The Prefrontal Cortex and Frontal Lobe Disorders
An Interview with Jordan Grafman, Ph.D.

by Brenda Patoine

January, 2006

Q: You’ve been studying the brain’s frontal lobes for 25 years and have called the prefrontal cortex the “crowning achievement” of the human brain. Why?

Grafman: I began studying the human prefrontal cortex right after completing my doctoral degree in Human Neuropsychology at the University of Wisconsin-Madison. I was studying Vietnam Veterans with penetrating missile wounds at Walter Reed Army Medical Center and began receiving letters and phone calls from the spouses of the patients describing problems in day-to-day functioning that the spouses felt would not be detected by our general test battery. These included problems ranging from behaving inappropri­ately in social situations to not being able to effectively design or carry out a plan. These observations, along with the evidence that our “tests of frontal lobe functions” were not sensitive or specific enough to pick up impairments in many of our patients, led me to contact some of the key investiga­tors in cognition (e.g., Alan Newell) and neuropsychology (e.g., Tim Shallice) who I thought had a “handle” on these issues. While they were generous with their time and comments, I wasn’t satisfied with the approaches being taken and began my own long journey to try to better characterize what role(s) the prefrontal cortex plays in human behavior.

The human prefrontal cortex... is a crowning achievement of the human brain...and is a work in progress.

My research indicates that the human prefrontal cortex is especially designed to store in long-term memory the features that are unique to large structured sets of sequential events such as themes, morals, and plans. This enables us to put off immediate gratification, and allows us to out-think faster and stronger competitors. These observations form the foundation for the notion that the human prefrontal cortex is a crowning achievement of the human brain and that, like the rest of the brain, is a work in progress.

Q: You consider the prefrontal cortex to be the seat of “social cognition” and possibly “moral cognition” as well. What do these terms mean and what leads you to these conclusions?

A: Social cognition refers to the long-term memories we access when we interact socially with others, and that guide our social behaviors in routine and novel situations. These long-term memories contain information about how we accomplished social goals—from obtaining permission to do something, to taking leadership, to collaborating on a project —and incorporate information about perception and action. Moral cognition is a specific example of social cognition that pertains to ethical, legal, and “folk” justice, beliefs, and rules.

My colleagues and I (and others) have argued that the pre­frontal cortex is uniquely suited to manage social and moral cognition because it aids us in controlling our immediate reactions to a stimulus (like a face or gesture) and is critical for forecasting the consequences of a current behavior on a long-term goal. While other species have social cognitive abili­ties and some rudimentary features of moral cognition, social cognitive abilities reach their peak in humans (as does the anatomy and physiology of the prefrontal cortex). Like the prefrontal cortex, social cognition only matures in the second decade of life and shows some decline in old age.

In addition, brain damage in the prefrontal cortex due to head injuries, strokes, and dementing illnesses (among other brain disorders) often result in altered social cognitive abilities. Patients with lesions in the prefrontal cortex may behave inap­propriately in public, violating social rules such as personal space maintenance, social contracts, or inappropriate verbal­izations. The earliest example of this comes from the famous brain-injured patient Phineas Gage, but many modern-day Gages have been reported in great detail, highlighting the unfortunate case histories of these patients.

Functional neuroimaging studies now routinely identify the importance of the prefrontal cortex for mediating social and moral behavior.

Finally, functional neuroimaging studies now routinely identify the importance of the prefrontal cortex for mediating social and moral behavior in studies examining all kinds of social behavior.

Q: What have you learned about how the brain processes “good” attitudes vs. “bad” attitudes? Does it surprise you that the underlying circuitry is so distinct?

A: We have been very interested in studying social attitudes, including stereotypes, because they are examples of simple associative knowledge that can influence behavior—often outside an individual’s awareness. My colleagues and I think that these attitudes are rudimentary forms of more complex social behaviors and therefore are likely to be stored in the ventromedial prefrontal cortex. We have data from patient studies and from fMRI studies in normal volunteers that support this inference. But the picture can become more complicated once you distinguish among types of attitudes.

For example, we have found a hemispheric asymmetry under­lying good and bad attitudes, with negative attitudes being more strongly associated with right frontal lobe activity and positive attitudes with left frontal lobe activity. While at first this might seem surprising, in fact, there is accumulating evidence that the right hemisphere appears to be much more involved in various forms of avoidance behavior, whereas the left hemisphere appears to be much more involved in approach behavior. Our attitude data would fit nicely into that view. Of course, the devil is in the details, and we want to know what underlying representations and mechanisms might mediate such a distinction.

Q: NINDS has just completed a Phase 1 study showing that electrical stimulation (“direct current polarization”) of the frontal lobes is safe and can enhance verbal fluency in healthy adults. What are the prospects for using this approach to treat frontal lobe disorders, such as frontotem­poral dementia (FTD)? Does this suggest a day when we might selectively “tickle” groups of neurons to enhance a deficient (or desired) cognitive or social trait?

A: Based on our findings with normal volunteers, we are cautiously optimistic about using direct current (DC) polariza­tion to modulate cortical cognitive functions. We have begun studies to use DC polarization in patients with frontotemporal dementia (FTD) to try to improve their language fluency. Even a small change over a short period of time would be welcome since there are few treatment alternatives for FTD.

DC polarization is safer than transcranial magnetic stimulation (TMS), another stimulatory therapy under investigation, although it may not have the same precision as TMS for local/regional stimulation. Nevertheless, TMS is tied to the laboratory because of the equipment required, whereas DC polarization requires only a small battery pack about the size of an iPod. Another advantage to using DC polarization is that even though the stimulating pad that is placed on the scalp covers a fairly large region of the brain, the therapy is still more focal than current drugs, and doesn’t have the unintended side effects that drugs may have.

Although we hope that it has some therapeutic efficacy (additional, larger trials in patients will determine this), the possibility that DC polarization could be used to do something like boost a student’s test-taking ability is a long way down the line. Moreover, any artificial enhancement of cognition carries with it the same ethical issues that using steroids in sports competitions would have, in terms of setting new standards of achievement.

Q: How can your group’s research shed light on diseases like FTD?

A: My section at the NINDS (and our collaborators, including John Hardy at the NIH and Dino Ghetti at the University of Indiana) is one of several laboratories throughout the world studying frontotemporal dementia. Like other laboratories, we are collecting medical histories, information on environ­mental exposures, genetic information, structural and functional brain images, and neuropsychological data. We also hope to eventually have brain tissue from autopsies.

We have several goals in studying patients with FTD. We hope to better understand the pathophysiology of the various sub­types of FTD so we can develop symptomatic interventions in the short term. In the long run, we hope to better characterize the molecular biological signatures of the various FTDs so that molecular-level interventions that address the underlying pathology can be fashioned. Given that so many of our patients have agreed to autopsies, we should be able to eventually pro­vide improved information about the differential diagnosis of the FTDs for clinicians to use. Last but not least, we will employ experimental cognitive tasks to study the cognitive and behavioral deficits these patients exhibit, which will not only inform us about the manifestations of FTD, but will also teach us about the normal functions of the prefrontal cortex and anterior temporal lobes.