Friday, May 18, 2007

More About the Nucleus Accumbens

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.
And now we return to our continuing [plodding] coverage of the 2007 meeting of the Cognitive Neuroscience Society.

In today's installment, we'll learn about:

Deep Brain Stimulation in the Nucleus Accumbens for Major Depression

Previously, The Neurocritic has written about deep brain stimulation of area 25 in the ventral anterior cingulate cortex as a treatment for intractable depression:

The Sad Cingulate

Sad Cingulate on 60 Minutes and in Rats

I hadn't heard of the nucleus accumbens (NAcc) as a DBS target region, but it makes sense 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" (Pecina et al., 2006) in the NAcc that respond to food and pharmaceutical and financial and... er uh sexual rewards (Knutson & Cooper, 2005).

The poster presented at the meeting actually had nothing to do with the clinical efficacy of DBS in the NAcc, but the fact that electrodes were implanted there allowed the authors (Cohen et al., 2007, based in Germany) to record neuronal activity from the human NAcc, quite a rare opportunity. In their experiment, EEG activity (local field potentials) was recorded in the NAcc while the patients performed a reward-based learning task (choose a coin: one rewards 75% of the time, the other 25%) with periodic reversals of the contingencies. Frequency information and event-related potentials (ERPs) were extracted from the data (see below).

Michael Cohen1, Nikolai Axmacher2, Roshan Cools3, Doris Lenartz4, Christian Elger2, Volker Sturm4, Thomas Schlaepfer2.

1UC Davis, 2University of Bonn, Germany, 3University of Cambridge, 4University of Cologne, Germany — The nucleus accumbens acts as a "gateway" between motivation and action: It receives inputs from limbic structures involved in emotion (i.e., amygdala and orbitofrontal cortex) and projects to structures involved in action selection and behavioral control (i.e., basal ganglia output structures). Studying the human nucleus accumbens is difficult because of limitations in spatial and temporal resolution of neuroimaging techniques such as PET and fMRI. To overcome these limitations, we recorded local field potentials from the nucleus accumbens of patients undergoing Deep Brain Stimulation for treatment of major depression. Electrodes were implanted into the nucleus accumbens, and before stimulation began, externalized leads were used to record electrical potentials. We recorded these potentials while patients engaged in a reward-based reversal learning task, in which patients could maximize their rewards by learning to adapt their behavior to changes in reinforcement contingencies. Behaviorally, patients quickly adapted their decision-making to maximize rewards, demonstrating that reinforcement learning circuits remained intact. ERPs from around 300-400 ms following feedback differentiated wins from losses, and predicted whether patients would choose the same or the opposite decision option on the following trial as on the current trial. Frequency decomposition revealed enhanced power in the gamma frequency band from 100-400 ms following feedback onset, and increased alpha band activity following wins compared to losses. The spatial and temporal resolution of these electrophysiological recordings provide novel insights into the function of the nucleus accumbens' role in using reinforcement information to guide behavior.
What about the clinical aspects? Did the patients improve after DBS? Yes. Although a very preliminary study in only 3 patients, all showed clinical improvement when the stimulator was on, compared to when it was off (Schlaepfer et al., 2007).
Schlaepfer TE, Cohen MX, Frick C, Kosel M, Brodesser D, Axmacher N, Joe AY, Kreft M, Lenartz D, Sturm V. Deep Brain Stimulation to Reward Circuitry Alleviates Anhedonia in Refractory Major Depression. Neuropsychopharmacology. 2007 Apr 11; [Epub ahead of print]

Deep brain stimulation (DBS) to different sites allows interfering with dysfunctional network function implicated in major depression. Because a prominent clinical feature of depression is anhedonia-the inability to experience pleasure from previously pleasurable activities-and because there is clear evidence of dysfunctions of the reward system in depression, DBS to the nucleus accumbens might offer a new possibility to target depressive symptomatology in otherwise treatment-resistant depression. Three patients suffering from extremely resistant forms of depression, who did not respond to pharmacotherapy, psychotherapy, and electroconvulsive therapy, were implanted with bilateral DBS electrodes in the nucleus accumbens. Stimulation parameters were modified in a double-blind manner, and clinical ratings were assessed at each modification. Additionally, brain metabolism was assessed 1 week before and 1 week after stimulation onset. Clinical ratings improved in all three patients when the stimulator was on, and worsened in all three patients when the stimulator was turned off. Effects were observable immediately, and no side effects occurred in any of the patients. Using FDG-PET, significant changes in brain metabolism as a function of the stimulation in fronto-striatal networks were observed. No unwanted effects of DBS other than those directly related to the surgical procedure (eg pain at sites of implantation) were observed. Dysfunctions of the reward system-in which the nucleus accumbens is a key structure-are implicated in the neurobiology of major depression and might be responsible for impaired reward processing, as evidenced by the symptom of anhedonia. These preliminary findings suggest that DBS to the nucleus accumbens might be a hypothesis-guided approach for refractory major depression.
To be continued....


Pecina S, Smith KS, Berridge KC. (2006). Hedonic hot spots in the brain. Neuroscientist 12:500-11.

Knutson B, Cooper JC. Functional magnetic resonance imaging of reward prediction. (2005). Curr Opin Neurol. 18:411-7.

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