Thursday, October 05, 2006

Sad Cingulate on 60 Minutes and in Rats

Happy to have stereotactic brain surgery while conscious!

Today is National Depression Screening Day, and the sad cingulate (ventral anterior cingulate cortex, or Brodmann area 25) is in the news again. 60 Minutes did a piece on two patients undergoing deep brain stimulation of area 25 as a treatment for intractable depression.

Changing Minds: Area 25
Experimental Brain Surgery May Help The Severely Depressed

(CBS) Eighteen million Americans suffer from major depression. Most of them are treated successfully with a combination of “talk therapy” and anti-depressant drugs. But millions of Americans – possibly as many as four million - are afflicted with what is known as “treatment-resistant” depression. For them, nothing works, not even electric shock treatments. They endure lives of debilitating sadness and some end up committing suicide.

But as correspondent Lesley Stahl reports, early results from an experiment in Canada have raised hopes for an answer to their suffering. It involves surgery on a region of our brains called Area 25. And, for the small group of patients who have signed up, the risks seem worth taking, because this is their last resort.
As invasive procedures go, there is reason to believe that targeted DBS will turn out to be vastly superior to One Flew Over The Cuckoo's Nest-type permanent psychosurgery or amnesia-inducing electroconvulsive therapy (also in the news thanks to Kitty Kukakis), but not a miracle cure or "the depression off switch" (as discussed previously by The Neurocritic). The initial study was conducted at the University of Toronto, with preliminary results published last year (Mayberg et al., 2005). Dr. Helen Mayberg (now at Emory University in Atlanta, Georgia) and her colleagues are currently recruiting patients with treatment resistant depression to participate in a clinical trial using chronic, high frequency stimulation of the subgenual cingulate white matter.

Now how about rats? Do they get depressed? Certainly not in the

glassy eyes and quotes from Kafka
existential (or melting-reality) sort of way. But in a new study, ibotenic acid-induced lesions in the rat rostral cingulate cortex were associated with subsequent impairment in the forced swim test:

The forced swim test (FST) is the most widely used model for assessing potential antidepressant activity in rodents following acute or short-term treatment.
We can certainly protest (quite loudly) that "giving up and floating around the pool" behavior is not much of a model for human depression, but rats aren't very well going to be up all night listening to Bright Eyes or Radiohead and reading Beckett. Moreover, is rat rostral ACC comparable to human ventral ACC? It's interesting that Mayberg et al. (2000) found that resting glucose metabolism in ventral ACC to be overly active in depressed people (and a reduction in activity was associated with antidepressant treatment response), but here we see that permanent damage to rostral ACC in rats acted as a pro-depressant:

Bissiere S, McAllister KH, Olpe HR, Cryan JF. (2006). The rostral anterior cingulate cortex modulates depression but not anxiety-related behaviour in the rat. Behav Brain Res. Sep 30; [Epub ahead of print]

A growing body of functional imaging studies suggests that human depression and anxiety symptoms are associated with functional abnormalities in the circuitry formed by the rostral anterior cingulate cortex (rACC) and its direct limbic and paralimbic connections. In rodents however, the role of the rACC (rCG1/rCG2) remains unknown in depression-related behaviours and elusive in acute anxiety. In order to address this, we specifically lesioned the rat rCG1/rCG2, and assessed the behavioural outcome using a modified forced swim test (FST) and the elevated plus maze (EPM), tests for depression and anxiety related behaviours respectively. Lesions of the rostral anterior cingulate cortex significantly increased the time spent immobile in the FST without affecting climbing or swimming performances, suggesting a pro-depressant effect. On the contrary, none of the parameters measured in the EPM was affected by the lesion. These data point to an involvement of the rCG1/rCG2 in depression-related coping behaviours.
However, other investigators find that resting metabolic activity in ventral ACC is reduced in both unipolar and bipolar depression (Drevets et al., 1997), more in agreement with the rat study, but contrary to Mayberg et al. What's up with that? Here's what Mayberg et al. (2005) suggest:

The baseline pattern of subgenual cingulate hyperactivity in combination with frontal hypoactivity described here in this TRD patient group is a finding that is in contrast to the hypoactivity reported in a more rostral region of subgenual medial prefrontal cortex in familial bipolar and unipolar depressed patients (Drevets et al., 1997). This distinction suggests important differences across subtypes of depression that are potentially relevant to the pathophysiology of major depressive disorders and perhaps their treatment.
And here, you can screen your own mental health using a self-assessment program.

The house is reeling
I'm kneeling by the tub
Lonely is as lonely does
Lonely is an eyesore
The feeling describes itself

--Throwing Muses, Fish


Cryan JF, Page ME, Lucki I. (2005). Differential behavioral effects of the antidepressants reboxetine, fluoxetine, and moclobemide in a modified forced swim test following chronic treatment. Psychopharmacology (Berl). 182:335-44.

Drevets WC, Price JL, Simpson JR Jr, Todd RD, Reich T, Vannier M, Raichle ME. (1997). Subgenual prefrontal cortex abnormalities in mood disorders. Nature 386:824-7.

Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, McGinnis S, Jerabek PA. (2000). Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry 48:830-43.

Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, Kennedy SH. (2005). Deep brain stimulation for treatment-resistant depression. Neuron 45:651-60.

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At October 06, 2006 9:22 PM, Anonymous Anonymous said...

So what is the Neurocritic's opinion of fMRI-targeted TMS as a substitute for ECT in less-intractible cases of depression? On the one hand, I think this has to be a win becasue you can apparently get therapeutically useful results without the seizures. On the other hand, since we really don't have a good idea about why ECT itself works in the first place, I feel somewhat skittish.

At October 09, 2006 1:20 AM, Blogger The Neurocritic said...

TMS would seem to be a much more benign alternative to ECT. There are a number of clinical trials recruiting patients. Some studies report that about 50% of patients experience an improvement of symptoms (e.g., Fitzgerald et al., 2006), but as to which treatment protocol is better, high-frequency stimulation (5-20 Hz) of left dorsolateral prefrontal cortex OR low-frequency stimulation (1 Hz) of right dorsolateral prefrontal cortex... ??

I don't think it's common at all to use fMRI to locate the treatment stimulation site, one reason being that 10 or 20 or more sessions of rTMS are typical. However, in many studies, structural MRIs are taken initally.

At October 19, 2006 11:24 AM, Blogger The Neurocritic said...

Anonymous #2, it would be pointless for me to present the voluminous scientific evidence that depression and other mental illnesses have a biological basis, since you are the equivalent of a fundamentalist Christian who believes in the literal Genesis creation myth. The only difference is that you use foul language and personal insults in your lunatic rantings.

At November 03, 2006 4:12 PM, Blogger The Neurocritic said...

Addendum to the rTMS commentary: an article that reviews previous studies and concludes that... the extant results are inconclusive!

Fitzgerald et al. (in press). An analysis of functional neuroimaging studies of dorsolateral prefrontal cortical activity in depression. Psychiatry Research: Neuroimaging.

Repetitive transcranial magnetic stimulation (rTMS) is currently undergoing active investigation for use in the treatment of major depression. Recent research has indicated that current methods used to localize the site of stimulation in dorsolateral prefrontal cortex (DLPFC) are significantly inaccurate. However, little information is available on which to base a choice of stimulation site. The aim of the current study was to systematically examine imaging studies in depression to attempt to identify whether there is a pattern of imaging results that suggests an optimal site of stimulation localization. ... There was considerable heterogeneity in the results between studies. Changes in Brodmann area 9 were relatively consistently identified in resting, cognitive activation and treatment studies included in the meta-analysis. However, there was little consistency in the direction of these changes or the hemisphere in which they were identified. At this stage, the results of imaging studies published to date have limited capacity to inform the choice of optimal prefrontal cortical region for the use in rTMS treatment studies.

At March 13, 2007 2:57 AM, Anonymous Anonymous said...

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