Limbic changes identified by imaging in bipolar patients

Department of Psychiatry, University of North Carolina Center of Excellence for Research and Treatment of Bipolar Disorders, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7160, USA.
Current Psychiatry Reports (Impact Factor: 3.24). 12/2009; 10(6):505-9. DOI: 10.1007/s11920-008-0080-8
Source: PubMed


The hippocampus and amygdala are key limbic regions for memory formation and emotion modulation that are potentially involved in the cognitive and affective symptoms of bipolar disorder. Here we discuss the most consistent MRI literature in bipolar disorder, focusing on the role of the hippocampus and amygdala. In child and adolescent patients, a unique pattern of abnormalities has begun to emerge, with volume deficits in the hippocampus and amygdala already detectable early in the illness course. In adults, it is unclear whether hippocampal volumes are abnormal, whereas the amygdala is reported to be larger and hyperactive to external emotional stimuli. However, available findings are often conflicting, and most studies suffer from limitations. Future longitudinal magnetic resonance studies should focus on juvenile patients; first-episode, drug-free patients; and unaffected family members. Jointly with genetic, postmortem, and neuropsychological studies, these studies will be extremely valuable in separating state from trait brain abnormalities and further characterizing the pathophysiology of bipolar disorder.

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Available from: Paolo Brambilla, Dec 08, 2014
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    • "Further, several mood stabilizers (lithium, valproate, carbamazepine, and lamotrigine) are known to modulate adult neurogenesis in dentate gyrus [11,123], highlighting a putative therapeutic mechanism for these medications. Although few direct links between BD and neurogenesis have been reported, decreased hippocampal volume and altered hippocampal function do occur in BD [5,124] and could result, at least in part, from decreased neurogenesis. "
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    ABSTRACT: Bipolar disorder (BD) is a multi-factorial disorder caused by genetic and environmental influences. It has a large genetic component, with heritability estimated between 59-93%. Recent genome-wide association studies (GWAS) using large BD patient populations have identified a number of genes with strong statistical evidence for association with susceptibility for BD. Among the most significant and replicated genes is ankyrin 3 (ANK3), a large gene that encodes multiple isoforms of the ankyrin G protein. This article reviews the current evidence for genetic association of ANK3 with BD, followed by a comprehensive overview of the known biology of the ankyrin G protein, focusing on its neural functions and their potential relevance to BD. Ankyrin G is a scaffold protein that is known to have many essential functions in the brain, although the mechanism by which it contributes to BD is unknown. These functions include organizational roles for subcellular domains in neurons including the axon initial segment and nodes of Ranvier, through which ankyrin G orchestrates the localization of key ion channels and GABAergic presynaptic terminals, as well as creating a diffusion barrier that limits transport into the axon and helps define axo-dendritic polarity. Ankyrin G is postulated to have similar structural and organizational roles at synaptic terminals. Finally, ankyrin G is implicated in both neurogenesis and neuroprotection. ANK3 and other BD risk genes participate in some of the same biological pathways and neural processes that highlight several mechanisms by which they may contribute to BD pathophysiology. Biological investigation in cellular and animal model systems will be critical for elucidating the mechanism through which ANK3 confers risk of BD. This knowledge is expected to lead to a better understanding of the brain abnormalities contributing to BD symptoms, and to potentially identify new targets for treatment and intervention approaches.
    Biology of Mood and Anxiety Disorders 10/2012; 2(1):18. DOI:10.1186/2045-5380-2-18
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    • "Greater neuroplasticity is likely inherent with higher vulnerability to environmental and internal insults. In line with this notion, cellular defi cits and structural changes in the associative cortical and limbic areas are associated with some neurological or neuropsychiatric disorders (e.g., mode disorders, schizophrenia, epilepsy , Alzheimer's disease) in the adolescent, adult and aged human populations (Arendt, 2005; Di Cristo, 2007; Brambilla et al., 2008; Pavuluri and Passarotti, 2008; Siebzehnrubl and Blumcke, 2008). "
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    ABSTRACT: A novel population of cells that express typical immature neuronal markers including doublecortin (DCX+) has been recently identified throughout the adult cerebral cortex of relatively large mammals (guinea pig, rabbit, cat, monkey and human). These cells are more common in the associative relative to primary cortical areas and appear to develop into interneurons including type II nitrinergic neurons. Here we further describe these cells in the cerebral cortex and amygdala, in comparison with DCX+ cells in the hippocampal dentate gyrus, in three age groups of rhesus monkeys: young adult (12.3 +/- 0.2 years, n = 3), mid-age (21.2 +/- 1.9 years, n = 3) and aged (31.3 +/- 1.8 years, n = 4). DCX+ cells with a heterogeneous morphology persisted in layers II/III primarily over the associative cortex and amygdala in all groups (including in two old animals with cerebral amyloid pathology), showing a parallel decline in cell density with age across regions. In contrast to the cortex and amygdala, DCX+ cells in the subgranular zone diminished in the mid-age and aged groups. DCX+ cortical cells might arrange as long tangential migratory chains in the mid-age and aged animals, with apparently distorted cell clusters seen in the aged group. Cortical DCX+ cells colocalized commonly with polysialylated neural cell adhesion molecule and partially with neuron-specific nuclear protein and gamma-aminobutyric acid, suggesting a potential differentiation of these cells into interneuron phenotype. These data suggest a life-long role for immature interneuron-like cells in the associative cerebral cortex and amygdala in nonhuman primates.
    Frontiers in Neuroanatomy 10/2009; 3:17. DOI:10.3389/neuro.05.017.2009 · 3.54 Impact Factor
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    ABSTRACT: AbstractIn this thesis we have studied genetic elements potentially contributing to the pathophysiology of psychiatric disorders, focusing on different sources of human genome variability, including SNPs and CNVs, which can affect not only coding genes but also RNA regulatory elements, such as miRNAs. First, we have interrogated different candidate genes for psychiatric disorders overlapping with known CNVs, finding 14 different genes variable in copy number in psychiatric disorders but not in control individuals. Then, narrowing the analysis on mood disorders, we explored GSK3β gene considering both SNPs and a partially overlapping CNV. The GSK3β promoter and intron 1 region was found significantly associated with an earlier onset of the major depressive disorder. Finally, we have found evidence possibly pointing to a precise post-transcriptional regulation of circadian rhythms by miRNAs in mood disorder patients. Concretely, a variant in the precursor form of miR-182 could play an important role in fine-tuning its target sites involved in the control of sleep/wake cycles. Overall, we have provided evidence of different types of genome variation on neuronal genes or miRNA regulatory regions that can potentially contribute to the development of psychiatric disorders.ResumEn aquesta tesi hem estudiat elements genètics que podrien contribuir potencialment en la fisiopatologia dels trastorns psiquiàtrics, centrant-nos en diferents fonts de variabilitat genòmica humana, incloent els SNPs i els CNVs, els quals poden afectar no només a gens codificants sinó també a elements reguladors, com els miRNAs. Primer, vam interrogar diferents gens candidats per trastorns psiquiàtrics solapats amb CNVs coneguts, trobant que 14 gens eren variables en el número de còpia en pacients però no en individus controls. Després, restringint lanàlisi a trastorns afectius, vam explorar el gen GSK3β considerant SNPs així com també un CNV que se solapa parcialment amb el gen. Vam trobar la regió del promotor i de lintró 1 del gen GSK3β associada de manera significativa amb una inferior edat dinici del trastorn de depressió major. Finalment, hem trobat evidències que possiblement indiquen una precisa regulació post-transcriptional dels ritmes circadians per miRNAs en pacients amb trastorns afectius. Concretament, una variant en la forma precursora del miR-182 podria jugar un paper important en la fina regulació dels seus gens diana implicats en el control dels cicles de son i vigília. En general, hem aportat evidències de què diferents tipus de variació genòmica en gens neuronals o regions reguladores com els miRNAs podrien contribuir potencialment en el desenvolupament de trastorns psiquiàtrics.
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