Biomarker Envy III: Medial Prefrontal Cortex

May 28, 2011

Well, what do you know…. No sooner did I publish my last post about the “depression biomarker” discovered by a group of Japanese scientists, than yet another article appeared, describing a completely different biomarker.  This time, however, instead of simply diagnosing depression, the goal was to identify who’s at risk of relapse.  And the results are rather tantalizing… Could this be the real deal?

The paper, to be published in the journal Biological Psychiatry, by Norman Farb, Adam Anderson, and colleagues at the University of Toronto, had a simple research design.  They recruited 16 patients with a history of depression, but who were currently in remission (i.e., symptom-free for at least five months), as well as 16 control subjects.  They performed functional MRI (fMRI) imaging on all 32 participants while exposing them to an emotional stressor: specifically, they showed the subjects “sad” or “neutral” film clips while they were in the MRI scanner.

Afterward, they followed all 16 depressed patients for a total of 18 months.  Ten of these patients relapsed during this period.  When the group went back to look for fMRI features that distinguished the relapsers from the non-relapsers, they found that the relapsers, while viewing the “sad” film clips, had greater activity in the medial prefrontal cortex (mPFC).  The non-relapsers, on the other hand, showed greater activation in the visual cortex when viewing the same emotional trigger.

Even though the number of patients was very small (16 total), the predictive power of the tests was actually quite high (see the figure at right – click for a larger version).  It’s certainly conceivable that a test like this one might be used in the future to determine who needs more aggressive treatment—even if our checklists show that a depressed patient is in remission.  As an added bonus, it has better face validity than simply measuring a chemical in the bloodstream: in other words, it makes sense that a depressed person’s brain responds differently to sad stimuli, and that we might use this to predict outcomes.

As with most neuroimaging research, the study itself was fairly straightforward.  Making some sense out of the results, however, is another story.  (Especially if you like salmon.)

The researchers had predicted, based on previous studies, that patients who are prone to relapse might show greater activity in the ventromedial prefrontal cortex (VMPFC) and lower activity in the dorsolateral PFC (DLPFC).  But that’s not what they found.  Instead, relapsers had greater activity in the mPFC (which is slightly different from the VMPFC).  Moreover, non-relapsers had greater activity in the visual cortex (specifically the calcarine sulcus).

What might this mean?  The authors hypothesize that mPFC activity may lead to greater “ruminative thought” (i.e., worrying, brooding).  In fact, they did show that mPFC activation was correlated with scores on the RSQ-R, a psychological test of ruminative thought patterns.  Regarding the increased visual cortex activity, the authors suggest that this may be protective against further depressive episodes.  They surmise that it may be a “compensatory response” which might reflect “an attitude of acceptance or observation, rather than interpretation and analysis.”

In other words, to grossly oversimplify:  if you’re in recovery from depression, it’s not a good idea to ruminate, worry, and brood over your losses, or to internalize someone else’s sadness (even if it’s just a 45-second clip from the movie “Terms of Endearment”—which, by the way, was the “sad stimulus” in this experiment).  Instead, to prevent another depressive episode, you should strengthen your visual skills and use your visual cortex to observe and accept (i.e., just watch the darn movie!).

This all seems plausible, and the explanation certainly “fits” with the data.  But different conclusions can also be drawn.  Maybe those “recovered” patients who had less mPFC activity were simply “numb” to any emotional stimuli.  (All patients were taking antidepressants at the time of the fMRI study, which some patients report as having a “numbing” effect on emotions.)  Moreover, it has been said that depression can sometimes be beneficial; maybe the elevated mPFC activity in relapsers was an ongoing attempt to process the “sad” inputs in a more productive way?  As for the protective effect of visual cortex activity, maybe it isn’t about “acceptance” or “non-judgment” at all, but something else entirely?  Maybe those patients just enjoyed watching Shirley Maclaine and Jack Nicholson.

Nevertheless, the more psychologically minded among us might gladly embrace their explanations.  After all, it just seems “right” to say:  “Rumination is bad, acceptance and mindfulness (NB:  the authors did not use this term) is good.”  However, their “mediation analysis” showed that rumination scores did not predict relapse, and acceptance scores did not predict prolonged remission.  In other words, even though these psychological measures were correlated with the MRI findings, the psychological test results didn’t predict outcome.  Only the MRI findings did.

This leads to an interesting take-home message.  The results seem to support a psychological approach to maintaining remission—i.e., teaching acceptance and mindfulness, and avoiding ruminative tendencies—but this is only part of the solution.  Activity in the mPFC and the visual cortex might underlie pro-depressive and anti-depressive tendencies, respectively, in depressed patients, via mechanisms that are entirely unknown (and, dare I say it, entirely biologic?).

[An interesting footnote:  the risk of relapse was not correlated with medications.  Out of the ten who relapsed, three were still taking antidepressants.  Of the other seven, four were engaged in mindfulness-based cognitive therapy (MBCT), while the others were taking a placebo.]

Anyway, this paper describes an interesting finding with potential real-world application.  Although it’s a small study, it’s loaded with testable follow-up hypotheses.  I sincerely hope they continue to fire up the scanner, find some patients, and test them.  Who knows—we might just find something worth using.

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