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

Quantification of appetite-regulating hormones in children with hypothalamic and common obesity

Background. Current understanding of the appetite-regulating neuroendocrine circuitry remains incomplete, and efficacious treatments for both common and hypothalamic obesity (HyOb) are lacking. Concurrently, the expanded role of oxytocin (OXT) in energy homeostasis and human behaviour is beginning to be understood. Objectives. To optimise and translate an OXT enzyme immunoassay (EIA) to elucidate whether there were any unique differences in the plasma endocrine milieu in patients with HyOb. Methods. Optimisation work was carried out using EIAs with polyclonal and monoclonal secondary antibodies. Obese (BMI>+2 SDS) and lean (BMI≤+2 SDS) children with (HyOb and HyLean) and without (Ob and Lean) hypothalamic disorders (septo-optic dysplasia or suprasellar tumours) were phenotyped using the Dykens’ Hyperphagia Questionnaire Score (DHQS). Plasma concentrations of leptin, insulin, OXT, BDNF, αMSH, acylated ghrelin, AgRP and copeptin were measured. Results. Solid phase extraction demonstrated markedly variable OXT recovery, and potentially increased rather than decreased interference. A polyclonal secondary antibody-containing EIA showed significant cross-reactivity with several peptides in human plasma compared to a monoclonal secondary antibody-containing EIA. Of the 122 children recruited (50 HyOb, 29 HyLean, 24 Ob, 19 Lean, mean age 11.3±3.9 years) there were no differences in DHQS or hormone concentrations between HyOb and Ob groups. Obesity was associated with compensatorily increased leptin and insulin, and decreased ghrelin and AgRP concentrations. More rapidly increasing BMI was independently associated with a younger age and lower plasma αMSH concentrations. OXT concentrations did not show any correlation with BMI or DHQS. Conclusion. The use of plasma extraction processes and EIAs in the literature needs re-examination. The plasma endocrine milieu in HyOb vs. common obesity does not differ, with a compensatory increase in anorexigens and decrease in orexigens. Lower plasma αMSH was associated with more rapid weight gain, suggesting that MC4R agonists may be a therapeutic option in all forms of obesity