Emerging biosignature of brain function and intervention in pediatric bipolar disorder.
ABSTRACT 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.
SourceAvailable from: Mani N Pavuluri[Show abstract] [Hide abstract]
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.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 01/2015; 40(1):249-51. DOI:10.1038/npp.2014.229 · 7.83 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Pediatric bipolar disorder is a severe mental illness whose pathophysiology is poorly understood and for which there is an urgent need for improved diagnosis and treatment. MR spectroscopy is a neuroimaging method capable of in vivo measurement of neurochemicals relevant to bipolar disorder neurobiology. MR spectroscopy studies of adult bipolar disorder provide consistent evidence for alterations in the glutamate system and mitochondrial function. In bipolar disorder, these 2 phenomena may be linked because 85% of glucose in the brain is consumed by glutamatergic neurotransmission and the conversion of glutamate to glutamine. The purpose of this article is to review the MR spectroscopic imaging literature in pediatric bipolar disorder, at-risk samples, and severe mood dysregulation, with a focus on the published findings that are relevant to glutamatergic and mitochondrial functioning. Potential directions for future MR spectroscopy studies of the glutamate system and mitochondrial dysfunction in pediatric bipolar disorder are discussed.American Journal of Neuroradiology 02/2014; DOI:10.3174/ajnr.A3844 · 3.68 Impact Factor