Lower Orbital Frontal White Matter Integrity in Adolescents With Bipolar I Disorder

doi:10.1097/CHI.0b013e3181900421

Journal of the American Academy of Child & Adolescent Psychiatry

Volume 48, Issue 1, January 2009, Pages 79-86

https://doi.org/10.1097/CHI.0b013e3181900421 Get rights and content

Abstract

Objective

To examine white matter microstructure, as assessed via diffusion tensor imaging (DTI), in adolescents with bipolar I disorder compared with control volunteers.

Method

Twenty-six (12 male and 14 female subjects) adolescents (mean age, 16.0 years) with bipolar I disorder and 26 (14 male and 12 female subjects) control volunteers (mean age, 15.3 years) completed structural and DTI examinations. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) maps were compared between groups in the brain white matter using a voxelwise analysis after intersubject registration to Talairach space. Exploratory analyses were performed to assess structure-function correlations in a subgroup of 11 patients with available neuropsychological measures.

Results

Compared with the control volunteers, the patients demonstrated abnormalities in white matter regions predicted to differ a priori between groups, including lower FA in the right orbital frontal lobe and higher ADC in the right and left subgenual region (p < .005, uncorrected; cluster size ≥ 100). There were no areas of higher FA or lower ADC in patients compared with control volunteers. Lower FA across regions that differed significantly between groups correlated significantly with slower visuomotor speed among patients with bipolar disorder.

Conclusions

Abnormalities involving the orbital frontal and subgenual white matter in adolescents with bipolar disorder are consistent with neurobiological models that implicate dysregulation of affective systems and impulsivity in the pathophysiology of the disorder. Preliminary findings suggest that white matter abnormalities in pediatric bipolar disorder have functional correlates and may be useful in constructing neurobiological models of the disorder.

Section snippets

Subjects

Twenty-six adolescents with a diagnosis of bipolar I disorder and 26 control volunteers participated in this study (Table 1). All of the subjects and, separately, a parent or guardian, were interviewed using the Schedule for Affective Disorders and Schizophrenia for School-Age Children—Present and Lifetime version.¹⁸ None of the comparison subjects met DSM-IV criteria for an Axis I disorder, and none of their first-degree relatives had a diagnosis of bipolar disorder, unipolar disorder, or any

Results

The patients did not differ significantly from control volunteers in distributions of relevant demographics (Table 1). In addition, independent groups t tests did not reveal any significant (p > .05) difference in FSIQ between patients (mean 97.7, SD 17.7) and control volunteers (mean 100.4, SD 16.3) or between groups where FSIQ was not estimated. Bipolar I adolescents demonstrated significantly (p < .005, uncorrected; cluster size ≥ 100) lower FA in the right orbital frontal region compared

Discussion

The main findings of this study support our a priori hypothesis that adolescents with bipolar I disorder have abnormalities in the ventral prefrontal white matter, including orbital frontal and subgenual regions. Specifically, patients demonstrated lower FA in the right orbital frontal white matter and higher ADC bilaterally in the subgenual white matter compared with the control volunteers. Regions of lower FA and higher ADC were also observed in nonhypothesized regions in patients compared

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Reduced white matter integrity is observed in bipolar disorder (BD), and is associated with cardiovascular risk in adults. This topic is underexplored in youth, and in BD, where novel microvascular measures may help to inform understanding of the vascular-brain connection. We therefore examined the association of retinal vascular caliber with white matter integrity in a cross-sectional sample of adolescents with and without BD.
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Arteriolar caliber was elevated in adolescents with BD relative to controls (F(1,79) = 6.15, p = 0.02, η²_p = 0.07). In the overall sample, higher venular caliber was significantly associated with lower corpus callosum FA (β = −0.24, p_uncorrected = 0.04). In voxel-wise analyses, higher arteriolar caliber was significantly associated with lower corpus callosum and forceps minor FA in the overall sample (β = −0.46, p = 0.03). A significant diagnosis-by-venular caliber interaction on FA was noted in 5 clusters including the right retrolenticular internal capsule (β = 0.72, p = 0.03), corticospinal tract (β = 0.72, p = 0.04), and anterior corona radiata (β = 0.63, p = 0.04). In each instance, venular caliber was more positively associated with FA in BD vs. controls.
Retinal microvascular measures are associated with white matter integrity in BD, particularly in the corpus callosum. This study was proof-of-concept, designed to guide future studies focused on the vascular-brain interface in BD.
Neuroimaging alterations associated with medication use in early-onset bipolar disorder: An updated review
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Pediatric bipolar disorder (PBD) is a severe disorder characterized by mood fluctuations starting at a young age. Several neuroimaging studies revealed a specific biological signature of PBD involving alterations in the amygdala and prefrontal regions. Considering the growing concerns regarding the effects of PBD treatments on developing brains, this review aims to provide an overview of the studies investigating the effect of mood stabilizers, antipsychotics, and anticonvulsants on neuroimaging findings in PBD.
We searched PubMed, Scopus, and Web of Science to identify all structural magnetic resonance imaging (sMRI), functional magnetic resonance imaging (fMRI), and diffusion tensor imaging (DTI) studies exploring the effects of medications on neuroimaging findings in PBD. A total of 18 studies met our inclusion criteria (fMRI n = 11, sMRI n = 6, DTI n = 1).
Although the findings varied highly across the studies, some investigations consistently indicated that medications primarily affect the prefrontal cortex and the amygdala. Moreover, despite some exceptions, the reported medication effects predominantly lean towards structural and functional normalization.
The reviewed studies differ in methods, medications, and fMRI paradigms. Furthermore, most studies used observational approaches with small sample sizes, minimizing the statistical power.
Evidence suggests the potential of antipsychotics and mood stabilizers to modulate the neuroimaging findings in PBD patients, mostly normalizing brain structure and function in key mood-regulating regions.
Is Structural Connectivity Different in Child and Adolescent Relatives of Patients with Bipolar Disorder? A Narrative Review According to Studies with DTI
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El trastorno afectivo bipolar (TAB) se ha asociado con una disminución de la integridad de la sustancia blanca. Los estudios con imágenes con tensor de difusión (DTI) han permitido elucidar con una mayor calidad estos cambios. Debido a la gran heredabilidad del TAB, se han realizado estudios en familiares de pacientes con TAB acerca de la integridad de la sustancia blanca, y se ha encontrado que la conectividad estructural también puede estar afectada. Dicha alteración se ha propuesto como un potencial biomarcador de vulnerabilidad a este trastorno. Sin embargo, los estudios en niños y adolescentes son pocos.
Revisar la literatura sobre los cambios en la integridad de la sustancia blanca determinados mediante DTI en niños y adolescentes con alto riesgo.
Se describe la conectividad estructural cerebral en la población pediátrica en estudios que utilizaron DTI. Se describen los cambios en el proceso de mielinización desde su evolución dentro del neurodesarrollo normal hasta los hallazgos en la anisotropía fraccional (AF) en pacientes con TAB y los familiares en alto riesgo.
Los estudios demuestran que tanto pacientes con TAB como sus familiares en riesgo presentan disminución de la AF en regiones cerebrales específicas. Los estudios en niños y adolescentes con riesgo familiar de TAB señalan una AF reducida en tractos axonales implicados en funciones emocionales y cognitivas. La disminución de la AF puede considerarse como un biomarcador de vulnerabilidad al TAB.
Bipolar disorder (BD) has been associated with a decrease in white matter integrity. Diffusion tensor imaging (DTI) studies have enabled these changes to be elucidated with higher quality. Due to BD's high heritability, some studies have been conducted in relatives of BD patients looking at white matter integrity, and have found that structural connectivity may also be affected. This alteration has been proposed as a potential BD biomarker of vulnerability. However, there are few studies in children and adolescents.
To conduct a review of the literature on changes in white matter integrity determined by DTI in high-risk children and adolescents.
Brain structural connectivity in the paediatric population is described in studies using DTI. Changes in the myelination process from its evolution within normal neurodevelopment to the findings in fractional anisotropy (FA) in BD patients and their high-risk relatives are also described.
Studies show that both BD patients and their at-risk relatives present a decrease in FA in specific brain regions. Studies in children and adolescents with a high risk of BD, indicate a reduced FA in axonal tracts involved in emotional and cognitive functions. Decreased FA can be considered as a vulnerability biomarker for BD.
Structural brain imaging in early-onset psychosis
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We present brain structure findings in adolescents with early-onset psychosis (EOP) using magnetic resonance imaging (MRI). After brief descriptions of central MRI methods, we review findings on subcortical and cortical brain morphology, and white matter microstructure, and their relationship to clinical measures and antipsychotic medication use. The subcortical volumetric profile in EOP is similar to adults with psychotic disorders, except for smaller intracranial volumes, suggesting a greater neurodevelopmental influence in youth. Larger basal ganglia volume may be ascribed to antipsychotic medication use. The cortical brain abnormalities largely overlap with findings in adults with psychosis, particularly involving cortical thinning in prefrontal and superior temporal cortices. Diffusion tensor imaging studies find lower regional fractional anisotropy, but with unclear regional specificity. Attempts to associate brain structural changes to clinical measures have shown limited success. We discuss possibilities for future discoveries, highlighting the need for large collaborative and longitudinal studies, and new methods application.
White Matter Abnormalities in Late Onset First Episode Mania: A Diffusion Tensor Imaging Study
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A first manic episode after 50 years of age is uncommon. Late Onset Mania might be indicative of abnormalities in white matter, probably related to vascular, degenerative, or inflammatory processes.
To determine if patients with late onset mania have reduced white matter integrity according to Magnetic Resonance Diffusion Tensor Imaging (DTI) and structural MRI.
Twenty-two patients with late onset mania (>50 years old) and 22 age-paired healthy subjects were included in the study. Fractional anisotropy (FA) was used as a quantitative measure of white matter integrity. Fazekas scale was assessed also to measure white matter abnormalities in the FLAIR sequence. The Frontal Assessment Battery, COGNISTAT and Trail making test A and B were used as cognitive measurements.
According to DTI, commissural connections (left corpus callosum), and limbic connections (right and left uncinate fasciculus) were different between the patients and the comparison group. Fractional anisotropy values in the left corpus callosum showed significant correlations with neuropsychological measures, and with the Fazekas scale score. According to Fazekas scale, a pathological score in the FLAIR sequence was significantly more frequent in the patients as compared to the comparison group.
Patients with first episode mania in late life have relevant white matter abnormalities not explained by age, affecting interhemispheric and fronto-limbic networks probably related to executive functioning and emotional processing, at the level of the corpus callosum and the uncinate fasciculus. The etiology of this white matter loss of integrity in patients with late-onset mania is yet to be explored.
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Citation Excerpt :
In TDC youth, FA in the corpus callosum and superior corona radiata was found to correlate with CF as assessed with Stroop or Stroop-like tasks (Seghete et al., 2013; Treit et al., 2014). Interestingly, DTI studies have shown that BD youths have decreased FA compared to TDC in areas associated with attention and cognitive control, including the anterior corona radiata (Lagopoulos et al., 2013; Pavuluri et al., 2009) and WM areas adjacent to the cingulate cortex (Frazier et al., 2007; Gao et al., 2013; Gonenc et al., 2010) and prefrontal and orbitofrontal cortices (Kafantaris et al., 2009; Adler et al., 2006). BD youths also have decreased FA, compared to TDCs, in the corpus collosum, a tract essential for facilitating interhemispheric communication (Barnea-Goraly et al., 2009; James et al., 2011; Lagopoulos et al., 2013; Saxena et al., 2012).
Prior studies using behavioral tasks and neuroimaging have shown that children and adolescents with bipolar disorder (BD) have deficits in cognitive flexibility (CF)—defined as adaptation to changing rewards and punishments. However, no study, to our knowledge, has examined the white matter microstructural correlates of CF in youth with BD. To address this gap, we examined the relationship between CF assessed with the Cambridge Neuropsychological Testing Automated Battery (CANTAB)’s Intra-Extra Dimensional Set Shift task (ID/ED) and diffusion tensor imaging analyzed with FSL's preprocessing tools and Tract-Based Spatial Statistics (TBSS). We found a significantly different relationship between microstructural integrity of multiple white matter regions and CF performance in BD (n=28) and age-matched typically developing control (TDC) youths (n=26). Evaluation of the slopes of linear regressions in BD vs. TDC (ID/ED Simple Reversal error rate vs. fractional anisotropy) revealed significantly different slopes across the groups, indicating an aberrant relationship between CF and underlying white matter microstructure in youth with BD. These results underscore the importance of examining specific CF-neuroimaging relationships in BD youth. Future longitudinal studies could seek to define the white matter microstructural trajectories in BD vs. TDC, and relative to CF deficits and BD illness course.

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This work was supported by grants from the National Institute of Mental Health to Dr. Kafantaris (R03 MH064554 and R01 MH60845), Dr. Lencz (K01 MH65580), Dr. Szeszko (K01 MH01990), and the Feinstein Research Institute of the North Shore—Long Island Jewish Health System General Clinical Research Center (M01 RR018535).

Preliminary findings from this study were presented at the Sixth International Conference on Bipolar Disorder, Pittsburgh, PA, June 2005.

The authors thank Joshua Vogel, B.A., Kelly Dillon, B.A., Alison Berest, B.S., Ellen Leigh, Ph.D., and Kim Gallelli, Ph.D., for support in subject recruitment, assessment, and image processing.

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Lower Orbital Frontal White Matter Integrity in Adolescents With Bipolar I Disorder

Abstract

Objective

Method

Results

Conclusions

Section snippets

Subjects

Results

Discussion

Biol Psychiatry

Biol Psychiatry

Lancet

Schizophr Res

Biol Psychiatry

Neuroimage

Neuroimage

Biol Psychiatry

J Am Acad Child Adolesc Psychiatry

J Neurosci Methods

Biol Psychiatry

Eur Psychiatry

Biol Psychiatry

Basal ganglia volumes and white matter hyperintensities in patients with bipolar disorder

Am J Psychiatry

White matter hyperintensities in subjects with bipolar disorder

Psychiatry Clin Neurosci

Introduction to diffusion tensor imaging mathematics. Part I. Tensors, rotations, and eigenvectors

Concepts Magn Reson

Structural magnetic resonance imaging of the adolescent brain

Ann N Y Acad Sci

Evidence for disruption in prefrontal cortical functions in juvenile bipolar disorder

Bipolar Disord

White matter abnormalities observed in bipolar disorder: a diffusion tensor imaging study

Bipolar Disord

Abnormal white matter tracts in bipolar disorder: a diffusion tensor imaging study

Bipolar Disorders

Evidence of white matter pathology in bipolar disorder adolescents experiencing their first episode of mania: a diffusion tensor imaging study

Am J Psychiatry

Cortical white matter microstructural abnormalities in bipolar disorder

Neuropsychopharmacol

A simplified method to measure the diffusion tensor from seven MR images

Magn Reson Med

White matter abnormalities in obsessive-compulsive disorder: a diffusion tensor imaging study

Arch Gen Psychiatry

A fully automatic multimodality image registration algorithm

J Comput Assist Tomogr

Manual for Administration of Neuropsychological Test Batteries for Adults and Children