Wednesday, November 18, 2009

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

Taken from Fig. 1 (Bewernick et al., 2009). Hamilton Depression Rating Scale (PDF) over time.

Two and a half years ago, The Neurocritic wrote about the very early results of deep brain stimulation (DBS) in the nucleus accumbens for severe, refractory depression. You can read about the details of the procedure and its scientific motivation here:

More About the Nucleus Accumbens

NAcc Localization for DBS

Briefly, the nucleus accumbens (NAcc) is considered one of the brain's PLEASURE CENTRES:
When the cortex has received and processed a sensory stimulus indicating a reward, it sends a signal announcing this reward to a particular part of the midbrain–the ventral tegmental area (VTA)–whose activity then increases. The VTA then releases dopamine not only into the nucleus accumbens, but also into the septum, the amygdala, and the prefrontal cortex.

The nucleus accumbens then activates the individual’s motor functions, while the prefrontal cortex focuses his or her attention.
It makes sense as a DBS target region 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.

The current paper by Bewernick et al., 2009 reports on the results from 10 patients who received NAcc-DBS for at least 12 months. These patients were severely ill and completely non-responsive to any other treatment. On average, they had been continuously depressed for 10 years, were completely unable to work, had been hospitalized numerous times, had failed over 20 medication treatment courses, were currently on 4 different drugs, had received over 20 electroconvulsive therapy (ECT) treatments, and 316 hours of therapy, all to no avail.

The primary results are illustrated in Fig. 1 above. Half the patients (n=5) were considered "treatment responders" who experienced a 50% reduction of depressive symptom severity as assessed by the HDRS, and half did not respond. Anxiety scores also declined in the responders, and engagement in pleasant activities increased.

There were some adverse events related to the surgical procedure (swollen eye in 6 patients, pain and dysphasia in 3), as well as transient adverse events related to stimulation parameter changes e.g., anxiety (n=3), hypomania, paresthesia, and agitation (all n=2). Nonetheless, the authors concluded on a positive note:
DBS to the nucleus accumbens had clinically relevant antidepressant and antianhedonic effects in a patient population that was at least as treatment-resistant as those reported on in other studies of DBS in major depression (Lozano et al., 2008; Malone et al. 2009). The efficacy to adverse event ratio in this small group was favorable. Site-specific antianxiety effects also could be demonstrated.

By targeting one site in a network of brain regions implicated in processing of affective stimuli, it was possible to manipulate anhedonia in particular. Additional studies with larger sample sizes and rigid selection criteria are needed to analyze effects of stimulation to different targets on specific symptoms and clinical phenotypes of depression. In the future, symptom-based DBS therapy, adapted to the individual needs of the patients, could be a plausible treatment option for severe TRD.


Bewernick, B., Hurlemann, R., Matusch, A., Kayser, S., Grubert, C., Hadrysiewicz, B., Axmacher, N., Lemke, M., Cooper-Mahkorn, D., & Cohen, M. (2009). Nucleus Accumbens Deep Brain Stimulation Decreases Ratings of Depression and Anxiety in Treatment-Resistant Depression. Biological Psychiatry DOI: 10.1016/j.biopsych.2009.09.013

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.

Malone DA Jr, Dougherty DD, Rezai AR, Carpenter LL, Friehs GM, Eskandar EN, Rauch SL, Rasmussen SA, Machado AG, Kubu CS, Tyrka AR, Price LH, Stypulkowski PH, Giftakis JE, Rise MT, Malloy PF, Salloway SP, Greenberg BD. (2009). Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression. Biol Psychiatry 65:267-75.

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At November 22, 2009 3:29 PM, Anonymous Anonymous said...

I wonder about the longer-term effectiveness of this treatment. For instance, does the rest of the brain react by eventually undoing the effects of the stimulation?

At November 26, 2009 4:10 AM, Anonymous Anonymous said...

The list of co-authors is incompletely cited: Bettina H. Bewernick, René Hurlemann, Andreas Matusch, Sarah Kayser, Christiane Grubert, Barbara Hadrysiewicz, Nikolai Axmacher, Matthias Lemke, Deirdre Cooper-Mahkorn, Michael X. Cohen, Holger Brockmann, Doris Lenartz, Volker Sturm and Thomas E. Schlaepfer. Volker Sturm is the neurosurgeon and Thomas Schlaepfer heads the psychiatric neurosurgery work group.

At November 26, 2009 9:50 AM, Blogger The Neurocritic said...

Thank you for posting the complete reference list. The shortening was an inadvertent result of the software that creates code to track references so they appear on their website.

At November 28, 2009 4:17 AM, Blogger Neuroskeptic said...

An interesting study, but I wish they'd have made it placebo-controlled - it's so easy with DBS, you just turn off the stimulator. There are "ethical issues", but I think the biggest ethical issue is that DBS is being used in extremely ill people with very little placebo-controlled evidence...

At December 30, 2009 7:57 PM, Blogger deselby said...

Here again, this time not quite so late to the party... I am a current patient in the Reclaim Study at UPenn, where the DBS targets the VC/VS, not the nucleus accumens (not that I have a fraking clue what the difference is -- I am a severely depressed person, not a neuroscientist). Anyway, the study is/was, for a long 16 weeks, double-blind and placebo-controlled (or rather "control-group"-controlled -- they had implants but they were all set to zero). As I said in my other comment, there have been good times and bad times, but they've finally found a setting that at least leaves days feeling more like extra-long days rather than months or even years, and I have even laughed a couple of times in the last two weeks (don't remember when I last did that). So try and take it from me, really, and I'll hurt you, even if I am nowhere near remission. And I don't care right now about the longer-term effectiveness either. If it stops working, I'll eventually kill myself. But for now, I only wish to die every OTHER day!!!


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