Tuesday, October 30, 2007

...But My Subgenual Cingulate Is Sad

In the previous post, The Neurocritic discussed an article in Nature in which greater activity in the rostral anterior cingulate cortex (rACC) was associated with optimism1 (Sharot et al., 2007). "But wait!" you might say, "what about the sad cingulate?" Neuroimaging studies have shown that the sad subgenual cingulate (Brodmann area 25), located beneath the genu of the corpus callosum, is overly active in depression (Mayberg et al., 2000; see also Greicius et al., 2007). This excessive activity is dampened in those who respond to six weeks of fluoxetine treatment (Prozac, an SSRI antidepressant), but remains elevated in those who don't. Is this the same brain region in the two experiments? Let's take a look.

On the left is Fig. 2a of Mayberg et al. (2000), showing a decrease in area 25 (Cg25) activity in fluoxetine responders, as measured by PET. On the right is Fig. 2b of Sharot et al. (2007), showing the optimistic rACC region. At first glance, the two "hot spots" appear to be in quite similar locations. However, there are differences in the precise centers of mass, as indicated by the respective x y z coordinates (according to Talairach and Tournoux, a standard 3D atlas of the human brain), and in the designated Brodmann areas (numbered cortical regions based on cytoarchitecture).

x, y, z BA
Mayberg 10,22,-14 25
Sharot -11, 42, -1 32

The x coordinate indicates right or left hemisphere, y is anterior/posterior, and z is dorsal/ventral. Although activations in medial structures generally aren't discussed in terms of left/right hemisphere, because the margin of error is often greater than the distance from the midline (x = 0), here they're centered 10 mm right and 11 mm left of midline, respectively. Furthermore, the Sharot activation is 20 mm in front of the Mayberg activation. Finally, the activations are indicated by different Brodmann areas. Hmm, not the same.

More recently, Mayberg's group demonstrated that deep brain stimulation (DBS) in area 25 was effective in treating severe intractable depression in a small group of patients (Mayberg et al., 2005).
Each [of the six patients] met stringent criteria for treatment resistance defined as failure to response to a minimum of four different antidepressant treatments, including medications, evidence-based psychotherapy, or electroconvulsive therapy, administered at adequate doses and duration during the current episode.
In this procedure, a stimulating electrode is stereotaxically implanted in the targeted region. Dr. Helen Mayberg and her colleagues at Emory University are still recruiting patients with treatment resistant depression to participate in a clinical trial using chronic, high frequency stimulation of the subgenual cingulate white matter. To determine the anatomical connectivity of the sad cingulate region, a new study performed tractography (using diffusion-weighted magnetic resonance imaging) to trace the pathways mediating treatment response with DBS (Johansen-Berg et al., 2007). The authors compared the connections of the subgenual ACC (sACC, blue/cyan) and the perigenual ACC (pACC, red/yellow), which appears to be the optimistic rACC region of Sharot and colleagues.

Figure 3 (Johansen-Berg et al., 2007). Connectivity-based parcellation of ACC and location of electrode contacts. (A, B) Population probability maps of connectivity-defined sACC and pACC. Color scales represent the population probability of a voxel belonging to sACC (from 50% [dark blue] to 80% [light blue] probability) or pACC (from 50% [red] to 80% [yellow] probability). Also shown are the locations of effective electrode contacts from 9 patients overlaid in black. Effective electrode locations are mainly localized within the sACC subregion.

Can we directly link the "optimistic rACC" (pACC) to depression, as stated in the Nature paper? Or more specifically, to DBS efficacy [and Prozac efficacy], as indicated by the work of Mayberg and colleagues? Not really. The effective electrode contacts were in sACC. The critical comparison of sACC vs. pACC connectivity is illustrated below. Is the latter highly interconnected with the amygdala? Doesn't seem to be.

From Figure 4 (Johansen-Berg et al., 2007). Tracts from sACC and pACC regions. (A–F) Population maps of results of probabilistic tractography from the pACC and sACC subregions. Color scales represent the population probability of a voxel belonging to a pathway from pACC (A, B, red to yellow) or sACC (C–F, dark blue to light blue). Abbreviated labels indicate gray matter regions that are connected with sACC or pACC via these pathways. (A, B): Pathways from pACC connect with the anterior midcingulate cortex, AMCC (A); frontal pole, FP (A); nucleus accumbens, NAC (A); hypothalamus (A); and fornix (B). (C, D, E, F): Pathways from the sACC connect with the orbitofrontal cortex, OFC (C, F); NAC (C, D); hypothalamus (C, D); AMCC (C); fornix (C); and amygdala (E, F).

How do we account for these discrepancies in the Nature paper? The tractography article was published after the former went to press, but earlier work by Mayberg et al. was neglected. However, other results were cited (Drevets et al., 1997). These investigators found resting metabolic activity in ventral ACC to be reduced in both unipolar and bipolar depression, contrary to sad cingulate hyperactivity. 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.
What have we learned? Location matters. It's helpful to read the literature. So it goes...


1 Positive correlation with optimism was for the contrast imagine future events (positive) versus imagine future events (negative).


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.

Greicius MD, Flores BH, Menon V, Glover GH, Solvason HB, Kenna H, Reiss AL, Schatzberg AF. (2007). Resting-state functional connectivity in major depression: abnormally increased contributions from subgenual cingulate cortex and thalamus. Biol Psychiatry 62:429-37

Johansen-Berg H, Gutman DA, Behrens TE, Matthews PM, Rushworth MF, Katz E, Lozano AM, Mayberg HS. (2007). Anatomical Connectivity of the Subgenual Cingulate Region Targeted with Deep Brain Stimulation for Treatment-Resistant Depression. Cereb Cortex. Oct 10; [Epub ahead of print]. free PDF

Chronic deep brain stimulation (DBS) of subgenual cingulate white matter results in dramatic remission of symptoms in some previously treatment-resistant depression patients. The effects of stimulation may be mediated locally or via corticocortical or corticosubcortical connections. We use tractography to define the likely connectivity of cingulate regions stimulated in DBS-responsive patients using diffusion imaging data acquired in healthy control subjects. We defined 2 distinct regions within anterior cingulate cortex based on anatomical connectivity: a pregenual region strongly connected to medial prefrontal and anterior midcingulate cortex and a subgenual region with strongest connections to nucleus accumbens, amygdala, hypothalamus, and orbitofrontal cortex. The location of electrode contact points from 9 patients successfully treated with DBS lies within this subgenual region. The anatomical connectivity of the subgenual cingulate region targeted with DBS for depression supports the hypothesis that treatment efficacy is mediated via effects on a distributed network of frontal, limbic, and visceromotor brain regions. At present, targeting of DBS for depression is based on landmarks visible in conventional magnetic resonance imaging. Preoperatively acquired diffusion imaging for connectivity-based cortical mapping could improve neurosurgical targeting. We hypothesize that the subgenual region with greatest connectivity across the distributed network described here may prove most effective.

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.

Sharot T, Riccardi AM, Raio CM, Phelps EA. (2007). Neural mechanisms mediating optimism bias. Nature. Oct 24; [Epub ahead of print].

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At November 01, 2007 9:36 AM, Anonymous Anonymous said...

Are you sure that the difference isn't due to any MNI/Talairach coordinate system differences? The former is confusingly referred to as Talairach frequently. As you probably know, the two systems are nearly identical for subcortical systems but get increasing misaligned in cortical regions.

At November 01, 2007 11:55 AM, Blogger The Neurocritic said...

I considered that, Anonymous. The Sharot paper refers to Talairach coordinates in Fig. 2 and says in the Methods:

Individual data were transformed into Talairach space for group analysis.

Mayberg et al. (2000) refers to Talairach coordinates and cites the atlas.

Mayberg et al. (2005) says:

Brain locations are reported as x, y, z coordinates in MNI space with approximate Brodmann areas (BA) identified by mathematical transformation of SPM99 coordinates into Talairach space(http://

However, Mayberg et al. (2005) specifically discuss the differences between their subgenual locus and that of Drevets et al. (1997), as quoted in the post.

At November 01, 2007 1:42 PM, Blogger The Neurocritic said...

Sharot et al. analyzed their data using Brain Voyager (QX, version 1.7). I don't know if Brain Voyager uses the MNI brain (from the Montreal Neurological Institute) like SPM. If so, the MNI converted to Talairach coordinates are:
-10.89, 40.65, -2.88
according to Approach 2: a non-linear transform of MNI to Talairach by Matthew Brett.

At November 27, 2007 12:29 PM, Anonymous Anonymous said...

Neurocritic: “The Neurocritic discussed an article in Nature in which greater activity in the rostral anterior cingulate cortex (rACC) was associated with optimism1 (Sharot et al., 2007). "But wait!" you might say, "what about the sad cingulate?" Neuroimaging studies have shown that the sad subgenual cingulate (Brodmann area 25), located beneath the genu of the corpus callosum, is overly active in depression (Mayberg et al., 2000; see also Greicius et al., 2007).”
But wait… did the neurocritic actually read the Nature paper carefully? If he had he might have seen this:
“….it has been shown that the rACC’s response to positive and negative stimuli reflects situational specificity. For example, both the rACC and amygdala were more sensitive to positive stimuli in subjects that focused on obtaining goals (promotional context) and to negative stimuli in subjects that focused on avoiding failure (prevention context)22..... in the current study the rACC is tracking the subjective salience of the stimuli by assessing emotional, motivational and autobiographical information, and possibly regulating such signals…”
In other words, the rACC may show greater activity in response to positive events in optimistic subjects, but greater activity to negative events in pessimistic (depressed?) subjects. Indeed, this is what was reported in this paper.

At November 28, 2007 9:35 PM, Blogger The Neurocritic said...

One major point of this post was to explore, and question, whether the rACC region reported by Sharot et al. (2007) is the same one that has been implicated in major depression by Mayberg et al. These two may not be the same region (in my humble estimation). Another point was to examine Sharot et al.'s results in light of the new DTI findings from Johansen-Berg et al. (2007), in terms of connectivity to the amygdala (which is substantial for subgenual area 25, not so much for rACC).

These two issues are independent of the comments from the New Anonymous...

At November 28, 2007 9:54 PM, Blogger The Neurocritic said...

...and I was unfamiliar with reference 22 (Cunningham et al., 2005), quoted by New Anonymous.

Here are the Cunningham et al. anterior cingulate coordinates (in MNI space), pasted in directly from the paper:

Negative Valence (Good/Bad) Correlation With Prevention:
Anterior cingulate BA32 -4, 36, 16

Positive Valence (Good/Bad) Correlation With Promotion:
Anterior cingulate BA32 -4, 44, 16

Those locations look quite a bit dorsal to -11, 42, -1, and they're nowhere near the ballpark of BA25.

At December 03, 2007 11:05 AM, Anonymous Anonymous said...

It seems there is a basic misunderstanding regarding the spatial resolution of fMRI. Unfortunately one cannot make specific spatial localization with conventional fMRI. All the fMRI studies cited here used convention (low-resolution) fMRI + spatial smoothing in data analysis + averaging across brains. The fMRI peaks reported indicate approximate localization. They are reported to give the reader a general idea of localization. Furthermore, they are only the localization of the peak affect. The affect usually spreads beyond the peak. For this reason in most studies discussion of localization in the conclusion is worded in general terms (i.e – rACC and not BA 32). Thus, the comparisons above are not very meaningfull.

At December 04, 2007 10:15 PM, Blogger The Neurocritic said...

Yes, I know about issues with spatial smoothing, averaging, etc. However, I would have thought one could be more precise than 2 cm (which is, of course, rather important for DBS)...

At October 24, 2009 8:14 AM, Anonymous Anonymous said...

There are gross anatomical variations from one brain to another. I often find it striking that Talairach coordinates are still used because they're based on some 80-year old french alcoholic woman's brain. The MNI series is a better estimation of anatomical localization when it comes to aggregating regions and making claims about activation and source localization. Overall, fMRI has a lot of problems, but it still remains a sophisticated and useful methodology. One must be aware of its cavaets when reading about fMRI findings and what can be surmised from them.

Overall, the rostral cingulate seems to be important for salience detection. It being highly innervated with the amgydala suggests that the rACC is important for purposive, goal-directed behavior in the presence of salient environmental cues. It's all rather fascinating, but makes it easy to endorse a neo-phrenological view of the brain, which is folly. The brain is a dynamic system, and fMRI only shows signal-to-noise ratios of areas, but the entire brain is always active and interacting with many other areas. Its astonishing complexity is often simplifed to make it more palatable, but often at the cost of ontological validty, if I may be so bold.

At September 28, 2013 7:52 PM, Anonymous Mike said...

My psychiatrist and I are discussing the possibility of my undergoing a bilateral anterior cingulotomy. I was wondering why cingulotomies choose the lesion location they do, and what effect does this have on the 'sad cingulate' and the 'happy cingulate', as well as, possibly, if anyone knows, effects on other limbic areas e.g. amygdala due to its afferent and efferent connections thereto. Sorry for my simplistic questions, I am but a decade long severely depressed layman.


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