Dose-Dependent Effects of Endotoxin on Neurobehavioral Functions in Humans

Clinical and experimental evidence document that inflammation and increased peripheral cytokine levels are associated with depression-like symptoms and neuropsychological disturbances in humans. However, it remains unclear whether and to what extent cognitive functions like memory and attention are affected by and related to the dose of the inflammatory stimulus. Thus, in a cross-over, double-blind, experimental approach, healthy male volunteers were administered with either placebo or bacterial lipopolysaccharide (LPS) at doses of 0.4 (n = 18) or 0.8 ng/kg of body weight (n = 16). Pro- and anti-inflammatory cytokines, norephinephrine and cortisol concentrations were analyzed before and 1, 1.75, 3, 4, 6, and 24 h after injection. In addition, changes in mood and anxiety levels were determined together with working memory (n-back task) and long term memory performance (recall of emotional and neutral pictures of the International Affective Picture System). Endotoxin administration caused a profound transient physiological response with dose-related elevations in body temperature and heart rate, increases in plasma interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α and IL-1 receptor antagonist (IL-1ra), salivary and plasma cortisol, and plasma norepinephrine. These changes were accompanied by dose-related decreased mood and increased anxiety levels. LPS administration did not affect accuracy in working memory performance but improved reaction time in the high-dose LPS condition compared to the control conditon. In contrast, long-term memory performance was impaired selectively for emotional stimuli after administration of the lower but not of the higher dose of LPS. These data suggest the existence of at least two counter-acting mechanisms, one promoting and one inhibiting cognitive performance during acute systemic inflammation

Preliminary Study of White Matter Abnormalities and Associations With the Metabotropic Glutamate Receptor 5 to Distinguish Bipolar and Major Depressive Disorders

Background Understanding distinct neurobiological mechanisms underlying bipolar disorder (BD) and major depressive disorder (MDD) is crucial for accurate diagnosis and the discovery of novel and more effective targeted treatments. Previous diffusion-weighted MRI studies have suggested some common frontotemporal corticolimbic system white matter (WM) abnormalities across the disorders. However, critical to the development of more precise diagnosis and treatment is identifying distinguishing abnormalities. Promising candidates include more prominent frontotemporal WM abnormalities observed in BD in the uncinate fasciculus (UF) that have been associated with frontal-amygdala functional dysconnectivity, and with suicide that is especially high in BD. Prior work also showed differentiation in metabotropic glutamate receptor 5 (mGlu5) abnormalities in BD versus MDD, which could be a mechanism affected in the frontotemporal system. However, associations between WM and mGlu5 have not been examined previously as a differentiator of BD. Using a multimodal neuroimaging approach, we examined WM integrity alterations in the disorders and their associations with mGluR5 levels. Methods Individuals with BD ( N  = 21), MDD ( N  = 10), and HC ( N  = 25) participated in structural and diffusion-weighted MRI scanning, and imaging with [ 18 F]FPEB PET for quantification of mGlu5 availability. Whole-brain analyses were used to assess corticolimbic WM matter fractional anisotropy (FA) across BD and MDD relative to HC; abnormalities were tested for associations with mGlu5 availability. Results FA corticolimbic reductions were observed in both disorders and altered UF WM integrity was observed only in BD. In BD, lower UF FA was associated with lower amygdala mGlu5 availability ( p  < .05). Conclusions These novel preliminary findings suggest important associations between lower UF FA and lower amygdala mGlu5 levels that could represent a disorder-specific neural mechanism in which mGluR5 is associated with the frontotemporal dysconnectivity of the disorder

Cerebellar and Prefrontal Cortical Alterations in PTSD: Structural and Functional Evidence

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

Supplementary Table 1 -Supplemental material for Cerebellar and Prefrontal Cortical Alterations in PTSD: Structural and Functional Evidence

<p>Supplemental material, Supplementary Table 1 for Cerebellar and Prefrontal Cortical Alterations in PTSD: Structural and Functional Evidence by Sophie E. Holmes, Dustin Scheinost, Nicole DellaGioia, Margaret T. Davis, David Matuskey, Robert H. Pietrzak, Michelle Hampson, John H. Krystal and Irina Esterlis in Chronic Stress</p

Supplementary Figures -Supplemental material for Cerebellar and Prefrontal Cortical Alterations in PTSD: Structural and Functional Evidence

<p>Supplemental material, Supplementary Figures for Cerebellar and Prefrontal Cortical Alterations in PTSD: Structural and Functional Evidence by Sophie E. Holmes, Dustin Scheinost, Nicole DellaGioia, Margaret T. Davis, David Matuskey, Robert H. Pietrzak, Michelle Hampson, John H. Krystal and Irina Esterlis in Chronic Stress</p