Imaging Monoaminergic Systems and their Pharmacological Control

Abstract

The natural sciences always and only enhance the human condition by producing knowledge which empowers us to control the natural world, where otherwise it would control us. Nowhere is the power of uncontrollable natural phenomena to curb or limit human well-being more pervasive than in the human mind itself. Monoamines are a class of neurotransmitters consistently implicated in the etiology of nonvolitional neuropsychological phenomena. They are a cornerstone of those mental functions which humans most desire, but are least able to control. Unsurprisingly, drugs targeting these neurotransmitter systems are widely used in clinical, therapeutic, performance-enhancing, and recreational contexts. To the detriment of patients and users, however, currently available drugs are strongly lacking in terms of effect amplitude, reliability, and persistence, as well as suitability for long-term use. We present novel research, which advances the descriptive understanding of drug-naïve monoaminergic function and of monoaminergic drug effects. Our work includes methods development, the investigation of functional monoaminergic neurophenotypes, and the imaging-based profiling of longitudinal drug treatment. The neurobiological representations we put forward are instrumental to refining the understanding of psychopharmacological intervention profiles and the phenomena which they are able to modulate. Methodologically, we tackle technological impediments to large-scale (longitudinal, multi-cohort, and multi-center) preclinical brain imaging. Our first article deals with the challenge of automatically and reliably preparing preclinical magnetic resonance imaging (MRI) data for sharing and analysis. Our second article deals with the improvement of mouse brain registration and the definition of a reference space. Both of the above, as well as further relevant data analysis, rely heavily on high-level software tools. We consequently make an excursion into neuroscientific software management, which needs to be as accessible, reproducible, and transparent as the research it supports. In our third article we present the first whole-brain read-out of ventral tegmental area (VTA) dopaminergic signalling in the mouse. We perform a multivariate analysis of experiment parameters, and formulate specific guidelines for assay reuse or refinement. In our fourth article we apply a previously established serotonergic activity read-out to a longitudinal selective serotonin reuptake inhibitor (SSRI) drug treatment. We produce the first functional neuroimaging profile of longitudinal serotonergic drug effects, and we identify distinct brain clusters based on longitudinal activation trajectories. Our findings both support the autoinhibition down-regulation theory for the SSRI action mechanism, and complement it, by suggesting a prominent role for brainstem involvement. As all trajectories show significant treatment but no post-treatment effects, we also provide neuroimaging evidence strongly suggesting that the intervention fails to elicit persistent homeostatic shifts in healthy subjects. We openly share all acquired data, and all code required to reproduce our analyses. We suggest that the novel methods and the neurophenotypical profiling concept which we put forward may revitalize psychopharmacological research. Our work ultimately serves to advance the understanding of monoaminergic function and its manipulation, as is needed to fulfill the increasing need for the betterment of the human mind, in and outside of the clinical context.