Monday, April 30, 2007

Dropping acid

In the May issue of Harper's you'll find an insightful essay by Gary Greenberg entitled "Manufacturing depression: A journey into the economy of melancholy." Greenberg, a psychotherapist and freelance writer, has previously written equally engaging pieces in Harper's, Mother Jones, Wired, The New Yorker, and McSweeney's.

"Manufacturing depression" tells the story of Greenberg's experience as an enrollee in a psychopharmacology study at Massachusetts General, in which the effectiveness of omega-3 fatty acids in treating major depression was being tested.

His story with the Mass General researchers begins with an evaluation of depression to see if he was an appropriate fit for the study. Greenberg thought that he'd meet the criteria for what the DSM calls minor depression, "figur[ing] anyone paying sufficient attention was bound to show the two symptoms out of the nine". Heavily abbreviated, those criteria are:
  1. depressed mood nearly every day
  2. markedly diminished interest in activities nearly every day
  3. significant weight loss or weight gain
  4. insomnia or hypersomnia nearly every day
  5. psychomotor agitation or retardation nearly every day
  6. fatigue or loss of energy nearly every day
  7. feelings of worthlessness or excessive guilt nearly every day
  8. diminished ability to concentrate, nearly every day
  9. recurrent thoughts of death, suicidal thoughts
To his surpise, Greenberg is deemed ineligible for the minor depression study because he meets the criteria for major depression (at least five of the symptoms above). He's whisked away into the omega-3 study, and insightful deconstruction of psychiatry ensues.

I won't spoil the rest of the essay; instead here are my two cents on one of Greenberg's relatively minor critiques of the experience. As in any pharmacological trial, the omega-3 fatty acid study is a double-blind, placebo-controlled study; he doesn't know whether or not he's getting the omega-3 or placebo, and nor do the researchers he's interacting with. The thing that surprised me was that at the end of the study, the researchers still could not "break the blind," i.e., tell him which one he was taking.

Evidently the argument for not breaking the blind on each patient's completion of the study is that otherwise, the researchers who represent the "double" part of the blind could detect a pattern across participants.

Surely, if this is the only concern, there are ways to get around this problem, such as having another researcher in the lab, or the pharmacologist who knows the assignments, notify the participant in some other way than through the researcher who administers the examinations?

In the end, Greenberg does find out which one he took, but only after mailing the rest of his pills off to the lab.

Recommended reading:

Greenberg, G. (2007, May). Manufacturing depression: A journey into the economy of melancholy. Harper's, 314, 35-46.

Listen to WBUR's On Point radio program related to the article

Spiegel, A. (2005, January). The dictionary of disorder: How one man revolutionized psychiatry. The New Yorker.

Sunday, April 29, 2007

The fog of war

The New York Times front page today features an article on the cognitive side effects of chemotherapy, sometimes known as "chemobrain." (Chemotherapy fog is no longer ignored as illusion.) The reported symptoms include short-term memory loss, difficulties with concentration and multi-tasking, and word-finding problems (anomia). The symptoms sound like those typically reported in aging populations under the syndrome of "mild cognitive impairment" or MCI.

The angle that the NY Times takes with the piece is that cancer patients have been complaining about these symptoms for years, and only recently have doctors taken the concerns seriously. On the other hand, it's clear even from reading the Times piece that objective evidence for the existence of this phenomenon is mixed. It's hard to know whether a subtle word finding or working memory problem that cancer patients experience following chemotherapy is different from what they would have experienced had they not chosen chemo. (I'm guessing that you can't very readily do a true random assignment, clinical-trial style, experiment to address a question like this.)

The mechanism through which chemotherapy would directly affect cognition is an even bigger mystery. The Mayo Clinic's website suggests that some of the chemotherapy drugs may be getting across the blood-brain barrier, which keeps a lot of substances in the blood from affecting the brain directly. Alternatively, the effects could be a more indirect effect of stress or depression caused by chemo (or of the cancer diagnosis itself) or of hormone therapy, which is part of the treatment regimen for some forms of cancer. The existing studies of the chemobrain phenomenon seem to be based primarily on breast-cancer patients, who often undergo hormone therapy in addition to chemo.

A quick Pubmed search for Tim Ahles of Sloan-Kettering, one of the investigators referenced in the Times, led me to his recently published article in Nature Reviews Cancer. In that article, he and co-author Andrew Saykin suggest that genetic risk factors predispose some individuals both to cancer and to cognitive decline. In other words, this could be a classic example of the third-variable problem; the chemotherapy may not be directly causing mild cognitive impairment, but rather both the need for chemo and the MCI might both stem from a third factor (a common genetic predisposition). This isn't just getting bogged down in semantics; if the direct relationship between chemo and so-called chemobrain existed, then avoiding chemo would result in avoiding chemobrain. This would not be the case if the relationship were mediated primarily by a third-variable. Of course, the dynamics of this are much more complicated, as Ahles and Saykin discuss, and may involve a complex web of interactions between the predispositions and the suite of more direct effects of cancer, chemotherapy, and all its associated treatments and stressers.

Recommended reading:
Ahles, T. A., & Saykin, A, J. (2007). Candidate mechanisms for chemotherapy-induced cognitive changes. Nature Reviews Cancer, 7, 192-201.

Friday, April 27, 2007

In love with simplistic brain theories

The number two most-emailed article at the New York Times today is Tuesday's article, "If you want to know if Spot loves you so, it's in his tail." The article covers a study published last month in Current Biology by A. Quaranta, M. Siniscalchi, and G. Vallortigara, of the University of Bari and the University of Trieste.

Quaranta et al. studied 30 dogs by presenting them with four kinds of stimuli under experimental settings: the dog's owner, a human stranger, a "dominant" unfamiliar dog, and a cat. They found that when the dogs saw their owners, there was a statistically significant (p < .00001) bias in the direction of tail wagging; there was more wagging to the right. Seeing a human stranger resulted in a similar bias to the right (p = .00007), but with less amplitude. With the cat, the bias persisted (p = .03) but will still less amplitude. When the strange, dominant dog - a Belgian Shepherd Malinois - appeared, the dogs were more likely to wag their tails to the left (p = .014).

The authors suggest that this result ties in to one of the many theories of emotion and hemispheric asymmetry that have been proposed: one by Richard Davidson of the University of Wisconsin which suggests that "approach" and "withdrawal" behaviors are associated with the left and right cerebral hemispheres, respectively. Given how cerebrum and body are wired up, movements on the left side of the body are associated with neural events in the right hemisphere, and vice versa.

I was intrigued by this paper and Davidson's hypothesis, and was a little bit skeptical that the approach-withdrawal theory is as widely accepted as the NY Times would have it. As Sandra Blakeslee, the author of the Times piece puts it:
Research has shown that in most animals, including birds, fish and frogs, the left brain specializes in behaviors involving what the scientists call approach and energy enrichment. In humans, that means the left brain is associated with positive feelings, like love, a sense of attachment, a feeling of safety and calm. It is also associated with physiological markers, like a slow heart rate.

At a fundamental level, the right brain specializes in behaviors involving withdrawal and energy expenditure. In humans, these behaviors, like fleeing, are associated with feelings like fear and depression. Physiological signals include a rapid heart rate and the shutdown of the digestive system.
For readers who were in school in the '80s, you might remember some of the "I'm left brained, you're right brained" pseudoscience that educators used to disseminate to unsuspecting fifth graders as solid neuroscientific fact. (Alison Gopnik, writing yesterday on Slate, compares today's obsession with mirror neurons with the asymmetry craze of yesteryear.) So let's consider this "fundamental" brain asymmetry a moment:

The approach-withdrawal asymmetry hypothesis is one of several inter-related hypotheses that have been put forth over the years concerning possible asymmetric processing of emotion in the brain. (See Demaree et al., 2005 for a review.)
  1. Right hemisphere. It has long been observed that neurological patients with damage to the right hemisphere are likely to suffer affective complaints than are patients with left-hemisphere damage. Earlier theories had suggested a stronger role for the right hemisphere in all emotional processing (which may still hold up when it comes to the perception of emotional states in others).
  2. Valence model. Another class of theories argued that "positive emotions" entailed a greater left hemisphere component, and "negative emotions" a greater right hemisphere component.
  3. Approach-withdrawal. Davidson and colleagues extended the valence model by incorporated a strong prefrontal component and emphasizing behavior (or the planning of behavior) rather than simply the emotional state.
  4. Behavioral activation and behavioral inhibition. Demaree et al. also discuss a related extension to which J. A. Gray is a major contributor. This is similar to approach-withdrawal, but with some subtle differences in prediction, e.g., the left hemisphere, and not the right, would be involved in the "active avoidance" of a negative stimulus (i.e., big Belgian shepherds).
The evidence for all of these theories is equivocal, even when considering the neuropsychological, sodium amytal, and EEG data on which they were primarily based, not to mention the later brain imaging evidence that posed more serious problems.

More generally, Davidson's approach-withdrawal asymmetry hypothesis is specific to the realm of emotion and emotion-driven behavior, and specific to particular areas of the brain, most notably regions within the prefrontal cortex and the amygdalae. It does not argue for anything so fundamental about the entire "left brain" and the "right brain." Even if it proved to be an adequate description for this specific problem space, it would still be one particular asymmetry that results from one network of brain regions coming together to solve one class of problems. "At a fundamental level," brain function and behavior represent myriad neural networks and problem spaces, each of which has its own peculiar pattern of hemispheric asymmetry.

Recommended reading:
McManus, C. (2002). Right hand left hand: The origins of asymmetry in brains, bodies, atoms, and cultures. Cambridge, MA: Harvard University Press.

For some other bloggers' takes on the story:
Frontal Cortex
John Hawks