“How weary, stale, flat and unprofitable seem to me all the uses of this world!” laments literature’s most celebrated depressive. Many people who suffer from Hamlet’s malady might echo his sentiment: Their condition seems less a matter of black moods than an empty feeling where enjoyment used to be. In fact, anhedonia, an inability to feel pleasure, is as much a defining symptom of depression as unremitting sadness.
But although researchers have made important strides in understanding how the brain misfires during depression, they have almost exclusively focused on the disease’s darkest feelings. “Even though we’ve known for decades you can be clinically depressed without sadness, just blunted affect, that aspect has been underrepresented in neuroscience research,” says Gabriel S. Dichter, director of the clinical affective neuroscience laboratory at the University of North Carolina. “The situation has changed in the last three to five years. We’ve started to look at neural correlates of anhedonia, to see what brain regions are responsible.”
Most evidence points toward areas involved in reward and motivation—structures such as the nucleus accumbens within the dorsal and ventral striatum. Results, however, have been inconsistent on whether depressed people show reduced reward circuit activity. Now new studies suggest that timing may be the overlooked factor.
A lack of stamina
In a study in Proceedings of the National Academy of Science (pdf), University of Wisconsin researchers led by Aaron S. Heller compared functional magnetic resonance imaging (fMRI) readings of 27 individuals who met standard criteria for major depressive disorder with 19 healthy controls. The participants were told to try to enhance, suppress, or simply observe the emotion aroused by a series of pleasant or unpleasant images.
During the first half of the 37-minute sessions, there was virtually no difference between depressed and control subjects. Nucleus accumbens activity increased when the study participants viewed pleasant scenes, with the greatest gains occurring when positive feelings were amplified with strategies like imagining oneself in the scene.
But in the second half, things changed. While pleasant scenes continued to activate the reward circuit in controls, the response virtually disappeared in the depressed group. Trying to enhance pleasureable feelings only accentuated the difference.
The fMRI data corresponded to real-world experience. When participants were asked to rate how intensely they felt positive emotions, the depressed individuals whose nucleus accumbens activity declined most sharply during the experiment reported the least pleasure and happiness.
When the researchers took a closer look at the data in the depressed group, a more complex timing issue emerged. Early in the study, the researchers found that as the nucleus accumbens became activated, so did the prefrontal cortex. Later on, the connection disappeared. “This suggests diminishing communication between brain regions,” Heller says. “The prefrontal cortex is involved in adaptive regulation of emotion,” he adds, and failure to maintain contact corresponds to “the inability of the depressed subjects to reflect on positive emotion and enhance it.”
The findings show that “it’s the time course of positive emotion processing that’s abnormal in depression,” says Richard J. Davidson, a senior author of the paper. “Initial reactivity to positive affect was identical in depressed patients and controls. The difference resided only in the capacity to sustain it.”
The broken link, he adds, matches other recent studies suggesting that connectivity between neural networks is key in psychological function and dysfunction.
New treatment strategies
“This is a terrific paper, and I’m really glad they wrote it,” says Greg J. Siegle, director of the University of Pittsburgh’s cognitive affective neuroscience program. “Davidson’s group have been pioneers of the psychochronobiology of affect.” What they found “shows that depression isn’t a disorder like atrophy or a lesion or a chemical imbalance, which would persist whenever it was measured. I’d liken it more to fatigue. It’s only after a time that depressed people can’t experience what’s normal for others.”
Anhedonia, then, might be understood less as an outright incapacity for enjoyment than a lack of “stamina.” This suggests that therapists might benefit from building up depressed people’s ability to remain engaged in pleasurable activities. “Rather than a traditional therapy session of 45 minutes once a week, or even once a day, it may be more important to have brief periods of therapy sprinkled throughout the day,” Davidson says.
The study may have implications for drug development as well. “While the specific neurochemical substrates aren’t clear, [anhedonia] may be associated with differences in receptor density in particular regions, or differences in the time course of receptor occupancy or saturation,” Davidson adds. “It’s certainly something that warrants exploration at the molecular level.”
Dichter observes that the experiment itself involved a kind of therapeutic intervention. “The researchers taught simple emotional strategies to up-regulate positive feelings and showed that the brain systems mediating reward responded to this training.” Retesting patients after a course of cognitive behavior therapy (CBT) using such techniques, he says, would be interesting.
Dichter’s own research, recently reported in Journal of Affective Disorders (pdf) and in Biological Psychiatry (pdf), in fact shows how simple therapy can rehabilitate the brain’s reward responses. His team analyzed fMRI scans of 12 adults with major depressive disorder and 15 controls, taken while the subjects bet on a wheel of fortune.
The researchers divided the task into a “selection” phase, when the participants decided how to bet; “anticipation,” while the wheel was spinning; and “feedback,” when they responded to winning or losing. While differences appeared throughout, the anticipation phase was of particular interest, Dichter says. “Most of our affective lives involve anticipation—we look forward to a paycheck, to intellectual satisfaction, to a degree. A central defect in depression is a deficit in anticipating pleasure. You can’t look forward to pleasurable outcomes.”
In the study, the striatum was activated most strongly during anticipation—even more than when actually receiving a reward, Dichter says. In depressed subjects, however, this activity was weakest when compared to controls.
The participants then underwent 12 weeks of “Behavioral Activation Therapy for Depression” sessions, in which therapists encouraged the patients to spend more time on activities they might enjoy and to avoid the withdrawal behavior that they’d otherwise engage in.
Nine patients responded; their depression, as measured on two standard scales, improved significantly. Two of the remaining three were “somewhat better,” Dichter says.
This improvement extended to brain function. After therapy, responses in the depressed group seemed closer to normal in all three phases of the wheel task, but the change during anticipation was “particularly meaningful,” he says. “The firing in the reward area was almost comparable to controls.”
Showing that simply taking action can positively change the brain might motivate depressed people to “get out of bed even when they don’t think it’s worth it,” Dichter says. “It may help patients buy into psychotherapy and at the same time accept the biological nature of their disease.” (Dichter has also received grants from the Dana Foundation for research into the mechanisms of autism.)
“Often patients, and to some extent clinicians, say, ‘Psychotherapy changes thinking, drugs change the brain—I want drugs,” Siegle says. “This paper tells a very different message. Not only does psychotherapy change the brain, it specifically changes the mechanisms that are disrupted by depression. Rather than treating the brain like soup, it can target the regions that have functional deficits.” Drugs can even be a worse choice, he adds, because while they influence the same reward circuits by ramping up presence of the neurotransmitter dopamine, they affect other parts of the brain as well, causing side effects.
Both sets of studies suggest that brain imaging might help personalize therapy by pinpointing problematic areas. “Brain activity profiles could suggest what psychotherapy is likely to be helpful, or whether a patient needs medication that targets one mechanism or psychotherapy that targets another,” Siegle says. (One of his studies found that a distinctive fMRI pattern predicted response to CBT.) “What we need now are large randomized trials that match patients to treatments, based on work just like this.”