Then, in 1988, Mayberg did a second study comparing the brain activity of depressed and non-depressed patients with Huntington’s disease. It showed exactly the same pattern. In a third study, she scanned a subgroup of stroke patients with damage to the basal ganglia and, again, observed a similar pattern of disconnection.
Finding a common pattern of abnormal brain activity in depressed patients with three different types of neurological disease was a significant breakthrough. In Parkinson’s, Huntington’s, and stroke, however, depression is a secondary condition that results from a primary neurological disorder. How relevant would her PET findings be for the vast majority of depressed people whose depression was unrelated to an underlying neurological disorder?
To find out, Mayberg did PET scans on a small group of patients who were in hospital for severe depression – known clinically as unipolar depression – and who had not responded to drug treatment. Once again the PET scans showed a much lower than normal level of activity in the paralimbic regions connecting the cortical thinking brain and the limbic emotional brain.
In her testing of these four distinct groups of patients, Mayberg had found a consistent biomarker of depression: an uncharacteristically low level of activity in the paralimbic regions. She knew that there was a break in one of the circuits connecting limbic and cortical regions of the brain, making it much harder for the emotional and cognitive regions of the brain to talk to each other. She also suspected that the “short” in this limbic-cortical circuit was only one of many faults in the whole brain network. She had discovered a small island; the next step was to try to expand the map of depression.
In 1991, Mayberg was recruited by the University of Texas Health Science Center at San Antonio, which had just opened a $38-million (U.S.) research imaging facility equipped with more advanced, higher-resolution PET scanners. One visiting scientist dubbed the centre’s diverse brain-mapping activities “a Manhattan project of the mind,” after the crash program to develop the atomic bomb during World War II. The centre encouraged a cross-fertilization of ideas through multidisciplinary collaborations, making it an ideal place for Mayberg to begin a new chapter in her exploration of the human brain.
The Texas medical centre had a big depression clinic, where Mayberg could do PET scans on a broader, more representative population of depressed people than she had studied at Johns Hopkins. Some of them were severely depressed and completely immobilized. “In San Antonio, we saw depressed patients in the real world,” she says. “Their brains were more ‘on.’”
Mayberg ultimately wanted her research to help patients by improving treatment, so she and the psychiatrist Stephen Brannan designed a PET study to tackle two of the most difficult questions in depression treatment: Why don’t antidepressants such as Prozac work right away? Why doesn’t everybody treated with drugs get better?
To find out, they looked at how brain-activity patterns change over time when patients are treated with antidepressants. In this study, fifteen men diagnosed with severe depression were given either a standard dose of Prozac or a placebo. They had PET scans before treatment, and again after one week and six weeks of treatment.
As well as investigating these treatment issues, Mayberg struggled to increase her understanding of how the emotional regions of the brain are altered in depression. From her own PET studies and those of other researchers, she knew that the higher cortical areas of the frontal lobe involved in thinking and attention are typically underactive in depressed people. “We understood that depression turns down cognitive processes in the brain,” Mayberg recalls, “but we couldn’t figure out how the wiring for mood was altered in depression.” To better understand that, she and Mario Liotti, a neurologist and neuropsychologist, set up an ingenious experiment called a “mood challenge study” to look at sadness in healthy people. “A lot of people in the field were adamant that depression and sadness are completely different. We thought, yes, they are different but not so different that they would involve different systems in the brain,” she says.
In the “sad” study, as they called it, eight healthy women were asked to write autobiographical scripts based on memories of terribly sad events. Each woman read her script aloud and a PET scan was then taken to photograph the state of her brain when she was intensely sad. The PET camera also took snapshots of each woman’s brain in a neutral state after the sad mood had passed.
