An image that surgeons use to prepare for implanting a deep brain stimulator (enlarged here) in the medial forebrain bundle, nerve fibers involved in depression

Psychological depression is more than an emotional state. Good evidence for that comes from emerging new uses for a technology already widely prescribed for Parkinson's patients. The more neurologists and surgeons learn about the aptly named deep brain stimulation, the more they are convinced that the currents from the technology's implanted electrodes can literally reboot brain circuits involved with the mood disorder. Thomas Schlaepfer, a psychiatrist from the University of Bonn Hospital and a leading expert in researching deep brain stimulation, describes in the interview that follows the workings of the technique and why it may help the severely depressed.

Can you explain what deep brain stimulation is and what it is currently used for?

Deep brain stimulation refers to the implantation of very small electrodes in both hemispheres of the brain, which are connected to a neurostimulator, usually placed under the skin on the right chest. This device is in size and function very similar to a heart pacemaker. It allows stimulations of different pulse width and frequency. Depending on the chosen stimulation parameters the electrodes in the brain are able to "neuromodulate" – to reversibly alter the function – of the surrounding brain tissue. Deep brain stimulation has gained widespread acceptance as a successful treatment for tremor associated with Parkinson’s disease. More than 80,000 patients worldwide have been treated with this method. Some see deep brain stimulation as a much less invasive and fully reversibly alternative to historical neurosurgical interventions, which require tiny amounts of brain tissue to be destroyed in order to have clinical effects.

2. Are there other possible uses for the technology?

Further neurological indications that are either already clinically used or under research are essential tremor, primary dystonia, treatment resistant cluster headache and certain other pain syndromes. Deep brain stimulation has only recently, in the last decade, been actively researched as a putative treatment for very treatment resistant psychiatric disorders. Since 1999, data on DBS treatment in patients with refractory obsessive- compulsive disorder have been published as small case series or case reports. Five research groups from Europe and the United States reported individual case studies on OCD. Overall there seems to be a very positive efficacy signal in this patient group. In the same time frame three groups started to actively look at the efficacy of deep brain stimulation in three different targets—the subcallosal cingulate cortex, the anterior limb of the capsula interna and the nucleus accumbens—have been published. Interestingly the overall response rate of 50 to 60 percent (response is defined as a decrease of at least 50 percent in from the baseline depression score) has been reported, a surprisingly high rate given the extreme treatment resistance of these patients, who underwent up to 60 courses of psychotherapy, electroconvulsive therapy and psychopharmacology.

3. Can you describe some of your recent findings and their importance for both DBS and the neuroscience of depression?

Thomas Schlaepfer

The fact that DBS to three very different targets in similarly depressed patients has about the same efficacy is somewhat puzzling. In addition stimulation intensities used in all of these three groups have been far higher than the currents for neurological indications such as Parkinson’s. A higher current likely stimulates a larger volume of brain tissue, which speaks somewhat against the hypothesis that targeting a specific site will produce an improvement in a patient.

Anhedonia – the inability to experience pleasure in previously pleasurably experienced situations – is a key symptom in depression. A couple of studies have demonstrated that an important structure in processing reward signals, the nucleus accumbens, is dysfunctional in severe depression. Based on these tenets we hypothesized that neuromodulation of the nucleus accumbens by DBS might have antidepressant effects, which we clearly demonstrated with our studies The nucleus accumbens acts as a relay structure, which processes reward input from the medial forebrain bundle (wirelike inputs to the nucleus accumbens), and if this reward signal is high enoug,h it activates the prefrontal cortex.

About three years ago we started to get interested in the medial forebrain bundle as the key input structure of the reward system together with Dr. Volker Coenen, a functional neurosurgeon, who has been looking at this system already for a longer time. The medial forebrain bundle projects from the ventral striatum area through the nucleus accumbens to the prefrontal cortex. In a study using diffusion tensor imaging (DTI), a method which displays fiber structures in the living brain, we were able to demonstrate that all three currently used targets for DBS in depression are either in close topographical relationship or overlap fibers of the medial forebrain bundle.

Given that relatively high stimulation intensities have an impact on larger volumes of brain tissue, we started to believe that all three methods might produce their antidepressant effects through their effects on parts of the fiber structure of the medial forebrain bundle, which fans out as it progresses from the deep brain to the frontal cortex. We further hypothesized that neuromodulation close to the origin of the medial forebrain bundle, the ventral tegmental area, would lead to better antidepressant effects at much smaller stimulation intensities. This now has been demonstrated in the recent study, in which we showed that most patients were either responders or remitters at much lower stimulation intensities (about 30 percent) than used in the other studies. The absolutely surprising finding was that our patients showed a rapid response, after two to five days. Indeed, there was both an immediate response and then a more sustained one. All patients experienced the very same acute effects a minute after stimulation had begun in the operating room: They immediately began to engage in verbal interactions, they looked around their immediate surroundings in the OR and became interested in the persons present there. Their heart rate rose by 10 beats per minute. Such strikingly similar effects in all patients point to the probability that you are tapping into an important, evolutionary old system involved with maintaining emotional equilibrium.

A more long-lasting response came two to five days after the onset of stimulation. This was very unexpected since previous DBS depression studies, psychotherapy and pharmacotherapy show a delayed effect that takes about a month. In another paper we showed that the only patient who did not respond to medial forebrain bundle stimulation probably did so because we caused a very small amount of bleeding, a rare, acute side effect of DBS, exactly at the origin of the medial forebrain bundle, a tragic event which probably robbed this patient of the very means of responding to DBS..

4. Are we gaining a better understanding through this work of the neural circuitry involved in depression? Can you describe what we've learned?

A very interesting feature of deep brain stimulation is that it not only might be developed in a successful treatment exactly for those patients who hitherto had little or nothing to hope from psychiatric interventions but also that it serves as a neuroscientific platform to study the brain circuits underlying depressive behavior. Over the last decades the underlying neurobiology of depression has been thoroughly reconceptualized away from dysfunctional neurotransmitters — the same ones targeted by Prozac and similar drugs — to dysfunctions in a widespread network of interconnected brain regions that process rewarding or aversive responses to emotional stimuli. Brain centers in this network interact and communicate with each other both electrically and neurochemically. Dysfunctions in one part of these networks likely have effects on other parts of this network and this research makes clear that there are very different forms of depression depending on which areas of the cortex or areas below the cortex are affected. Deep brain stimulation opens a new view on this network in the living human brain by allowing refined electrophysiological measurements that will almost certainly help to develop less invasive and even more efficacious treatments.

5. Deep brain stimulation has been widely used but it is frightening to many people, the idea of having the equivalent of a plate lodged in their heads or undergoing electroconvulsive therapy. Are these fears overblown?

The idea of holes drilled in the skull and electrodes placed deep into the brain is as a concept understandably frightening. However, worldwide experience in ten thousands of patients has shown that DBS is a surprisingly benign form of neurosurgery, although there are rare but sometimes significant side effects, such as hemorrhage in the brain or infection of the implanted material. It has become clear that the implantation of stimulation electrodes has no effects on cognition; there is no observable damage to the brain. As far as depression that hasn’t responded to other treatments, DBS has probably a far more benign side effect profile than any pharmacotherapy or electroconvulsive therapy, because its effects are extremely focused and reversible while medications usually affect the whole brain and body.

A recent study in patients with Parkinson’s disease has demonstrated that patients earlier on the disease course profit even more from the therapy. It might very well be that the same holds true for depression so that patients with severe forms of depression, which are not yet, completely treatment refractory might profit even more.

6. Will less invasive alternatives be coming along for neurostimulation, perhaps with transcranial magnetic stimulation or another technology?

Most likely deep brain stimulation for depression will be a transitional technology, which will lead to even more refined but less invasive treatments of the brain. The recent advance in optogenetics has shown for instance a new way of very precisely interacting with neurons. It might very well be the case that the groundwork laid by neuroscientific discoveries enabled by DBS will lead to new targets and technologies of interacting with dysfunctional brain networks.

7. Does your work on deep brain stimulation raise the prospect of new classes of drugs that might modulate the same neural circuits? Some of the work on ketamine has people excited. Is the DBS work related to this at all?

The fact that medial forebrain stimulation acts very rapidly was unexpected and points to the possibility that there is something like a rapid entry pathway into the pathology of depression. This rapid effect is shared with interventions using the anesthetic ketamine, which makes it possible, that both treatment approaches interact with the same pathway.

8. Are there some conditions that you think DBS should not be used for?

DBS seems indeed to be an extremely powerful method and it is only natural that researchers and clinicians think about other applications in patients with other disorders who do not respond to treatment by conventional methods. However, we are well-advised to tread carefully and to come up with scientifically based, testable hypotheses about dysfunctional neurocircuitry in these disorders before we apply this procedure in patients.

Image Source: Volker Coenen, University Freiburg, Germany