus during the negative condition; and decreased activation in left inferior and medial, and right middle frontal gyri, left inferior parietal lobe, and right striatum with positive condition. In the divalproex group, relative to HC, there was an increased activation in right superior temporal gyrus in the negative condition; and in left medial frontal gyrus and right precuneus with the positive condition. Greater pre-treatment right amygdala activity with negative and positive condition in the risperidone group, and left amygdala activity with positive condition in divalproex group, predicted poor response on YMRS. Risperidone and divalproex yield differential patterns of prefrontal activity during an emotion processing task in pediatric mania. Increased amygdala activity at baseline is a potential biomarker predicting poor treatment response to both the risperidone and divalproex.
PMCID: PMC3105215  PMID: 21592741
mania; child; treatment; medication; adolescent; prefrontal
7.  Relationships between Brain Activation and Brain Structure in Normally Developing Children 
Cerebral Cortex (New York, NY)  2009;19(11):2595-2604.
Dynamic changes in brain structure, activation, and cognitive abilities co-occur during development, but little is known about how changes in brain structure relate to changes in cognitive function or brain activity. By using cortical pattern matching techniques to correlate cortical gray matter thickness and functional brain activity over the entire brain surface in 24 typically developing children, we integrated structural and functional magnetic resonance imaging data with cognitive test scores to identify correlates of mature performance during orthographic processing. Fast-naming individuals activated the right fronto-parietal attention network in response to novel fonts more than slow-naming individuals, and increased activation of this network was correlated with more mature brain morphology in the same fronto-parietal region. These relationships remained even after effects of age or general cognitive ability were statistically controlled. These results localized cortical regions where mature morphology corresponds to mature patterns of activation, and may suggest a role for experience in mediating brain structure–activation relationships.
PMCID: PMC2758677  PMID: 19240138
attention; fMRI; imaging; language; morphometry
8.  Altered Frontal-Parietal Functioning During Verbal Working Memory in Children and Adolescents with Heavy Prenatal Alcohol Exposure 
Human brain mapping  2009;30(10):3200-3208.
This study evaluated the neural basis of verbal working memory (WM) function in a group of 20 children and adolescents with fetal alcohol spectrum disorders (FASDs) and 20 typically developing comparison participants using functional magnetic resonance imaging (fMRI). Both groups showed prominent activation in the frontal-parietal-cerebellar network known to be important for verbal WM. Despite equivalent behavioral performance between groups, alcohol-exposed individuals showed increased activation relative to typically developing individuals in left dorsal frontal and left inferior parietal cortices, and bilateral posterior temporal regions during verbal WM. These effects remained even when group differences on IQ were statistically controlled. This pattern of increased activation coupled with equivalent behavioral performance between groups suggests that individuals with FASD recruit a more extensive network of brain regions during verbal WM relative to typically developing individuals. These findings may suggest that frontal-parietal processing during verbal WM is less efficient in alcohol-exposed individuals.
PMCID: PMC2748151  PMID: 19263420
9.  Effects of prenatal methamphetamine exposure on verbal memory revealed with fMRI 
Efforts to understand specific effects of prenatal methamphetamine exposure on cognitive processing are hampered by high rates of concomitant alcohol use during pregnancy. We examined whether neurocognitive systems differed among children with differing prenatal teratogenic exposures when they engaged in a verbal memory task.
Patients and Methods
Participants (7-15 years old) engaged in a verbal paired associate learning task while undergoing functional magnetic resonance imaging. The MA group included 14 children with prenatal methamphetamine exposure, 12 of whom had concomitant alcohol exposure. They were compared to 9 children with prenatal alcohol but not methamphetamine exposure (ALC) and 20 unexposed controls (CON). Groups did not differ in age, gender, or socioeconomic status. Participants’ IQ and verbal learning performance were measured using standardized instruments.
The MA group activated more diffuse brain regions, including bilateral medial temporal structures known to be important for memory, than both the ALC and the CON groups. These group differences remained after IQ was covaried. More activation in medial temporal structures by the MA group compared to the ALC group cannot be explained by performance differences because both groups performed at similar levels on the verbal memory task.
More diffuse activation in the MA group during verbal memory may reflect recruitment of compensatory systems to support a weak verbal memory network. Differences in activation patterns between the MA and ALC groups suggest that prenatal MA exposure influences the development of the verbal memory system above and beyond effects of prenatal alcohol exposure.
PMCID: PMC2745202  PMID: 19525715
Teratogen; cognitive; development; imaging; neurobehavioral
10.  Neurodevelopmental Changes in Verbal Working Memory Load-Dependency: An fMRI Investigation 
NeuroImage  2008;42(4):1678-1685.
Development of working memory (WM) aptitude parallels structural changes in the frontal-parietal association cortices important for performance within this cognitive domain. The cerebellum has been proposed to function in support of the postulated phonological loop component of verbal WM, and along with frontal and parietal cortices, has been shown to exhibit linear WM load-dependent activation in adults. It is not known if these kinds of WM load-dependent relationships exist for cerebro-cerebellar networks in developmental populations, and whether there are age-related changes in the nature of load-dependency between childhood, adolescence, and adulthood. The present study used fMRI and a verbal Sternberg WM task with three load levels to investigate developmental changes in WM load-dependent cerebro-cerebellar activation in a sample of 30 children, adolescents, and young adults between the ages of 7 and 28. The neural substrates of linear load-dependency were found to change with age. Among adolescents and adults, frontal, parietal and cerebellar regions showed linear load-dependency, or increasing activation under conditions of increasing WM load. In contrast, children recruited only left ventral prefrontal cortex in response to increasing WM load. These results demonstrate that, while children, adolescents, and young adults activate similar cerebro-cerebellar verbal working memory networks, the extent to which they rely on parietal and cerebellar regions in response to increasing task difficulty changes significantly between childhood and adolescence.
PMCID: PMC2570587  PMID: 18586110

Results 1-10 (10)