Current Research

INFLAMMATION, MOTIVATION & DOPAMINE

Prior work suggests that dopamine dysfunction may be implicated in motivational impairments in depression. If this is true, then it is important to ask why this might be the case. One candidate mechanism is inflammation. Through a combination of functional and neurochemical imaging in a sample of depressed patients with varying levels of inflammation, this project will determine the extent to which inflammation contributes to motivational symptoms and whether corticostriatal circuit function mediates this relationship.

The goal of this project is to help validate the immune system and corticostriatal reward circuits as important targets for the development of novel anti-inflammatory treatment and prevention strategies, which in turn can be used to personalize treatments for patients with high inflammation and motivational deficits. Importantly, we do not propose this model as a means of accounting for all forms of anhedonic symptoms; rather, we suggest this as a possible mechanism that may occur in the context of high inflammation and altered dopamine-dependent corticostriatal network functions

Project Funding: NIH R01 (PI: Treadway)

While inflammation, corticostriatal network dysfunction and anhedonic symptoms may not be linked in all cases, we propose to establish the existence of a causal relationship between these elements in a subset of patients exhibiting reward-related deficits.

STRESS, NEUROPLASTICITY, & REINFORCEMENT LEARNING

A core feature of MDD is reward-processing deficits in the form of decreased reward motivation and anhedonia. Importantly, alterations in prefrontal glutamatergic signaling have been recently linked to the symptom of anhedonia. This cardinal symptom of depression involves deficits in appropriate processing of reward information in MDD, as evidenced by poor reinforcement learning, blunted motivation, and impaired decision-making.

The recent identification of prefrontal glutamate (Glu) and γ-aminobutyric acid (GABA) dysfunction in the pathophysiology of major depressive disorder (MDD) yields a promising avenue to explore, however, many questions remain regarding the precise etio-pathophysiological mechanisms through which altered neurotransmission may give rise to depressive symptomology.

Critically relevant to the proposed research, stress exerts deleterious effects over motivational and reward-processing systems, and can increase vulnerability for the development of reward-linked symptoms such as anhedonia, apathy and addiction. To address the relationship between stress, neuroplasticity and learning behavior, we will use pre and post-stress measures of MR Spectroscopy of medial prefrontal glutamate and GABA in combination with fMRI during a reward-learning paradigm.

All in all, this research will provide important new insights to the roles of Glu and GABA functioning in the pathophysiology of reward processing deficits in Major Depressive Disorder.

Project Funding: NIMH R00 (PI: Treadway)

PET MARKERS OF INFLAMMATION


If MDD is indeed associated with neuroinflammation, it is essential to develop new ways to measure neuroinflammation in vivo. The study uses a PET ligand [18F]FEPPA, which selectively binds to the translocator protein 18kDa, a well-established marker of neuroinflammation (Brown et al., 2007). Direct assessment will yield important insights into the specific brain areas most affected by inflammatory signaling in MDD. Moreover, by combining this approach with fMRI, we will be able to assess how inflamed brain areas are influencing neural function during reward motivation tasks.

Project Funding: NARSAD YI Award (PI: Treadway)

Shown on the right: Evidence of neuroinflammation in a single subject from PET imaging with [11C] PBR28.

AFFECTIVE DETERMINANTS OF EFFORT-BASED DECISION MAKING

Despite the widespread use and acceptance of self-report measures to assess psychological traits, a long-standing literature suggests that such measures are vulnerable to numerous biases including simple recall errors, misinterpretations of the item, and social-conformity pressures. To address this issue, a number of a psychological laboratories have advocated for the use of decision-making tasks as an alternative means of assessing motivation and reward-related symptoms (Treadway et al., 2009; Treadway & Zald, 2011; Montague et al., 2012). Such tasks ask individuals to chose how much they are willing to work, wait or risk in order to win various rewards. These measures have been used in a variety of behavioral and neuroimaging studies and in different clinical populations, and yet the extent to which different value-based decision-making tasks assess related and distinct constructs is largely unknown, as is their relationship to widely used trait measures of motivation.

There are two primary aims of this study: 1) Investigate the covariance of individual difference in discounting of monetary rewards on the basis of delay, effort and risk and 2) Examine associations between higher-order factors of reward-based decision-making and symptoms of depression and anxiety.

Shown on the right: Schematic diagram of two possible causal symptom networks that might result in similar scores on a dimensional measure of depressive symptom severity despite unique pathophysiologies.

NEURAL MECHANISMS OF MOTIVATION

The human striatum, and particularly dopaminergic neurons within the striatum, is believed to play a critical role in motivated decision-making and effort-discounting. However, the exact neural mechanisms underlying effort-based decision-making remain unknown. Specifically, adequate research has not been conducted to interpret and understand how the striatum responds to both effort and reward, as well as to their integration.

This study aims to better understand neural responses to effort and reward during effort-based choice. Using functional magnetic resonance imaging (fMRI), individuals complete a sequential effort-based decision-making task. This design is unique in that it allows for the isolation of neural responses to effort or reward alone, as well as to subjective value estimates (reward discounted by effort). Additionally, this design can provide essential evidence about how the human striatum encodes effort and reward information, and if any regions responding to these separate pieces of information may predict future behavioral choices. Particularly, it can help clarify whether there is anatomical segregation in the regions that track costs and benefits or whether the same regions are responding to both pieces of information in a similar manner.

Shown on the left: fMRI image of bilateral activation in the striatum. Research has shown that the striatum plays a critical role in the motivation and decision making processes. These processes are thought to be linked to dopamine function in that region and to have effects on motivation in patients with depression.