Serum levels of inflammatory cytokines, for example, tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), and IL-1 beta (IL-1β), are elevated in subjects with major depressive disorder (MDD). ...The reason why this occurs is unclear. Elevated levels of inflammatory cytokines could be a result of brain dysfunction in MDD. It is also possible that inflammatory cytokines contribute to depressive symptoms in MDD. If the first assumption is correct, one would expect levels to normalize with resolution of the depressive episode after treatment. Several studies have measured changes in cytokine levels during antidepressant treatment; however, the results vary. The purpose of this study was to pool all available data on changes in serum levels of TNFα, IL-6, and IL-1β during antidepressant treatment to determine whether these levels change. Studies were included if they used an approved pharmacological treatment for depression, patients had a diagnosis of MDD, and serum levels of TNFα, IL-6, and/or IL-1β were measured before and after treatment. Twenty-two studies fulfilled these criteria. Meta-analysis of these studies showed that, overall, while pharmacological antidepressant treatment reduced depressive symptoms, it did not reduce serum levels of TNFα. On the other hand, antidepressant treatment did reduce levels of IL-1β and possibly those of IL-6. Stratified subgroup analysis by class of antidepressant indicated that serotonin reuptake inhibitors may reduce levels of IL-6 and TNFα. Other antidepressants, while efficacious for depressive symptoms, did not appear to reduce cytokine levels. These results argue against the notion that resolution of a depressive episode is associated with normalization of levels of circulating inflammatory cytokines; however, the results are consistent with the possibility that inflammatory cytokines contribute to depressive symptoms and that antidepressants block the effects of inflammatory cytokines on the brain.
Synaptic loss and deficits in functional connectivity are hypothesized to contribute to symptoms associated with major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). The ...synaptic vesicle glycoprotein 2A (SV2A) can be used to index the number of nerve terminals, an indirect estimate of synaptic density. Here, we used positron emission tomography (PET) with the SV2A radioligand
CUCB-J to examine synaptic density in n = 26 unmedicated individuals with MDD, PTSD, or comorbid MDD/PTSD. The severity of depressive symptoms was inversely correlated with SV2A density, and individuals with high levels of depression showing lower SV2A density compared to healthy controls (n = 21). SV2A density was also associated with aberrant network function, as measured by magnetic resonance imaging (MRI) functional connectivity. This is the first in vivo evidence linking lower synaptic density to network alterations and symptoms of depression. Our findings provide further incentive to evaluate interventions that restore synaptic connections to treat depression.
The syndrome called depression may represent the common final pathway at which different aetiopathogenic processes converge. One such aetiopathogenic process is innate immune system activation. Some ...depressed patients have increased levels of inflammatory cytokines and other immunologic abnormalities. It is not known whether immune system activation contributes to the pathogenesis of depressive symptoms. Supporting this possibility is the observation that in both rodents and humans, exogenous immune stimuli such as endotoxin can produce symptoms that resemble depression. A new approach to depression research would be to use immune stimuli to elicit depressive symptoms in humans. Here we review each of the symptoms elicited in humans by endotoxin administration, and compare this model to two other immune depression paradigms: interferon-alpha treatment and typhoid vaccine administration, to assess to what degree endotoxin administration represents a valid model of immune depression. We also review corresponding behavioral changes in rodents and the potential molecular pathways through which immune system activation produces each symptom.
The discovery of ketamine as a rapid and robust antidepressant marks the beginning of a new era in the treatment of psychiatric disorders. Ketamine is thought to produce rapid and sustained ...antidepressant effects through restoration of lost synaptic connections. We investigated this hypothesis in humans for the first time using positron emission tomography (PET) and
CUCB-J-a radioligand that binds to the synaptic vesicle protein 2A (SV2A) and provides an index of axon terminal density. Overall, we did not find evidence of a measurable effect on SV2A density 24 h after a single administration of ketamine in non-human primates, healthy controls (HCs), or individuals with major depressive disorder (MDD) and/or posttraumatic stress disorder (PTSD), despite a robust reduction in symptoms. A post-hoc, exploratory analysis suggests that patients with lower SV2A density at baseline may exhibit increased SV2A density 24 h after ketamine. This increase in SV2A was associated with a reduction in depression severity, as well as an increase in dissociative symptoms. These initial findings suggest that a restoration of synaptic connections in patients with lower SV2A at baseline may underlie ketamine's therapeutic effects, however, this needs replication in a larger sample. Further work is needed to build on these initial findings and further establish the nuanced pre- and post-synaptic mechanisms underpinning ketamine's therapeutic effects.
Converging evidence suggests that major depressive disorder (MDD) affects multiple large-scale brain networks. Analyses of the correlation or covariance of regional brain structure and function ...applied to structural and functional MRI data may provide insights into systems-level organization and structure-to-function correlations in the brain in MDD. This study applied tensor-based morphometry and intrinsic connectivity distribution to identify regions of altered volume and intrinsic functional connectivity in data from unmedicated individuals with MDD (n=17) and healthy comparison participants (HC, n=20). These regions were then used as seeds for exploratory anatomical covariance and connectivity analyses. Reduction in volume in the anterior cingulate cortex (ACC) and lower structural covariance between the ACC and the cerebellum were observed in the MDD group. Additionally, individuals with MDD had significantly lower whole-brain intrinsic functional connectivity in the medial prefrontal cortex (mPFC). This mPFC region showed altered connectivity to the ventral lateral PFC (vlPFC) and local circuitry in MDD. Global connectivity in the ACC was negatively correlated with reported depressive symptomatology. The mPFC-vlPFC connectivity was positively correlated with depressive symptoms. Finally, we observed increased structure-to-function correlation in the PFC/ACC in the MDD group. Although across all analysis methods and modalities alterations in the PFC/ACC were a common finding, each modality and method detected alterations in subregions belonging to distinct large-scale brain networks. These exploratory results support the hypothesis that MDD is a systems level disorder affecting multiple brain networks located in the PFC and provide new insights into the pathophysiology of this disorder.
Altered metabotropic glutamate receptor 5 markers in PTSD Holmes, Sophie E.; Girgenti, Matthew J.; Davis, Margaret T. ...
Proceedings of the National Academy of Sciences - PNAS,
08/2017, Letnik:
114, Številka:
31
Journal Article
Recenzirano
Odprti dostop
Posttraumatic stress disorder (PTSD) is a prevalent and highly disabling disorder, but there is currently no targeted pharmacological treatment for it. Dysfunction of the glutamate system has been ...implicated in trauma and stress psychopathology, resulting in a growing interest in modulation of the glutamate system for the treatment of PTSD. Specifically, the metabotropic glutamate receptor 5 (mGluR5) represents a promising treatment target. We used 18FFPEB, a radioligand that binds to the mGluR5, and positron emission tomography (PET) to quantify in vivo mGluR5 availability in human PTSD vs. healthy control (HCs) subjects. In an independent sample of human postmortem tissue, we investigated expression of proteins that have a functional relationship with mGluR5 and glucocorticoids in PTSD. We observed significantly higher cortical mGluR5 availability in PTSD in vivo and positive correlations between mGluR5 availability and avoidance symptoms. In the postmortem sample, we observed up-regulation of SHANK1, a protein that anchors mGluR5 to the cell surface, as well as decreased expression of FKBP5, implicating aberrant glucocorticoid functioning in PTSD. Results of this study provide insight into molecular mechanisms underlying PTSD and suggest that mGluR5 may be a promising target for mechanism-based treatments aimed at mitigating this disorder.
Depression is associated with systemic inflammation, and the systemic inflammation caused by endotoxin administration elicits mild depressive symptoms such as fatigue and reduced interest. The neural ...correlates of depressive symptoms that result from systemic inflammation are poorly defined. The aim of this study was to use (18)F-FDG PET to identify brain regions involved in the response to endotoxin administration in humans.
Nine healthy subjects received double-blind endotoxin (0.8 ng/kg) and placebo on different days. (18)F-FDG PET was used to measure differences in the cerebral metabolic rate of glucose in the following regions of interest: insula, cingulate, and amygdala. Serum levels of tumor necrosis factor-α and interleukin-6 were used to gauge the systemic inflammatory response, and depressive symptoms were measured with the Montgomery-Åsberg Depression Rating Scale and other scales.
Endotoxin administration was associated with an increase in Montgomery-Åsberg Depression Rating Scale, increased fatigue, reduced social interest, increased levels of inflammatory cytokines, higher normalized glucose metabolism (NGM) in the insula, and, at a trend level, lower NGM in the cingulate. Secondary analyses of insula and cingulate subregions indicated that these changes were driven by the right anterior insula and the right anterior cingulate. There was a negative correlation between peak cytokine levels and change in social interest and between peak cytokine levels and change in insula NGM. There was a positive correlation between the change in NGM in the insula and change in social interest.
Systemic inflammation in humans causes an increase in depressive symptoms and concurrent changes in glucose metabolism in the insula and cingulate-brain regions that are involved in interoception, positive emotionality, and motivation.
Abstract Background At subanesthetic doses, ketamine, an N -methyl-D-aspartate glutamate receptor antagonist, increases glutamate release. We imaged the acute effect of ketamine on brain metabotropic ...glutamatergic receptor subtype 5 with a high-affinity positron emission tomography (PET) ligand 11 CABP688 ( E )-3-2-(6-methyl-2-pyridinyl)ethynyl-2-cyclohexen-1-one- O -(methyl-11 C)oxime, a negative allosteric modulator of the metabotropic glutamatergic receptor subtype 5. Methods Two 11 CABP688 PET scans were performed in 10 healthy nonsmoking human volunteers (34 ± 13 years old); the two PET scans were performed on the same day—before (scan 1) and during intravenous ketamine administration (.23 mg/kg over 1 min, then .58 mg/kg over 1 hour; scan 2). The PET data were acquired for 90 min immediately after 11 CABP688 bolus injection. Input functions were obtained through arterial blood sampling with metabolite analysis. Results A significant reduction in 11 CABP688 volume of distribution was observed in scan 2 relative to scan 1 of 21.3% ± 21.4%, on average, in the anterior cingulate, medial prefrontal cortex, orbital prefrontal cortex, ventral striatum, parietal lobe, dorsal putamen, dorsal caudate, amygdala, and hippocampus. There was a significant increase in measurements of dissociative state after ketamine initiation ( p < .05), which resolved after completion of the scan. Conclusions This study provides first evidence that ketamine administration decreases 11 CABP688 binding in vivo in human subjects. The results suggest that 11 CABP688 binding is sensitive to ketamine-induced effects, although the high individual variation in ketamine response requires further examination.
Metabotropic glutamate receptor subtype 5 (mGluR5) is integral to the brain glutamatergic system and cognitive function. This study investigated whether aging is associated with decreased brain ...mGluR5 availability.
Cognitively normal participants (n = 45), aged 18 to 84 years, underwent 18FFPEB positron emission tomography scans to quantify brain mGluR5. Distribution volume (VT) was computed using a venous or arterial input function and equilibrium modeling from 90 to 120 min. In the primary analysis, the association between age and VT in the hippocampus and association cortex was evaluated using a linear mixed model. Exploratory analyses assessed the association between age and VT in multiple brain regions. The contribution of gray matter tissue alterations and partial volume effects to associations with age was also examined.
In the primary analysis, older age was associated with lower 18FFPEB binding to mGluR5 (P = 0.026), whereas this association was not significant after gray matter masking or partial volume correction to account for age-related tissue loss. Post hoc analyses revealed an age-related decline in mGluR5 availability in the hippocampus of 4.5% per decade (P = 0.007) and a non-significant trend in the association cortex (P = 0.085). An exploratory analysis of multiple brain regions revealed broader inverse associations of age with mGluR5 availability, but not after partial volume correction.
Reductions in mGluR5 availability with age appear to be largely mediated by tissue loss. Quantification of 18FFPEB binding to mGluR5 may expand our understanding of age-related molecular changes and the relationship with brain tissue loss.
Background
Neuroimaging studies have revealed that disturbances in network organization of key brain regions may underlie cognitive and emotional dysfunction in posttraumatic stress disorder (PTSD). ...Examining both brain structure and function in the same population may further our understanding of network alterations in PTSD.
Methods
We used tensor-based morphometry and intrinsic connectivity distribution to identify regions of altered volume and functional connectivity in unmedicated individuals with PTSD (n = 21) and healthy comparison participants (n = 18). These regions were then used as seeds for follow-up anatomical covariance and functional connectivity analyses.
Results
Smaller volume in the cerebellum and weaker structural covariance between the cerebellum seed and the middle temporal gyrus were observed in the PTSD group. Individuals with PTSD also exhibited lower whole-brain connectivity in the cerebellum, dorsolateral prefrontal cortex (dlPFC) and medial prefrontal cortex. Functional connectivity in the cerebellum and grey matter volume in the dlPFC were negatively correlated with PTSD severity as measured by the DSM-5 PTSD Checklist (PCL-5; r = −.0.77, r = − 0.79). Finally, seed connectivity revealed weaker connectivity within nodes of the central executive network (right and left dlPFC), and between nodes of the default mode network (medial prefrontal cortex and cerebellum) and the supramarginal gyrus, in the PTSD group.
Conclusion
We demonstrate structural and functional alterations in PTSD converging on the PFC and cerebellum. Whilst PFC alterations are relatively well established in PTSD, the cerebellum has not generally been considered a key region in PTSD. Our findings add to a growing evidence base implicating cerebellar involvement in the pathophysiology of PTSD.
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