Translational psychiatry
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Translational psychiatry · Jan 2014
Too hard to control: compromised pain anticipation and modulation in mild traumatic brain injury.
Mild traumatic brain injury (MTBI) is a vulnerability factor for the development of pain-related conditions above and beyond those related to comorbid traumatic and emotional symptoms. We acquired functional magnetic resonance imaging (fMRI) on a validated pain anticipation task and tested the hypotheses that individuals with a reported history of MTBI, compared with healthy comparison subjects, would show increased brain response to pain anticipation and ineffective pain modulation after controlling for psychiatric symptoms. Eighteen male subjects with a reported history of blast-related MTBI related to combat, and eighteen healthy male subjects with no reported history of MTBI (healthy controls) underwent fMRI during an event-related experimental pain paradigm with cued high or low intensity painful heat stimuli. ⋯ Our results suggest that a potentially disrupted neurocognitive anticipatory network may result from damage to the endogenous pain modulatory system and underlie difficulties with regulatory pain processing following MTBI. In other words, our findings are consistent with a notion that brain injury makes it more difficult to control acute pain. Understanding these mechanisms of dysfunctional acute pain processing following MTBI may help shed light on the underlying causes of increased vulnerability for the development of pain-related conditions in this population.
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Translational psychiatry · Jan 2014
Hippocampal and behavioral dysfunctions in a mouse model of environmental stress: normalization by agomelatine.
Stress-induced alterations in neuronal plasticity and in hippocampal functions have been suggested to be involved in the development of mood disorders. In this context, we investigated in the hippocampus the activation of intracellular signaling cascades, the expression of epigenetic markers and plasticity-related genes in a mouse model of stress-induced hyperactivity and of mixed affective disorders. We also determined whether the antidepressant drug agomelatine, a MT1/MT2 melatonergic receptor agonist/5-HT2C receptor antagonist, could prevent some neurobiological and behavioral alterations produced by stress. ⋯ Decreased hippocampal level of the repressive epigenetic marks HDAC2 and H3K9me2, as well as increased level of the permissive mark H3K9/14ac suggested that chronic mild stress was associated with increased gene transcription, and clear-cut evidence was further indicated by changes in neuroplasticity-related genes, including Arc, Bcl2, Bdnf, Gdnf, Igf1 and Neurod1. Together with other findings, the present data suggest that chronic ultra-mild stress can model the hyperactivity or psychomotor agitation, as well as the mixed affective behaviors often observed during the manic state of bipolar disorder patients. Interestingly, agomelatine could normalize both the behavioral and the molecular alterations induced by stress, providing further insights into the mechanism of action of this new generation antidepressant drug.
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Translational psychiatry · Jan 2014
Women with the Alzheimer's risk marker ApoE4 lose Aβ-specific CD4⁺ T cells 10-20 years before men.
Adaptive immunity to self-antigens causes autoimmune disorders, such as multiple sclerosis, psoriasis and type 1 diabetes; paradoxically, T- and B-cell responses to amyloid-β (Aβ) reduce Alzheimer's disease (AD)-associated pathology and cognitive impairment in mouse models of the disease. The manipulation of adaptive immunity has been a promising therapeutic approach for the treatment of AD, although vaccine and anti-Aβ antibody approaches have proven difficult in patients, thus far. CD4(+) T cells have a central role in regulating adaptive immune responses to antigens, and Aβ-specific CD4(+) T cells have been shown to reduce AD pathology in mouse models. ⋯ Notably, women who carried the AD risk marker apolipoproteinE-ɛ4 (ApoE4) showed the earliest decline, with a precipitous drop between 45 and 52 years, when menopause typically begins. Aβ-CD4see requires a standard blood draw and provides a minimally invasive approach for assessing changes in Aβ biology that may reveal AD-related changes in physiology by a decade. Furthermore, CD4see probes can be modified to target any peptide, providing a powerful new tool to isolate antigen-specific CD4(+) T cells from human subjects.
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Translational psychiatry · Jan 2014
Comparative StudyCodeine-induced hyperalgesia and allodynia: investigating the role of glial activation.
Chronic morphine therapy has been associated with paradoxically increased pain. Codeine is a widely used opioid, which is metabolized to morphine to elicit analgesia. Prolonged morphine exposure exacerbates pain by activating the innate immune toll-like receptor-4 (TLR4) in the central nervous system. ⋯ This highlights the potential non-opioid receptor-dependent nature of codeine-enhanced pain sensitivity-although the involvement of other codeine metabolites cannot be ruled out. IL-1RA reversed codeine-induced hyperalgesia (P<0.001) and allodynia (P<0.001), and TLR4 knock-out protected against codeine-induced changes in pain sensitivity. Glial attenuation with ibudilast reversed codeine-induced allodynia (P<0.001), and thus could be investigated further as potential treatment for codeine-induced pain enhancement.
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Translational psychiatry · Jan 2014
Multicenter StudyQuantitative proteomics of delirium cerebrospinal fluid.
Delirium is a common cause and complication of hospitalization in older people, being associated with higher risk of future dementia and progression of existing dementia. However relatively little data are available on which biochemical pathways are dysregulated in the brain during delirium episodes, whether there are protein expression changes common among delirium subjects and whether there are any changes which correlate with the severity of delirium. We now present the first proteomic analysis of delirium cerebrospinal fluid (CSF), and one of few studies exploring protein expression changes in delirium. ⋯ These data not only provide confirmatory evidence that the inflammatory response is a component of delirium, but also reveal dysregulation of protein expression in a number of novel and unexpected clusters of proteins, in particular the granins. Another surprising outcome of this work is the level of similarity of CSF protein profiles in delirium patients, given the diversity of causes of this syndrome. These data provide additional elements for consideration in the pathophysiology of delirium as well as potential biomarker candidates for delirium diagnosis.