TCR: Dr. Dougherty, it looks like you've now literally "written the book" on neuroimaging in psychiatry (Essentials of Neuroimaging for Clinical Practice, Dougherty, Rauch, and Rosenbaum, eds., Wash D.C.: APPI, 2004). Congratulations! How did you get interested in this field, originally?
Dr. Dougherty: When I was a medical student at the University of Illinois I worked in a lab labeling receptors in rat brains, and then when I came to Mass General for psych residency, I learned that you can use PET and SPECT to look at receptors in vivo and I thought, "Wow that is really cool." So after residency I did a two-year research fellowship in radiology and nuclear medicine, and I've been doing research ever since.

TCR: I know that neuroimaging is a huge topic, but perhaps we could start with PET scanning, which has gotten plenty of press lately. How does the PET scan work exactly, in not too complicated terms?
Dr. Dougherty: It isn't like a CT scanner that creates radiation and shoots it through you. You have to actually inject the patient with a radioactive tracer which is then detected by the scanner. Usually, this tracer is a form of glucose labeled with an unstable isotope of fluorine (F-18), and it’s abbreviated “FDG.” FDG goes wherever glucose normally goes, and the scanner detects the radiation.

“Researchers have found that in depression, the limbic system in the brain tends to be hyperactive, while the higher cortical areas tend to be under-active.”
-Darin Dougherty

TCR: OK, but PET stands for “positron emission tomography.” You haven’t even mentioned positrons--how do they get involved?
Dr. Dougherty: F-18 and other unstable isotopes release positrons which are just very small subatomic, positively-charged particles, sort of the opposite of electrons. Very quickly, the emitted positron finds an electron and they smash into one another, causing what is called an "annihilation event." Gamma rays then shoot off in opposite directions from this little apocalypse, and that is what the PET camera detects.

TCR: So PET imaging allows you to detect where the most glucose metabolism is taking place at any given time.
Dr. Dougherty: Exactly. For example if you had someone do a visual task and then took a picture, you would see a lot of visual cortex activity compared to the rest of the brain. Or if someone squeezes a tennis ball with the left hand, you would see the right motor strip light up.

TCR: How is PET changing how we conceive of depression?
Dr. Dougherty: PET has helped us understand which brain regions are affected in depression. In simplistic terms, what researchers have found is that the limbic system in the brain tends to be hyperactive, while the higher cortical areas tend to be under-active. We all have strong affective experiences throughout the day, but most of us have a good functioning cortex to squelch much of this, allowing us to go about our business. But in depression, you have a double whammy in which your limbic system is heightening affective experience, but your cognitive cortical areas are not as well prepared to dampen that, so you get hit from both sides.

TCR: A recent study in Archives of General Psychiatry has gotten a fair amount of press in which researchers PETscanned patients who had recovered from depression and found differences between those who took medications versus those who improved with cognitive behavior therapy alone.
Dr. Dougherty: Right, and in that study the antidepressant seemed to have its effect by dampening the limbic system, whereas the cognitive therapy seemed to increase metabolic activity in the dorsal cortex. But it seems that repair of either brain region reciprocally leads to repair of the other area as well. So for treating depression, you have the choice of coming in from the "bottom" (the limbic system) with meds or from the "top" with cognitive behavioral therapy--or most ideally, with both.

TCR: You've also done research using PET to visualize receptor occupancy for neurotransmitters. How is this work affecting our view of the neurobiology of depression?
Dr. Dougherty: We have found that the conventional idea that there are abnormalities of serotonin, norepinephrine, and dopamine in depression is probably true. But PET is allowing us to pinpoint exactly how these abnormalities arise.

TCR: Okay, let's talk about serotonin. The simplistic view is that depression is a disorder of low levels of serotonin.
Dr. Dougherty: Right, and the prediction was that this would lead to a higher density of receptors because of upregulation.

TCR: So when there is low serotonin, the brain responds to that by synthesizing more receptors because it’s kind of "thirsty" for more serotonin.
Dr. Dougherty: Exactly. There are more receptors on the receiving neuron, so those receptors have a better chance of being hit by the little serotonin that is there. Up until recently, however, the studies weren't really supporting this theory.

TCR: So how are the newer PET techniques helping us to understand this issue?
Dr. Dougherty: We are now developing specific ligands that can attach to different subclasses of serotonin receptors. There are some fourteen different receptor subclasses of serotonin and different drugs we use affect different parts of the serotonin system. For example, BuSpar affects 5HT1A, the SSRIs affect the reuptake pump, nefazodone affects 5HT2 in addition to the reuptake pump. All of these drugs work a little differently. And what has been interesting is that many of the earlier studies were using ligands to look at 5HT2 receptors, and they were finding that depressive cohorts didn't differ much from controls in the density of 5HT2 receptors.

TCR: A finding that directly contradicts the idea of receptor upregulation in depression.
Dr. Dougherty: Right. The problem was that most of the ligands being used in these studies were for 5HT2A and 5HT2B. But now there is a whole new branch at the NIMH just to develop new ligands for use in PET imaging studies. And there are new ligands to look at other parts of the serotonin system like the 5HT1A receptor, which--in contrast to 5HT2--shows huge differences between depressives and controls. So the research is still rather nascent, but we are beginning to be able to tease apart what components of the neurotransmitter systems may be disordered in depression.

TCR: You also do some work with OCD, and I know there are some interesting PET findings there as well.
Dr. Dougherty: The PET findings in OCD have been replicated so many times that the neurocircuitry of the disease is now pretty clear. And what is going on essentially is that OCD patients have hyperactivity in the orbital frontal cortex, the caudate, the thalamus, and the anterior cingulate cortex. All of these areas are connected via a circuit, and the whole circuit is hyperactive. When I treat patients, I use the analogy of a treadmill that is going too fast and I explain that treatment slows down the treadmill enough so that patients can step off it. Neurologically, this is in fact what happens--the degree of hyperactivity in the orbital frontal cortex gradually normalizes, and this correlates with subsequent response to both behavioral therapy and medication. OCD as a disorder is probably the star in terms of psychiatric illnesses in which we have really been able to tease apart the neurobiology.

TCR: Alzheimer’s dementia is another area in which there are some promising PET findings. We review some of the studies on this in another article in this issue, but can you describe some of the typical PET findings in patients with AD?
Dr. Dougherty: In AD you get decreased metabolism in temporal and parietal areas first, and then it gradually moves forward into the frontal regions. The areas that are spared are the somatosensory cortex on each side. So in the worst cases you have what is called the “earmuff sign” because as you look at the brain the only areas that are lit up correctly are the two somatosensory cortices.

TCR: And radiologists have enough experience with normal PET patterns that they can fairly easily recognize a pattern suggestive of AD?
Dr. Dougherty: Yes they can, and while the sensitivity and specificity aren’t perfect, patients sometimes pay for these scans out of pocket, and I expect that sometime in the not too distant future insurance companies will pay for them as well.

TCR: Thank you Dr. Dougherty