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Neuropathological and neuromorphometric abnormalities in bipolar disorder: View from the medial prefrontal cortical network
Abstract
The question of whether BD is primarily a developmental disorder or a progressive, neurodegenerative disorder remains unresolved. Here, we review the morphometric postmortem and neuroimaging literature relevant to the neuropathology of bipolar disorder (BD). We focus on the medial prefrontal cortex (mPFC) network, a key system in the regulation of emotional, behavioral, endocrine, and innate immunological responses to stress. We draw four main conclusions: the mPFC is characterized by (1) a decrease in volume, (2) reductions in neuronal size, and/or changes in neuronal density, (3) reductions in glial cell density, and (4) changes in gene expression. These data suggest the presence of dendritic atrophy of neurons and the loss of oligodendroglial cells in BD, although some data additionally suggest a reduction in the cell counts of specific subpopulations of GABAergic interneurons. Based on the weight of the postmortem and neuroimaging literature discussed herein, we favor a complex hypothesis that BD primarily constitutes a developmental disorder, but that additional, progressive, histopathological processes also are associated with recurrent or chronic illness. Conceivably BD may be best conceptualized as a progressive neurodevelopmental disorder.
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“There is evidence of vmPFC gray matter loss in mood disorders7,115,116, which implies dendritic atrophy.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [116]
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A magnetic resonance imaging study of mood stabilizer‐ and neuroleptic‐naïve first‐episode mania
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Brooks, J. O., Bonner, J. C., Rosen, A. C., Wang, P. W., Hoblyn, J. C., Hill, S. J., & Ketter, T. A. (2009) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2008.06.007 · Cited by 57
Mirakhur, A., Moorhead, T. W. J., Stanfield, A. C., McKirdy, J. W., Sussmann, J. E., Hall, J., Lawrie, S. M., Johnstone, E. C., & McIntosh, A. M. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.12.006 · Cited by 55
Hájek, T., Calkin, C., Blagdon, R. A., Slaney, C., & Alda, M. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.11.007 · Cited by 55
Neurocognitive features in subgroups of bipolar disorder
Aminoff, S. R., Hellvin, T., Lagerberg, T. V., Berg, A. O., Andreassen, O. A., & Melle, I. S. (2013) · Bipolar Disorders · doi:10.1111/bdi.12061 · Cited by 55
Elevated GRIA1 mRNA expression in Layer II/III and V pyramidal cells of the DLPFC in schizophrenia
O’Connor, J. A., & Hemby, S. E. (2007) · Schizophrenia Research · doi:10.1016/j.schres.2007.09.022 · Cited by 55
Heart rate variability during motor and cognitive tasks in females with major depressive disorder
Nugent, A. C., Bain, E. E., Thayer, J. F., Sollers, J. J., & Drevets, W. C. (2011) · Psychiatry Research: Neuroimaging · doi:10.1016/j.pscychresns.2010.08.013 · Cited by 54
Self-citationChan, W., Yang, G., Chia, M., Woon, P., Lee, J., Keefe, R. S. E., Sitoh, Y., Nowinski, W. L., & Sim, K. (2010) · Bipolar Disorders · doi:10.1111/j.1399-5618.2010.00829.x · Cited by 54
Woo, T.-U. W., Shrestha, K., Lamb, D., Minns, M., & Benes, F. M. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.04.034 · Cited by 54
Bond, D. J., Ha, T. H., Lang, D. J., Su, W., Torres, I. J., Honer, W. G., Lam, R. W. M., & Yatham, L. N. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.08.030 · Cited by 54
Evidence for disruption in prefrontal cortical functions in juvenile bipolar disorder
Bearden, C. E., Glahn, D. C., Caetano, S. C., Olvera, R. L., Fonseca, M., Najt, P., Hunter, K., Pliszka, S. R., & Soares, J. C. (2007) · Bipolar Disorders · doi:10.1111/j.1399-5618.2007.00453.x · Cited by 52
Vagal nerve activity as a moderator of brain-immune relationships
Ohira, H., Matsunaga, M., Osumi, T., Fukuyama, S., Shinoda, J., Yamada, J., & Gidron, Y. (2013) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2013.04.011 · Cited by 47
Olvet, D. M., Burdick, K. E., & Cornblatt, B. A. (2012) · Cognitive Neuropsychiatry · doi:10.1080/13546805.2012.724193 · Cited by 40
Mosebach, J., Keilhoff, G., Gos, T., Schiltz, K., Schoeneck, L., Dobrowolny, H., Mawrin, C., Müller, S., Schroeter, M. L., Bernstein, H., et al. (2013) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2013.03.018 · Cited by 40
Pre- and perinatal hypoxia associated with hippocampus/amygdala volume in bipolar disorder
Haukvik, U. K., McNeil, T. F., Lange, E. H., Melle, I. S., Dale, A. M., Andreassen, O. A., & Agartz, I. (2013) · Psychological Medicine · doi:10.1017/s0033291713001529 · Cited by 39
Flagged first, then by citations
3 of the 211 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Stress weakens prefrontal networks: molecular insults to higher cognition
Arnsten, A. F. T. (2015) · Nature Neuroscience · doi:10.1038/nn.4087 · Cited by 752
The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders
Réus, G. Z., Fries, G. R., Stertz, L., Badawy, M., Passos, I. C., Barichello, T., Kapczinski, F., & Quevedo, J. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.05.018 · Cited by 594
Steullet, P., Cabungcal, J.-H., Coyle, J., Didriksen, M., Gill, K., Grace, A. A., Hensch, T. K., LaMantia, A.-S., Lindemann, L., Maynard, T. M., et al. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.47 · Cited by 360
The Emerging Neurobiology of Bipolar Disorder
Harrison, P. J., Geddes, J. R., & Tunbridge, E. M. (2017) · Trends in Neurosciences · doi:10.1016/j.tins.2017.10.006 · Cited by 246
Cotrena, C., Branco, L. D., Shansis, F. M., & Fonseca, R. P. (2016) · Journal of Affective Disorders · doi:10.1016/j.jad.2015.11.007 · Cited by 227
Metadata
- Authors
- Savitz, J. B., Price, J. L., & Drevets, W. C.
- Affiliations
- Laureate Institute for Brain Research (US)
- Washington University in St. Louis (US)
- Corresponding author
- Savitz, Jonathan B.
- Venue
- Neuroscience & Biobehavioral Reviews
- Publisher
- Elsevier BV
- Published
- 2014-05
- Volume
- 42
- Pages
- 132-147
- ISSN
- 0149-7634 (ISSN-L)
- OpenAlex
- W1968616230
- Cited by
- 145
- References
- 211
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 4 · 2023: 3 · 2022: 9 · 2021: 29 · 2020: 11 · 2019: 9 · 2018: 8 · 2017: 13 · 2016: 18 · 2015: 21 · 2014: 6
- FWCI
- 2.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience & Biobehavioral Reviews (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Keywords
- bipolar disorder, medial prefrontal cortex, neuropathology, neurodevelopmental disorders, neurodegeneration, neuron size, glial cell density, dendritic atrophy, GABAergic interneurons, gene expression, stress response, chronic disease
- MeSH terms
- Animals, Bipolar Disorder, Humans, Neural Pathways, Neuroglia, Neurons, Prefrontal Cortex
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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