Cerebral blood flow predicts differential neurotransmitter activity

Application of metabolic magnetic resonance imaging measures such as cerebral blood flow in translational medicine is limited by the unknown link of observed alterations to specific neurophysiological processes. In particular, the sensitivity of cerebral blood flow to activity changes in specific neurotransmitter systems remains unclear. We address this question by probing cerebral blood flow in healthy volunteers using seven established drugs with known dopaminergic, serotonergic, glutamatergic and GABAergic mechanisms of action. We use a novel framework aimed at disentangling the observed effects to contribution from underlying neurotransmitter systems. We find for all evaluated compounds a reliable spatial link of respective cerebral blood flow changes with underlying neurotransmitter receptor densities corresponding to their primary mechanisms of action. The strength of these associations with receptor density is mediated by respective drug affinities. These findings suggest that cerebral blood flow is a sensitive brain-wide in-vivo assay of metabolic demands across a variety of neurotransmitter systems in humans

Resting state EEG power spectrum and functional connectivity in autism: a cross-sectional analysis

BACKGROUND: Understanding the development of the neuronal circuitry underlying autism spectrum disorder (ASD) is critical to shed light into its etiology and for the development of treatment options. Resting state EEG provides a window into spontaneous local and long-range neuronal synchronization and has been investigated in many ASD studies, but results are inconsistent. Unbiased investigation in large and comprehensive samples focusing on replicability is needed. METHODS: We quantified resting state EEG alpha peak metrics, power spectrum (PS, 2-32 Hz) and functional connectivity (FC) in 411 children, adolescents and adults (n = 212 ASD, n = 199 neurotypicals [NT], all with IQ > 75). We performed analyses in source-space using individual head models derived from the participants' MRIs. We tested for differences in mean and variance between the ASD and NT groups for both PS and FC using linear mixed effects models accounting for age, sex, IQ and site effects. Then, we used machine learning to assess whether a multivariate combination of EEG features could better separate ASD and NT participants. All analyses were embedded within a train-validation approach (70%-30% split). RESULTS: In the training dataset, we found an interaction between age and group for the reactivity to eye opening (p = .042 uncorrected), and a significant but weak multivariate ASD vs. NT classification performance for PS and FC (sensitivity 0.52-0.62, specificity 0.59-0.73). None of these findings replicated significantly in the validation dataset, although the effect size in the validation dataset overlapped with the prediction interval from the training dataset. LIMITATIONS: The statistical power to detect weak effects-of the magnitude of those found in the training dataset-in the validation dataset is small, and we cannot fully conclude on the reproducibility of the training dataset's effects. CONCLUSIONS: This suggests that PS and FC values in ASD and NT have a strong overlap, and that differences between both groups (in both mean and variance) have, at best, a small effect size. Larger studies would be needed to investigate and replicate such potential effects

Serum neuron-specific enolase is related to cerebellar connectivity: A resting-state functional magnetic resonance imaging pilot study

Neuron-specific enolase (NSE) has been suggested as a prognostic biomarker for neuronal alterations resulting from conditions such as traumatic brain injury (TBI), neurodegenerative disease, or cardiac arrest. To validate serum NSE (sNSE) as a brain-specific biomarker, we related it to functional brain imaging data in 38 healthy adults to create a physiological framework for future studies in neuropsychiatric diseases. sNSE was measured by monoclonal two-site immunoluminometric assays, and functional connectivity was investigated with resting-state functional magnetic resonance imaging (rfMRI). To identify neural hubs most essentially related to sNSE, we applied graph theory approaches, namely, the new data‐driven and parameter‐free approach, eigenvector centrality mapping. sNSE and eigenvector centrality were negatively correlated in the female cerebellum, without any effects in male subjects. In cerebellar cortex, NSE expression was significantly higher than whole-brain expression as investigated in the whole brain and whole genome-wide atlas of the Allen Institute for Brain Sciences (Seattle, WA). Our study shows a specific linkage between the neuronal marker protein, sNSE, and cerebellar connectivity as measured with rfMRI in the female human brain, although this finding shall be proven in future studies including more subjects. Results suggest that the inclusion of sNSE in the analysis of imaging data is a useful approach to obtain more-specific information on the neuronal mechanisms that underlie functional connectivity at rest. Establishing such a baseline resting-state pattern that is tied to a neuronal serum marker opens new perspectives in the characterization of neuropsychiatric disorders as disconnective syndromes or nexopathies, in particular, resulting from TBI, neurodegenerative disease, or cardiac arrest, in the future

Brain-Derived Neurotrophic Factor and Antidepressive Effect of Electroconvulsive Therapy: Systematic Review and Meta-Analyses of the Preclinical and Clinical Literature

<div><p>Emerging data suggest that Electro-Convulsive Treatment (ECT) may reduce depressive symptoms by increasing the expression of Brain-Derived Neurotrophic Factor (BDNF). Yet, conflicting findings have been reported. For this reason we performed a systematic review and meta-analysis of the preclinical and clinical literature on the association between ECT treatment (ECS in animals) and changes in BDNF concentrations and their effect on behavior. In addition, regional brain expression of BDNF in mouse and human brains were compared using Allen Brain Atlas. ECS, over sham, increased BDNF mRNA and protein in animal brain (effect size [Hedge’s g]: 0.38―0.54; 258 effect-size estimates, <i>N</i> = 4,284) but not in serum (<i>g</i> = 0.06, 95% <i>CI</i> = -0.05―0.17). In humans, plasma but not serum BDNF increased following ECT (<i>g</i> = 0.72 vs. <i>g = 0</i>.<i>14;</i> 23 effect sizes, <i>n</i> = 281). The gradient of the BDNF increment in animal brains corresponded to the gradient of the BDNF gene expression according to the Allen brain atlas. Effect-size estimates were larger following more ECT sessions in animals (<i>r</i> = 0.37, P < .0001) and in humans (<i>r</i> = 0.55; <i>P</i> = 0.05). There were some indications that the increase in BDNF expression was associated with behavioral changes in rodents, but not in humans. We conclude that ECS in rodents and ECT in humans increase BDNF concentrations but this is not consistently associated with changes in behavior.</p></div

Prisma flow diagram of the search strategy and its results.

<p>Prisma flow diagram of the search strategy and its results.</p

Pooled effect-size estimates, heterogeneity and publication bias for the animal studies by sub-group meta-analyses indicated in the row.

<p>^<b>A</b> Effect-size estimates were of a larger magnitude in studies that measured central- as compared to serum BDNF (all <i>P</i>-values < .001). Furthermore, larger effect-size estimates were found in the DG as compared to those found in the hippocampus and the cortex (<i>P</i>-values < .05). There were no statistically significant differences in pooled effect-size estimates derived from the hippocampus, the cortex and other brain regions (all <i>P</i>-values > .5).</p><p>^<b>B</b> Chronic ECS yielded larger effect-size estimates as compared to single ECS (<i>P</i> < .0001).</p><p>^<b>C</b> Studies that sampled BDNF mRNA yielded larger effect-size estimates as compared to studies that sampled BDNF protein (<i>P</i> < .01).</p><p>^<b>D</b> Among the studies that are characterized as measuring BDNF mRNA were 3 effect-sizes on BDNF RNA and 9 on the precursor protein pro-BDNF. Excluding these effect-sizes did not change the results.</p><p>* Statistical significant at <i>P</i> < .05</p><p>** Statistical significance at <i>P</i> < .01</p><p>*** Statistical significance at <i>P</i> < .001.</p><p>Pooled effect-size estimates, heterogeneity and publication bias for the animal studies by sub-group meta-analyses indicated in the row.</p

Basic information on the clinical studies included in the meta-analysis.

<p>Abbreviations: MDD, major depressive disorder; BD, bipolar disorder</p><p>Basic information on the clinical studies included in the meta-analysis.</p

Pooled effect-size estimates, heterogeneity and publication bias for the clinical studies by sub-group meta-analyses indicated in the row.

<p>^A Effect size estimates were medium and significant in studies that measured BDNF in responders subgroup and non-significant in non-responders subgroup. However, there were no statistically significant differences in pooled effect-size estimates between the responders and non-responders subgroups (all P-values > .5).</p><p>* Statistical significance at P < .05</p><p>** Statistical significance at P < .01</p><p>*** Statistical significance at P < .001</p><p>Pooled effect-size estimates, heterogeneity and publication bias for the clinical studies by sub-group meta-analyses indicated in the row.</p