My Problem With John Horgan’s Problem With Optogenetics

There’s been a fair flap lately about John Horgan’s argument that optogenetics and its potential have been overhyped by both scientists and some journalists (including myself, I think, from my inclusion in one paragraph listing “glowing coverage”). I like it that Horgan is pushing back a bit, because I think the field stands in danger of being overhyped (and almost surely is, since it’s about the brain!). I’m not sure he’s picked out the right examples or made his point very well; I’ll leave that back-and-forth to the scrum.
But I do want to correct one part of his argument that seems fairly crucial — crucial enough that he made it his nut graph:

So what’s my problem with optogenetics? Actually, I have several problems. First is the gross oversell. For optogenetics to become an effective method for treating mental illnesses, you need specific knowledge about the illnesses’ neural underpinnings. You must know which neurons or neural circuits are overactive or underactive or otherwise abnormal.

But we lack such knowledge about depression, schizophrenia, bipolar disorder or any other major mental illness. As the director of the National Institute of Mental Health recently acknowledged, decades of research have not turned up any clear-cut physiological—that is, neural, genetic or chemical–correlates of the major mental illnesses. How can a brain-manipulation technique alleviate mental illness if we don’t know what to manipulate?

[from Why “Optogenetic” Methods for Manipulating Brains Don’t Light Me Up* | Cross-Check, Scientific American Blog Network.]

Great, concise phrasing. Unfortunately it overlooks one of the past decade’s most significant  lines of work in depression. This is the work of Helen Mayberg, which I’ve written about in a long feature in the New York Times Magazine 7 years ago; in a follow-up in Scientific American; and a post on optogenetics here. (You’re encouraged to read and judge for yourself whether I overhype  the work.)

Mayberg’s work presents exactly what Horgan says is absent: The identification of a specific target for the use of things like optogenetics. In a line of work 25 years and running now, Mayberg first painstakingly identified a specific brain region, known as Area 25 (labeled ACg in the center figure above), that seems to run amok in depression; and then, by quieting Area 25 in experimental surgeries that implanted deep brain stimulation (DBS) devices in it, achieved two rounds of remarkable results alleviating depression in a majority of horribly depressed patients. She continues to get promising results with this experimental technique, and large double-blind trials are in progress.

Neurologist Helen Mayberg’s hand-drawn diagram (in my notebook one day) of Area 25 connectivity involved in depression. Drawing and labels are Mayberg’s; handwritten notes above and below are mine.

Mayberg is quick to lodge two caveats that I think Horgan would be quick to lodge: First, that before we can consider this a viable treatment, the double-blind trials underway need to replicate her finding. Second, that the intrusiveness and expense of deep brain stimulation surgery, and perhaps of optogenetics, make those approaches to this area less than ideal, and we must hope to find another way to quiet this area if indeed the trials prove its viability.

I’m not saying this is a treatment ready for prime time, despite its great promise.  I am saying that given these results, it’s misleading — no, as much as I like Horgan, I must say it’s just wrong to declare that no one has yet identified any neurological correlates or targets for tools such as optogenetics or DBS. If Horgan wants to argue that by “clear-cut” he means “absolutely proven,” then  …  he needs to change “clear-cut” to “absolutely proven.”

But if we’re with Webster in defining “clear-cut” as “sharply outlined” or “distinct,” then I hope Horgan will agree that we can meet that definition by offering a sharply outlined and distinct pea-sized brain area whose targeting relieves crippling depression in half to two-thirds of catastrophically, otherwise incurably depressed patients.

Please proceed.

Note on top image: For some reason it wouldn’t let me add a caption, so here it is: Brain areas affected by four historical psychosurgical depression treatments. Area 25, aka the anterior cingulate, is identified as ACg in the center figure.