In 1991, the U.S. Food and Drug Administration approved the first ever treatment for chronic hepatitis C. The drug, called interferon-alpha, was also used to treat certain kinds of cancer. It works by sending the immune system into overdrive—but it also induces significant depressive episodes in around 30% of people who take it. Physicians halted many patients’ treatment with the drug because their risk of suicide was greater than the risk of their underlying disease. Multiple studies went on to indicate interferon-alpha could be used safely if patients were pretreated with an antidepressant medication, but the mystery behind why the drug caused depression among some patients remained.
More than two decades later, Michael Treadway, PhD, a professor of psychology at Emory University, and other researchers proposed an explanation. They suggested interferon-alpha induces chronic inflammation, kicking off a biochemical chain reaction that results in a reduction in the brain’s supply of dopamine, which is necessary for reward-driven motivation. “When the body becomes inflamed, immune cells shift their metabolism and they start consuming a lot more energy,” Treadway explained. “We think this shift triggers a reduction in dopamine levels as a way to signal to key motivation systems that you have less in the tank than you might think, and you’d better lay low for a while.”
Understanding why (and how) inflammation, stress, and other disruptors of the brain’s dopamine system cause depression and other mental disorders in some people but not others is a primary focus of Treadway’s Translational Research in Affective Disorders (TReAD) Lab at Emory. “A central question for me has always been why the dopamine system is vulnerable only in a certain subset of patients,” Treadway said.
For Treadway, one key aspect of the inflammation theory of depression is the dip in motivation. Learning about other sources of impairments in motivation and their role in mental disorders makes up the other major thrust of the TReAD Lab. Members of the lab explore questions about the links among inflammation, stress, motivation, and mental illness using novel behavioral paradigms, computational modeling, neuroimaging, magnetic resonance spectroscopy, transcranial magnetic stimulation, and genetic studies—all with an eye toward translating their research into treatments.
“Our basic science really sets the stage for some interesting and important clinical questions,” said graduate student Amanda Arulpragasam. Among the lab’s translational efforts are clinical trials to test the effectiveness of anti-inflammatory drugs and other therapies as treatments for depression, schizophrenia, and post-traumatic stress disorder (PTSD).
Indirect route to the study of depression
As an undergraduate at Columbia University, Treadway took a handful of psychology classes, but in what he calls “an act of adolescent rebellion,” he ultimately majored in music, eschewing the academic path taken by his physician mother and family therapist father. After graduating, he bounced around a few dot-com start-ups but found the work unfulfilling. He then discovered Buddhism as a way of working through some of his own depression. “That experience pulled me back into psychology and made me aware of how much psychological questions had always been of interest to me,” Treadway said. “That was an aha moment: ‘Why haven’t I been studying this all along?’ My early adolescent resistance faded away, and I realized that psychology could be a really great fit for me.”
Inspired to take psychology classes as a postbaccalaureate student, Treadway soon found a full-time research assistant position, and then he enrolled in a doctoral program at Vanderbilt University. In his early years, he took a few courses with Steven Hollon, PhD, a well-known researcher of cognitive behavioral therapy for depression. “Steve often talked about the importance of anhedonia in depression,” Treadway said. “Lots of depression researchers focus on negative mood, but the inability to enjoy things and feeling unmotivated seemed equally important in terms of treating depression, and less well understood.”
Inspired to learn more about anhedonia’s role in depression, Treadway joined the lab of Vanderbilt psychology professor David Zald, PhD, who at the time was developing innovative methods for using positron emission tomography (PET) to image the dopamine system in humans.
The first fruit of their collaboration was a behavioral measure called the Effort Expenditure for Rewards Task (EEfRT, pronounced “effort”) (PLOS ONE, Vol. 12, No. 4, 2009opens in new window), which has since been widely used to measure how much effort people are willing to put into tasks varying in levels of difficulty and reward. They then published a pair of studies incorporating the EEfRT. One showed that patients with depression were less willing to work hard for rewards than people without depression (Journal of Abnormal Psychology, Vol. 121, No. 3, 2012opens in new window). The other used PET imaging to show that dopamine release in healthy humans predicted how much effort they were willing to expend for rewards, a finding that had been seen in rodents but never before in people (The Journal of Neuroscienceopens in new window, Vol. 32, No. 18, 2012opens in new window).
Treadway and Zald also wrote an influential review paper proposing that anhedonia should be divided into two components—an inability to enjoy things and a lack of motivation to do things—and that these components were encoded separately in the brain (Neuroscience & Biobehavioral Reviews, Vol. 35, No. 3, 2011opens in new window). “There’s a lot of animal work suggesting those processes depend on very different circuits, and so one of our earliest contributions was to push the field toward thinking about anhedonia subdomains,” Treadway said.
Upon earning his PhD at Vanderbilt and completing a clinical internship at Harvard Medical School, Treadway landed a postdoctoral position at McLean Hospital in Belmont, Massachusetts. He worked with Diego Pizzagalli, PhD, a professor of psychiatry who is known for his work on reward circuitry dysfunction in depression and ways to treat it and for his research on stress. “Stress is one of the most significant proximal causes of depression, with almost 80% of first episodes of depression preceded by a period of significant life stress,” Treadway said. “We knew that in animals, stress induces several direct changes to the dopamine system. Could it be contributing to depression in humans by hindering motivation?”
In a series of papers, Treadway and Pizzagalli examined the impact of stress-related hormones on dopamine-reward pathways. In one paper, they showed that stress induced an increase in cortisol release across all participants, but those with either a high or low cortisol response reported more negative affect than those who had a moderate response, indicating that the effects of cortisol levels are not linear (The Journal of Neuroscienceopens in new window, Vol. 37, No. 33, 2017opens in new window). They also found that individual differences in stress-induced increases in the hormoneinterleukin-6 were associated with levels of signaling in the ventral striatum, a dopamine-rich brain region that plays a key role in reward learning (Biological Psychiatry, Vol. 82, No. 8, 2017opens in new window).
Inflammation, motivation, and depression
When Treadway began searching for a faculty position and a spot to launch his lab, he was immediately attracted to Emory by the pioneering work of psychiatrist and neuroscientist Andrew Miller, MD, who had first described the link between interferon-alpha and depression in cancer and hepatitis patients. “Being able to collaborate with Andy was a huge factor in my decision,” Treadway said. “He’s been trying to understand the role of inflammation in depression for several decades.”
Treadway went on to collaborate with Miller on the theory of the links among inflammation, depression, and motivation (Trends in Cognitive Sciences, Vol. 23, No. 5, 2019opens in new window). The TReAD Lab is now testing a prediction of the theory with a clinical trial of a powerful anti-inflammatory drug called infliximab. With funding from the National Institute of Mental Health (NIMH), the lab is investigating whether the drug might alter how the brain makes decisions about effort in patients with depression and high inflammation. The lab has also recently received additional grants from NIMH to investigate the impact of levodopa and the anti-inflammatory drug XPro1595 on depression and to study the role of dopamine and inflammation in PTSD. “There are lots of different ways to get depressed, and immune-metabolic processes might be one subtype that could have its own treatments beyond SSRIs or even conventional talk therapy,” Treadway said. “Targeting inflammation may be key in some patients.”
In addition, Treadway has been collaborating with stem cell biologists at Emory to develop neurons from induced stem cells to identify genetic vulnerabilities of the dopamine system to the effects of inflammation, with the goal of creating personalized treatments for a variety of mental disorders.
Deciding what is worth the effort
When he launched the TReAD Lab in 2015, Treadway not only continued with the work on inflammation and depression that he had started as a postdoctoral fellow but also expanded upon his graduate school research on the role effort plays in depression.
One of Treadway’s initial goals was better understanding how effort is encoded in the brain and whether it is treated the same as other response costs.
Previous research on rodents showed evidence for two opposing signals in the ventral striatum related to effort: an activation signal that prepares an animal to exert effort and an effort-discounting signal that helps the animal select rewards requiring the least effort. These signals, which had never been seen in humans, help animals work for what they need while ensuring they don’t work too hard for small rewards.
Led by graduate student Sho Suzuki, TReAD Lab researchers developed an fMRI task to examine effort-related signals in the ventral striatum in people navigating virtual reality mazes. The researchers scanned the brains of study participants as they were presented with maze navigation tasks that required different levels of effort and that offered varying amounts of reward. The researchers presented the effort and reward amounts sequentially to try to isolate the effort-activation signal during the anticipation and initiation of exerting various amounts of effort. The results indicated that two distinct regions of the ventral striatum were active during different phases when people exerted physical effort. Activity in the dorsal medial region was mainly associated with initiating effortful movement, while activity in the anterior region was mainly associated with assessing the potential costs and benefits of putting in the effort to move (Nature Human Behaviour, Vol. 5, No. 3, 2021opens in new window).
Suzuki is now creating more elaborate virtual environments to help identify specific modes of neural signaling when people are spontaneously motivated to initiate actions. “We want to model people’s decision-making tendencies in more realistic settings, which may provide a better measure of motivation in clinical populations,” he said.
Another disorder associated with low motivation is schizophrenia. Using the EEfRT to study people with and without schizophrenia, Treadway found that both groups were willing to exert low effort for small rewards, but only those without schizophrenia were willing to work harder for larger rewards. To better understand this, postdoc Jessica Cooper, PhD, developed a computational model to understand what information the two groups were using to make choices. She found that while many of those with schizophrenia used information about reward, probability, and effort expenditure to guide their decisions, more than half with the disease ignored this information and performed the task essentially randomly (Journal of Abnormal Psychology, Vol. 128, No. 7, 2019opens in new window). “The model indicated that in these patients, the random behavior in the task was most likely related to cognitive impairments that commonly occur in schizophrenia, rather than a lack of motivation,” Treadway said.
Treadway recently won an NIMH grant to study whether cellular and molecular pathways for immune function and metabolism are related to this random task behavior and could be used to define a distinct subpopulation of schizophrenia patients.
“What I’m seeing with my research, and that of others, is that there are many types of depression, schizophrenia, or any number of mental illnesses, each with its own source,” Treadway said. “I would really like to get to the point where we have discrete definable pathologies that are measurable, using objective tests, for different types of depression, for example, or even different symptoms of depression. That could really open up a world of new treatment possibilities.”
