Neurons Reflect Choice Based on Relative Value Decisions

Decisions, decisions. Paper or plastic? Stocks or bonds? Pizza or salad? From the first thing in the morning until late at night, people confront a head-scratching array of choices without an intrinsically correct answer.

In a study that posed a neurobiological question in the language of economic theory, HMS researchers have found neurons that appear to process such subjective choices in monkeys.

Diagram courtesy of Camillo Padoa-Schioppa

Ratings game. The activity of a single neuron, shown in the red U-shaped curve, correlates with the subjective value of a chosen juice. The black dots show the percentage of times the monkey chose cranberry juice (B) instead of grape juice (A). The middle black dot under the red dot shows that the monkey was just as likely to choose one portion of the preferred grape juice as three portions of cranberry, indicating an equivalent value. The activity of the neuron was low when the monkey received a low value (three portions of cranberry juice) and high when the monkey received a high value (three portions of grape juice).

“We’re often told we can’t compare apples and oranges, but truly we do it all the time,” said postdoctoral fellow Camillo Padoa-Schioppa, first author of the paper in the April 23 Nature. “Behavioral evidence suggests that choice results from two distinct processes. First, you assign values to the available options, and then you make a decision based on those values.”

For the study, Padoa-Schioppa recorded the electrical activity of 931 neurons of two monkeys, male and female, and correlated them with their behavior. In each session, the monkeys chose between varying amounts of different beverages, including grape juice, apple juice, peppermint tea, diluted cranberry juice, lemonade, and fruit punch. They selected their juices by looking at representative squares on a computer screen. In a typical day, they drank about one measuring cup of juice during the experiments.

The researchers identified dedicated neurons in the orbitofrontal cortex located above the eyeballs that appeared to assign a value to each beverage based on quality and quantity. “They kick in right away, most prominently when presented with an offer, ” Padoa-Schioppa said.

In the key finding, another group of neurons in the same area appeared to fire in response to the subjective value the monkeys gave to their choices, independent of quality and quantity (see illustration).

“We have a pretty good idea of how the brain handles the incoming sensory information and, on the output side, of how the brain controls movements we make to execute our choices,” said senior author John Assad, HMS associate professor of neurobiology. “We found a part of the brain that seems to be involved in governing decision-making—what it is that goes off in our heads when we choose Kung Pao chicken over General Gao’s chicken.”

The neural mechanisms for decision-making may also provide insight into certain psychiatric disturbances, such as addictions. People with lesions in the orbitofrontal cortex often show aberrations in choice behavior, the researchers said.

The research by Padoa-Schioppa and Assad belongs to a growing new field known as neuroeconomics, which refers to brain mechanisms underlying subjective choices. “This study gets at subjectivity in a hard-nosed and scientific way,” said Brian Knutson, an assistant professor of psychology and neuroscience at Stanford University, who conducts similar imaging studies of humans making economic choices. “It is also on the leading edge of monkey physiology studies that try to frame neurological questions using the analysis and methodologies of economics. We’re starting to see the basic links between monkey electrophysiology and human neuroimaging.”

—Carol Cruzan Morton and Leah Gourley

Study Strengthens Link Between Epstein–Barr Virus and MS

Several studies in the past decade have suggested that there may be a link between Epstein–Barr virus (EBV) and multiple sclerosis. The longest prospective study of this kind, reported in the April 10 online Archives of Neurology, found that a fourfold increase in certain EBV antibody titers resulted in a doubled risk of the disease.

Previous epidemiological studies noted a correlation between MS and antibodies to EBV detected in blood samples taken up to 10 years before MS onset. But because MS may have a long asymptomatic period, questions remained about when the disease actually began. “Does an increase in EBV antibody titers precede the onset of MS or is it a manifestation of the disease itself?” asked author Alberto Ascherio, HSPH associate professor of nutrition and epidemiology and HMS professor of medicine.

In this study, Ascherio and colleagues used data with a 15- to 20-year interval between blood sampling and the onset of MS symptoms to limit the chance that the disease process had already begun. They relied on a serum repository at Kaiser Permanente Northern California containing blood samples collected between 1965 and 1974 with corresponding medical records for patients active between 1995 and 1999. From the records, Ascherio, first author Gerald DeLorenze of Kaiser, and co-author Kassandra Munger, HSPH doctoral candidate in nutrition, identified 42 patients who developed MS. For each, they identified two control patients that matched in age and gender, but had not developed MS.

By screening blood samples from the repository for eight different antibodies, the researchers found that the mean levels of antibodies against the Epstein–Barr nuclear antigen (EBNA) complex and its component EBNA-1 were higher in the group of MS patients than in the control group and that the increase in titers for these antibodies occurred as much as 15 to 20 years prior to the onset of MS symptoms. They calculated that a fourfold increase in these titers resulted in approximately twice the risk of MS.

Most people contract EBV during childhood, but only some develop multiple sclerosis. A genetic predisposition for MS, being explored by the Harvard Center for Neurodegeneration and Repair, appears to be a critical factor. In some genetically susceptible people, T cells may become tuned to both EBV antigens and myelin antigens in a case of mistaken identity that provokes an autoimmune response.

—Elizabeth Dougherty

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