An RDoC-inspired examination of pharmacological, sex-specific, and hormonal modulators of Positive Valence Systems

Abstract

The Positive Valence Systems (PVS) are a major domain of the Research Domain Criteria framework (RDoC), which aims at promoting precision medicine for psychiatry, based on a profound understanding of the psychological and biological basis of shared behavioral symptoms. The PVS domain describes basic processes of reward processing, which can be disrupted in several mental disorders, such as schizophrenia, substance use disorders, and major depressive disorder. Investigating basic mechanisms of PVS constructs is important to understand central aspects which contribute to these transdiagnostic motivational syndromes. In my doctoral thesis, I investigated pharmacological, sex-specific, and hormonal modulators of PVS constructs. I focused on the constructs reward responsiveness and reward valuation in the context of motivational behavior in healthy humans. In study 1, I examined the neurotransmitter serotonin, and in particular a selective serotonin reuptake inhibitor (SSRI) as modulator of reward responsiveness on a neural level, using functional magnetic resonance imaging (fMRI). In studies 2 and 3, I inquired into sex-specific and hormonal modulators of reward valuation to elucidate sex-specific integration of benefits and costs on a behavioral level. In study 1, I found that an acute SSRI dose modulated the processing of punishment cues in caudate and thalamus brain regions, which have been identified as transdiagnostic neural markers of disrupted reward responsiveness. In study 2, I identified sex differences in reward valuation, which depended on different encoding of benefits, not costs. Study 3 did not yield substantial differences in reward valuation depending on different hormonal states in women. The RDoC initiative aims at understanding core features and modulators of shared behavioral symptoms, ranging from normal to abnormal behavior. Understanding basic mechanisms is an important first step towards transdiagnostic clinical translation. Within this scope, my work has implications for testing clinical translation of pharmacological and behavioral treatments specifically targeted to PVS constructs, which take sex-specific behavioral variability into account.