Wednesday, September 15, 2010

Modern Tract-Tracing for Historical Psychosurgery

Figure 3 (Schoene-Bake et al., 2010). Intersection of connectivity maps of Anterior Capsulotomy (red), Anterior Cingulotomy (blue), and Subcaudate Tractotomy (green) tracking results. Overlap of AC and ACT shown with magenta, AC and SCT in yellow, and ACT and SCT in cyan. The white area shows overlapping of AC, ACT, and SCT mean probability-tracking maps in axial (a), coronal (b), and sagittal (c) slices. Acg, anterior cingulate gyrus; ATR, anterior thalamic radiation; CST, corticospinal tract; FM, forceps minor; FP, frontal pole; Nacc, accumbens nucleus; PAG, periaqueductal grey matter; slMFB, superolateral branch of medial forebrain bundle; Thal, thalamus.


When I first saw a journal article titled Tractographic Analysis of Historical Lesion Surgery for Depression, I assumed the authors (Schoene-Bake et al., 2010) located some elderly patients who had received psychosurgery in the 1960s, then scanned them using diffusion tensor imaging to trace the white matter tracts affected by the surgeries. This was not the case, however. Instead, the paper is a lesion simulation study that used MRIs from a large sample of control participants.

Although this revelation was initially disappointing, the results included the pretty colorized DTI figure shown above.1 And it reviewed the four historical surgical approaches and their anatomical targets, shown in the table below.



Jumping ahead to the punchline, what were the conclusions?
Shared connectivities between the four surgical approaches mapped onto the most mediobasal aspects of bilateral frontal lobe fibers, including the forceps minor and the anterior thalamic radiations that contacted subgenual cingulate regions [Brodmann area 25]. Anatomically, convergence of these shared connectivities may derive from the superolateral branch of the medial forebrain bundle (MFB), a structure that connects these frontal areas to the origin of the mesolimbic dopaminergic ‘reward’ system in the midbrain ventral tegmental area [VTA]. Thus, all four surgical anti-depressant approaches may be promoting positive affect by converging influences onto the MFB.
Putting aside for a moment the actual efficacy of these surgeries, the claim is that disconnection of the "sad cingulate" from the VTA was at least partly responsible for improved mood. In modern times, the subgenual cingulate has been a target for deep brain stimulation (DBS) trials for intractable major depression (Mayberg et al., 2005; Lozano et al., 2008). In contrast to creating a permanent lesion, in DBS 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 subgenual cingulate region, these researchers performed tractography (using diffusion-weighted MRI) 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).


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.

Resting metabolic activity in subgenual cingulate was shown to be increased in the patients with treatment-resistant depression (Mayberg et al., 2005):
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.
Reflecting further on the historical lesion data, one might infer that a hyperactive subgenual cingulate ultimately inhibited activity in the VTA, a dopamine "reward center". The idealized lesions for all four surgical approaches are shown in the simulation below.


Figure 1 (Schoene-Bake et al., 2010). Mean probability maps of simulated lesions. (a) Anterior capsulotomy (AC); (b) anterior cingulotomy (ACT), I - sagittal, II - coronal, III - axial; (c) subcaudate tractotomy (SCT); and (d) stereotactic limbic leucotomy (SLL).

I would like to see how these simulated lesions compare to the actual surgical lesions from days of yore. Schoene-Bake et al. (2010) hope that a look back at the past will enhance the future of depression treatment:
DTI probabilistic connectivity analysis is a useful tool to explore and to simulate the structural and functional impact of past stereotactic lesion surgery approaches for treating psychiatric disorders. Our study shows overlapping fiber tracts from four classical historical lesion sites for treating depression. The most prominent shared tract revealed by the present work was the slMFB. This structure has some appeal as a new site that could be of interest for DBS in major depression, especially considering the historically established role of this brain reward-seeking network in regulating positive affective states.

Footnote

1 And who isn't cheered up by pretty colorized DTI figures?

References

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 6:1374-1383.

Lozano AM, Mayberg HS, Giacobbe P, Hamani C, Craddock RC, Kennedy SH. (2008). Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression. Biol Psychiatry 64:461-7.

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.

Schoene-Bake, J., Parpaley, Y., Weber, B., Panksepp, J., Hurwitz, T., & Coenen, V. (2010). Tractographic Analysis of Historical Lesion Surgery for Depression. Neuropsychopharmacology DOI: 10.1038/npp.2010.132

Subscribe to Post Comments [Atom]

4 Comments:

At September 15, 2010 8:03 AM, Blogger Neuroskeptic said...

Interesting study, although like you I was disappointed that it wasn't a study of actual psychosurgery veterans.

The sad little subgenual cingulate does seem to be doing something important in depression, but we should remember that in the old days psychosurgery wasn't just used for depression, it was also used for (what would now be called) OCD, mania, and more. And it apparently worked in pretty much all "emotional" disorders, though it did not help in psychosis except by making people care less about their symptoms.

So Mayberg's focus on the subgenual cingulate as being related to depression specifically, seems a bit odd. I bet it is doing the same thing in OCD, and more.

 
At September 15, 2010 9:50 PM, Blogger David Dobbs said...

Nice post, NC, and I'm intrigued by NSkeptic's comment as well. A couple years ago I did a long feature on Mayberg's work, and followups later. She focused on the ACC (Area 25) after a long, rigorous search that narrowed that area down as crucial in depression in particular. Her initial DBS trials were less an effort to test a treatment than to test the hypothesis that the hyperactive ACC in depressed people acted essentially as a gate between emotive and cognitive areas (v roughly speaking) that was stuck open. If I recall, neither her nor other studies found the ACC behaving that way in other emotional disorders.

Meanwhile, other efforts aiming DBS at other areas to treat depression or other problems have not yielded results as promising as Mayberg's. The one exception: Early trials she is running that target same ACC to treat Type II bipolar disorder are getting what seem promising results -- though n is still low and studies still young.

Finally, as Mayberg is v quick to note, this needs double-blind replication w full placebos on 2d track; some of the studies now underway are aimed at that.

My articles on this work are at

Times Mag feature: http://nyti.ms/DepSwitch

Followup on ACC circuitry in SciAm Mind: http://bit.ly/ACCwiring

Profile of Mayberg in SA Mind: http://bit.ly/ACCwiring

 
At September 16, 2010 10:03 AM, Anonymous Mike Lisieski said...

I'm in love with colorized DTI images. They give brain scanning, in an age where everybody has seen a million MRI images, a bit of flair (ntm the whole "utility of tract-tracing" thing - that's pretty cool too.)

 
At September 19, 2010 1:15 AM, Blogger The Neurocritic said...

Neuroskeptic - I didn't think the subgenual cingulate was the major region of hyperactivity in OCD -- orbitorfrontal cortex (lateral to SGC) is more typically implicated. That said, the same anterior limb of the internal capsule and ventral capsule/ventral striatum regions are DBS targets for both depression and OCD.

David - Thanks for your comment and the follow-up in your post Depression’s wiring diagram. I didn't realize Mayberg's current trial includes depressed patients with bipolar II, but it clearly says that at clinicaltrials.gov. There's obviously more of a risk of hypomania in these patients.

Mike - There's something artistic about colorized DTI images, nearly nearly Warhol-esque.

 

Post a Comment

Links to this post:

Create a Link

<< Home

eXTReMe Tracker