Emerging biosignature of brain function and intervention in pediatric bipolar disorder

Pediatric Brain Research and Intervention Center, University of Illinois at Chicago, Chicago, IL 60608, USA.
Minerva pediatrica (Impact Factor: 0.43). 06/2011; 63(3):183-200.
Source: PubMed


Pediatric bipolar disorder (PBD) is a complex illness with a chronic course, requiring multiple medications over the longitudinal course of illness, with limited recovery and high relapse rate. Beyond the placebo controlled trials of monotherapy, there is an increased need to understand how each medication influences regions of affective and cognitive circuitry function by normalization or deployment of alternative circuitry regions. Functional studies are beginning to unravel the improved function in the fronto-limbic and fronto-temporal affective circuitry, and based on the paradigm administered, also in the interfacing cognitive fronto-striato-temporo-parietal regions. Treatment studies illustrated a pattern of improvement in functional activity consistently among the affective ventrolateral and medial prefrontal regions, and variably in the cognitive dorsolateral prefrontal cortex. While there is decreased activity in amygdala with treatment for mania or depression among patients with PBD, there appears to be residual increased amygdala activity regardless of response, relative to healthy controls, suggesting a trait-like abnormality. Parallel biochemical abnormalities in magnetic resonance spectroscopic studies and fronto-limbic activity in magnetic resonance imaging studies of brain function at baseline provide maiden data on predicting outcome. This preliminary cohort of studies that probed the hypothesized circuitries underlying specific symptom constructs, coupled with futuristic paradigms and analytic methods, serve as a guidepost to generate the next generation of studies and build on the emerging biosignature towards specific treatment targets for personalized medicine in PBD.

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    • "We followed participants over a 3-year developmental period when the patients received systematic pharmacotherapy for optimal recovery. Based on the leads from conventional fMRI (Mayanil et al., 2011; Pavuluri et al., 2011), patients are predicted to show normalization, relative to HC, in cortico-subcortical fMRI activity. Alternatively, PBD patients might show partial recovery among these circuits with residual impairment. "
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    ABSTRACT: Time course of recovery showing initial prefrontal cortex changes at 16 weeks, extending to subcortical changes by 3 years in pediatric bipolar disorder: Pediatric bipolar disorder Functional magnetic resonance imaging (fMRI) Emotion Treatment effects a b s t r a c t Objective: Activation changes at the interface of affective and cognitive systems are examined over a 3 year period in pediatric bipolar disorder (PBD). Methods: Thirteen participants with PBD and 10 healthy controls (HC) matched on demographics and IQ were scanned at baseline, at 16 weeks, and after 3 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. Results: At baseline, in response to emotional vs. neutral words, patients with PBD showed greater activation than HC in the right dorsal lateral prefrontal cortex (DLPFC) and amygdala, ventral lateral prefrontal cortex (VLPFC), bilateral anterior cingulate cortex (ACC), and ventral striatum. Increased activation in DLPFC in the PBD group normalized by 16 weeks. By 3 years, normalization was observed in VLPFC, ACC, amygdala, and striatum. Limitations: Small sample size renders the present findings preliminary. Conclusions: Greater activation in fronto-striatal and fronto-limbic circuits were observed in unmedi-cated patients with PBD. Present findings suggest the possibility that DLPFC is most malleable to pharmacological intervention with systematic pharmacotherapy leading to immediate response, which extended to amygdalostriatal and ventral cortical regions at 3 years. The seminal observation from this study is the prolonged length of recovery time in the normalization of subcortical activity along with their interfacing cortical regions. Findings from this proof of concept study need to be replicated in a larger sample. & 2013 Elsevier B.V. All rights reserved.
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    • "For example, although mood stabilizers and antipsychotic medications can be effective, response rates to these drugs are quite poor (Kowatch and Delbello, 2005; Pavuluri et al., 2009a). Therefore, there is an urgent need to better understand the neural mechanisms underlying treatment response and to determine what factors might predict medication responsiveness (Mayanil et al., 2011; Passarotti and Pavuluri, 2011). Mechanistic models of drug impact on brain function in PBD are providing promising preliminary findings to discover such predictive biomarkers. "
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    ABSTRACT: The aim of this study was to determine functional connectivity among patients with pediatric bipolar disorder (PBD) who are responders to pharmacotherapy and those who are nonresponders, and learn how they differ from healthy controls (HC) while performing a task that engages affective and cognitive neural systems. PBD participants (n = 34; 13.4 ± 2.3 years) were defined as responders if there was ≥ 50% improvement in Young Mania Rating Scale (YMRS) scores (n = 22) versus nonresponders with < 50% improvement (n = 12) with one of three mood stabilizing medications (divalproex, risperidone, or lamotrigine). HC (n = 14; 14.2 ± 3.1 years) participants also were scanned at baseline and follow-up. During functional magnetic resonance imaging, participants performed a color-matching task in which they had to match the color of positive, negative, or neutral words with colored dots. Independent component analysis was used to identify functionally connected networks across the whole brain, which were subsequently interrogated using region-of-interest analyses to test for group differences. A frontolimbic network was identified that showed impaired functional integration in PBD relative to HC when participants viewed negatively valenced words. PBD medication responders showed greater connectivity of the amygdala into the network before and after treatment compared with nonresponders, with responders showing a pattern more similar to HC than to nonresponders. Regardless of medication type, the degree of amygdala functional connectivity predicted medication response as well as the improvement in YMRS scores across responders and nonresponders. These findings suggest that increased functional integration of the amygdala within the frontolimbic network might be a biomarker of general mood stabilizer medication responsivity in bipolar disorder.
    Brain Connectivity 12/2011; 1(5):411-22. DOI:10.1089/brain.2011.0035
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    ABSTRACT: Recent neuroimaging studies have uncovered much about the specific neural deficits in adult bipolar disorder (ABD), but despite promising results, neuroimaging research for pediatric bipolar disorder (PBD) is still developing. The neuroimaging literature is highly heterogeneous, varying in the paradigms used and in participants' mood states and medication status. Despite this variability, several dominant patterns emerge. In response to emotional stimuli, both ABD and PBD show limbic hyperactivity coupled with hypoactivity in ventral prefrontal emotion regulation systems. This pattern occurred most robustly in response to negative incidental stimuli and was especially apparent in manic PBD. ABD showed more variability in ventral prefrontal activity, possibly due to maturational and medication factors. On numerous cognitive paradigms, PBD showed dorsal prefrontal hypoactivity linked to ventral dysfunction, whereas ABD showed compensatory frontal, parietal, and temporal activity with paradigm-specific variations. In emotion-cognition interaction paradigms, patients show dysregulation in regions interfacing between cognitive and emotional brain systems (e.g., ventral prefrontal and cingulate cortices), which expend extra effort to process emotional stimuli effectively and recruit additional posterior attention systems to cope with affective instability. In addition, novel functional connectivity techniques have uncovered connectivity deficits between frontal and limbic regions in ABD and PBD at rest and during active emotional and cognitive tasks. Finally, the neuroimaging literature currently lacks cross-sectional studies comparing PBD with ABD and longitudinal studies following children and adolescents with BD into adulthood. Such studies would provide important insights into patients' prognosis and would determine targets for early interventions in the evolving illness diathesis.
    The Israel journal of psychiatry and related sciences 07/2012; 49(2):75-83. · 0.79 Impact Factor
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