Anhedonia in depression: biological mechanisms and computational models

Abstract

Anhedonia is a severe condition that describes a near-complete absence of enjoyment, motivation, and interest. A core feature of depression, clinical manifestations of anhedonia can include deficits in experiencing pleasure, approach-related motivated behavior, and learning how to match expectations to the environment. To date, the precise neurobiological mechanisms of anhedonia in major depression are still poorly understood. We have previously argued that contradictory findings and the inability to identify specific neurobiological substrates for anhedonic symptoms may result from sample heterogeneity, suboptimal methods of assessment, and the challenge of dissociating between different components of anhedonia. Recently, however, computational advances to the operationalization of psychiatric symptoms have enhanced the ability to evaluate the neurobiology of constituent elements of this symptom domain. In this paper, we review (1) advances in behavioral and computational methods of assessing reward processing and motivation and (2) the development of new self-report, neurological, and biological methods of subtyping that may be useful in future pursuits to expand our understanding of the neurobiology of anhedonia in depression.

Figures

Figure 1

The computational approach to assessing anhedonia and related symptoms. This conceptual diagram outlines the hypothetical operationalization of behavioral manifestations of anhedonia and related symptoms within a computational psychiatry framework. Clinically defined facets of anhedonia have typically been associated with behavioral manifestations that are difficult to quantify or measure directly and are often confused with other related symptoms. However, computational approaches allow for objective assessment through association with computational parameters. To date, there is insufficient data to support specific mapping between behavioral and computational terms, but we present this hypothetical example as a representation of the potential to operationalize clinical behaviors using computational approaches.

Figure 2

Potential signaling pathways linking peripheral inflammation to disruption of dopaminergic function. Adapted from [66]. As suggested by one recent study [59], individuals who go on to develop a depressive phenotype following stress show increased permeability of the blood brain barrier (BBB) to peripheral cytokines such as IL-6. The peripheral cytokines that cross the blood brain barrier, as well as central cytokines produced by activated microglia, may contribute to oxidative stress and reactive oxygen species (ROS) generation. This, in turn, may increase the oxidation of tetrahydrobiopterin (BH4), a cofactor required for the conversion of phenylalanine to tyrosine and tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), thereby impeding DA synthesis. Additionally, central inflammatory cytokines may decrease the expression or function of the vesicular monoamine transporter 2 (VMAT2) as well as increase the expression or function of the dopamine transporter (DAT), increasing DA and leading to increased generation of ROS. Finally, inflammatory cytokines may also decrease DA signaling by reducing DA D2 receptors. D1, dopamine 1 receptor 1; D2, dopamine 2 receptor; DDC, dopamine decarboxylase; NOS, nitric oxide synthase; PAH, phenylalanine hydroxylase; ROS, reactive oxygen species; SN; substantia nigra; TH, tyrosine hydroxylase; VTA, ventral tegmental area.