Thursday, January 19, 2012

Deep Brain Stimulation for Bipolar Depression

The Melancholia of Kirsten Dunst and Lars von Trier

“Gray wool, clinging to my legs, it's heavy to carry along”

The disastrous wedding reception of the severely depressed Justine precedes the end of the world, depicted as a highly stylized and artistic event feared by some but welcomed by others. Kirsten Dunst plays the role of von Trier's own melancholia, which was the inspiration for his film.

The image above occurred out of context, at the very beginning, during the bombastic Wagnerian apocalyptic prelude to Part One, "Justine" and Part 2, "Claire." We don't hear Justine say those words until later, when she had lost the ability to care for herself. "She should be hospitalized," I thought at the time, and wondered why no one was getting her psychiatric help. But then we wouldn't have a movie that deals with internal struggle and suffering.

Deep Brain Stimulation for Treatment-Resistant Depression

Severe depression that is refractory to treatment, i.e. unresponsive to psychotherapy, multiple trials of antidepressant drugs (often combined with atypical antipsychotics, mood stabilizers, benzodiazepines, etc.) and electroconvulsive therapy (ECT), takes a tremendous toll on the long-suffering patients and their families. An alternative treatment modality, deep brain stimulation (DBS), has been in clinical trials for intractable depression for nearly 10 yrs. It works using the same sort of device used in DBS for Parkinson's disease, which has been remarkably successful in alleviating symptoms. Electrodes are implanted deep in the brain, targeting the ventral portion of the anterior cingulate cortex, in Brodmann's area 25.

Other brain regions have been targeted for DBS in major depressive disorder, including the nucleus accumbens, but today we'll focus on the work of Dr. Helen Mayberg and her colleagues at Emory University in Atlanta, Georgia.

Figure 1 (Holtzheimer et al., 2012). Surgical targeting. Preoperative MRI shows the sagittal (A) and coronal (B) views of the planned optimal subcallosal cingulate (SCC) white matter target (red circle). The dotted black line indicates the subcallosal plane of interest, parallel to the anterior-posterior commissural line; the dotted white line indicates the rostral limit of the subcallosal plane; and the dotted red line indicates the midsubcallosal plane. The red circle indicates demarcation of the SCC white matter target and surrounding gray matter. C and D, Postoperative computed tomography scan merged with preoperative MRI showing a typical case with the deep brain stimulation electrodes in situ. Note that the contacts span the SCC gray and white matter in the vertical plane proximal to the split of the cingulum bundle and rostral medial frontal white matter tracts (C, red arrows, sagittal view). Contacts are numbered by convention (1-4 on the left, 5-8 on the right), inferior to superior. Contacts 2 and 3 are directly in the SCC white matter, and contacts 1 and 4 are in the inferior and superior gray matter, respectively.

Why stimulate subcallosal cingulate/area 25 1 in depression? Previous neuroimaging studies by Mayberg and colleagues (2000) showed that resting glucose metabolism in this region is overly active in depressed people, and a reduction in activity was associated with antidepressant treatment response. Another key observation was made using a mood induction paradigm in healthy volunteers (Mayberg et al., 1999). After the participants remembered a sad autobiographical memory, their SCCs showed greater blood flow relative to a neutral mood state. Thus, the "sad cingulate" was implicated in normal sadness as well as in depression.

The most recent DBS report, published in the Archives of General Psychiatry (Holtzheimer et al., 2012), is a follow-up after two years of chronic, high frequency stimulation of the subgenual cingulate white matter. The basic findings have been summarized elsewhere, including Providentia, with a review of possible mechanisms at The Scicurious Brain.

The aspect of the study that I'd like to focus on today is the inclusion of patients with Bipolar-Type II (BP-II) for the first time, in addition to those with unipolar depression. Just as with the unipolar patients, those with BP-II had to be in a depressive episode for at least 1 yr.

The specific DSM-IV diagnostic criteria for Bipolar II Disorder are:
A. Presence (or history) of one or more Major Depressive Episodes.

B. Presence (or history) of at least one Hypomanic Episode.

C. There has never been a Manic Episode or a Mixed Episode.

D. The mood symptoms in Criteria A and B are not better accounted for by Schizoaffective Disorder and are not superimposed on Schizophrenia, Schizophreniform Disorder, Delusional Disorder, or Psychotic Disorder Not Otherwise Specified.

E. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

Are the same neural circuits implicated in treatment-resistant depression also involved in BP-II? Remarkably, there is nothing in the literature that presents a rationale for using DBS for bipolar depression specifically, nor about why the subgenual cingulate white matter should be the target. A 2010 review by Lipsman, Lozano, and others from the Toronto neurosurgical group stated: "There are currently no trials or reports in the literature on the use of DBS for the exclusive treatment of bipolar disease or bipolar depression." However, Mayberg's ongoing clinical trial at Emory has included individuals with Bipolar Type II (current episode depressed) since it began in 2006. Those with Bipolar I have always been excluded. Why? Is it because a DBS-triggered hypomanic state is less likely in BP-II than in Bipolar I, or is it that full-blown mania might be more easily triggered by stimulation of SCC? We don't really know whether there's any empirical evidence behind these choices.

The Holtzheimer et al. (2012) paper mentions an earlier trial (Mayberg et al., 2005; Lozano et al., 2008) that included BP-II participants by accident (n=2), saying that "neither received significant benefit from SCC DBS." In those studies, conducted by the Toronto group, individuals with bipolar disorder were specifically excluded (Lozano et al., 2008), but...
One patient who initially was diagnosed with unipolar depression had more accurately, in retrospect, previously undiagnosed bipolar II disorder.
Different medications are prescribed as first-line treatments for unipolar and bipolar depression: antidepressants vs. mood stabilizers, respectively. In fact, antidepressants are most often contraindicated in bipolar depression because of the risk of a switch to hypomania/mania (Daray et al., 2010). Shouldn't we be concerned about DBS-induced hypomania? Interestingly, that was not an issue in this study:
No hypomania or mania occurred, and there was no significant change in Young Mania Rating Scale scores in any patient. None of the instances of anxiety was associated with other hypomanic symptoms.

In their review, Lipsman et al. (2010) cautiously concluded that DBS for refractory bipolar depression might be a good idea, with the subgenual cingulate as a potential target:
Given the evidence presented here, including neuroimaging, both structural and functional, as well as circuitry data and previous experience with DBS, a case can be made to carefully evaluate neurostimulation in highly selected cases of treatment-resistant bipolar depression. A convergence of data suggest that the anterior cingulate, and specifically the subgenual cingulate, should be a leading target for intervention, as it is in the best position to modulate cortico-limbic circuits mediating depressed mood. It also happens that the sgACC has been postulated as interacting in circuits responsible for impulsivity and mania, and an effect of DBS on irritability and agitation could be monitored as well (95, 96). There is sufficient unmet clinical need and a strong scientific rationale for a trial to address the utility of DBS in refractory bipolar depression and to determine whether this is a viable and safe alternative for a patient population with no other treatment alternatives.
Finally! We did find a rationale, but looks like it's a little late in the game.2

What have we learned so far? Subcallosal DBS for bipolar depression is relatively safe and does not appear to trigger hypomania. But is hypomania the opposite of sadness? Not exactly. Although an expansive and elated mood can be one feature of hypomania, it isn't a necessary one. The mood can be irritable instead. Other symptoms can include alterations in cognition (racing thoughts, distractibility, grandiosity), impulsivity, and an excessive pursuit of rewarding activities without concern for the consequences (i.e., spending the kids' college fund to buy yourself a luxury speedboat). The latter symptom might be more closely related to abnormal activity in the brain's reward circuitry. Indeed, mania-like episodes have been triggered in patients with Parkinson's disease and OCD, who have electrode placements in dopamine-rich areas. Readers who are skeptical that behavioral "addictions"/compulsions3 can exist should read the literature on dopamine agonist therapy and subthalamic DBS in Parkinson's patients.

In cases of unipolar depression, the nucleus accumbens (NAcc) has been another region of interest. It makes sense as a DBS target area from the standpoint of anhedonia (inability to experience pleasure from normally pleasurable life events) in major depression. Why not stimulate the "pleasure center" when you're feeling blue? Extensive research in animals and humans has demonstrated "hedonic hot spots" in the NAcc. However, this could be a disaster in cases of bipolar depression.

As we've seen in a number of studies, quieting the overly active "sad cingulate" can ameliorate depressive symptoms. I would be interested in seeing the details of the clinical ratings on instruments such as the HRSD {PDF}. Did the deeply sad mood and suicidal thoughts show the greatest improvement? In cases of NAcc stimulation, did symptoms of anhedonia improve the most?

Returning to the present DBS study, the clinical efficacy results are summarized in the table below. Note that the dropout rate over 2 yrs was higher for the bipolar (4 of 7) than for the unipolar participants (2 of 10). This was not adequately explained.

ADDENDUM Jan 21 2012: The first author of the article, Dr. Paul Holtzheimer, clarified that not all patients had reached the 2 yr follow-up point yet. 24 weeks of active DBS was the primary efficacy end point reached by all 17 patients. Only one participant (unipolar) had dropped out of the study.

Nonetheless, among the 11 patients who received 2 yrs of chronic stimulation, the response and remission rates were high (92% and 58%, respectively). Providing such an improved quality of life in a population that had experienced misery and poor functioning for so long is an achievement.

In the movie Melancholia, Justine is buoyed by learning the world is about to end. Now,4 an alternative ending may exist to lift people out of an apocalyptic abyss.

Further Reading:

A Depression Switch?

The Sad Cingulate

Sad Cingulate on 60 Minutes and in Rats

Good News/Bad News Update on Nucleus Accumbens DBS for Treatment-Resistant Depression

Mania and Artistic 'Surprise' Induced by Deep Brain Stimulation


1 The terms subcallosal cingulate, area 25, and subgenual cingulate have been used interchangeably in the literature.

2 Mayberg used to be part of the Toronto group but is currently at Emory.

3 Also known as impulse control disorders (e.g., for gambling, sex, or shopping). Whether these are properly known as addictions is a matter of debate. The point here is that these behaviors can be initiated through dopamine therapies.

4 In rare, selected cases.


Daray FM, Thommi SB, Ghaemi SN. (2010). The pharmacogenetics of antidepressant-induced mania: a systematic review and meta-analysis. Bipolar Disord. 12:702-6.

Holtzheimer, P., Kelley, M., Gross, R., Filkowski, M., Garlow, S., Barrocas, A., Wint, D., Craighead, M., Kozarsky, J., Chismar, R., Moreines, J., Mewes, K., Posse, P., Gutman, D., & Mayberg, H. (2012). Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Unipolar and Bipolar Depression. Archives of General Psychiatry DOI: 10.1001/archgenpsychiatry.2011.1456

Lipsman, N., McIntyre, R., Giacobbe, P., Torres, C., Kennedy, S., & Lozano, A. (2010). Neurosurgical treatment of bipolar depression: defining treatment resistance and identifying surgical targets. Bipolar Disorders, 12 (7), 691-701 DOI: 10.1111/j.1399-5618.2010.00868.x

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, 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, Liotti M, Brannan SK, McGinnis S, Mahurin RK, Jerabek PA, Silva JA, Tekell JL, Martin CC, Lancaster JL, Fox PT. (1999). Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry 156:675-82.

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.

A beautiful movie about the end of the world

Melancholia is also the name of the giant blue planet that destroys the Earth.

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At January 20, 2012 5:55 PM, Anonymous Anonymous said...

Jesus 60% remit with such invasive treatment? Why don't they just get some good psychotherapy????

At January 20, 2012 5:59 PM, Blogger The Neurocritic said...

You must have missed the very first sentence under the Deep Brain Stimulation for Treatment-Resistant Depression subtitle, you know, the part that said they didn't remit with psychotherapy:

"Severe depression that is refractory to treatment, i.e. unresponsive to psychotherapy, ..."

At January 21, 2012 4:18 AM, Anonymous Paul Holtzheimer, MD said...

Thanks for a very informative summary of our paper. To clarify a couple of points: it was more that there wasn't a rationale to NOT include bipolar patients except for a concern about inducing mania - we wanted to test this in a group that, if they did become manic, might be more easily managed. Also, we had only one drop out from the study (between years one and two); this was a unipolar patient. The other patients were still in the study but had not yet reached the other time points. The dataset was closed with the 17th patient reached the 24 week time point, but we reported out to 2 years since the majority of patients were out that far.

Again - great summary otherwise.

At January 21, 2012 12:16 PM, Blogger The Neurocritic said...

Dr. Holtzheimer - Thank you very much for stopping by to read the post, clarify the points about patient inclusion, and especially to explain that not all patients had reached the 2 yr mark yet (meaning my inferred dropout rate was inaccurate). I will issue a correction in the post.

One thing that's probably not mentioned enough in press reports is that great improvements in quality of life can occur in patients who do not achieve full remission. Recovering from very severe depression to a level of mild or moderate depression is a significant treatment response, albeit not full remission.

I congratulate you and your colleagues for the ongoing clinical trials to provide treatment for a previously intractable group of patients.

At January 26, 2012 4:04 PM, Anonymous Anonymous said...


The area labelled here as area 25 is in fact Brodmann area 24, not 25!

This is a perpetual mistake made by the Mayberg group as if they were trying to rewrite history and it leads to numerous mistakes throughout the literature!!!

Despite this annoyance, their research is otherwise brilliant.

At January 27, 2012 12:07 AM, Blogger The Neurocritic said...

Anonymous of Jan 26, 2012 4:04PM - The text of the Wikipedia page on human area 24 isn't that great, as BA 24 extends quite caudally and is not confined to ventral anterior cingulate area 24.

According to this Brodmann map, the red dot in Fig. 1A seems close to the 24/25 border. Perhaps this is why the Toronto and Emory groups moved to calling it subcallosal cingulate:

"The subcallosal cingulate gyrus which consists of BA25 as well as parts of BA24 and BA32 has been implicated as playing an important role in major depression and has been the target of deep brain stimulation to treat that disease.[4]."

At January 16, 2015 12:58 PM, Blogger Ann Inhisname said...

Laymen- My daughter is on 3 different antidepressants . She has mild mood swings, but most of the time she is depressed. Are you saying that people like my daughter would probably not benefit from DBS? She would not be a good candidate for your study? Would ECT be better for people like her? Thank you for your answers. Please email me with an answer if you can. She needs help!

At January 18, 2015 10:15 AM, Blogger The Neurocritic said...

I'm sorry that I can't provide medical advice on this site. You can check this link at to see if there is an ongoing clinical trial in your area. I hope you can find help for your daughter.


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