Despite numerous advances in our understanding of the neurophysiology of depression and the development of pharmacologic treatments, many treated individuals remain symptomatic. Electroconvulsive therapy is an effective approach for patients who do not respond to standard treatments, and recently, vagus nerve stimulation also was approved for treatment-resistant depression. Investigational strategies that directly target the brain are also proving to be successful, including transcranial magnetic stimulation, magnetic seizure therapy, and deep brain stimulation (DBS). On behalf of Medscape, Alisa R. Gutman interviewed Helen S. Mayberg, MD, Professor of Psychiatry and Neurology, Emory University, Atlanta, Georgia, about her groundbreaking research into the neurophysiologic loci of depression and the benefits of DBS for patients with intractable illness.
Medscape: Your recent clinical study evaluating the use of deep brain stimulation (DBS) for treatment-resistant depression has shown promising results. What other options are there for patients with treatment-resistant depression?
Dr. Mayberg: Electroconvulsive therapy (ECT) is the most effective treatment for major depression, particularly in patients who fail to respond to standard treatments such as psychotherapy or medication. In some patients, medication augmentation strategies can be effective. Most recently, vagus nerve stimulation has obtained US Food and Drug Administration (FDA) approval for treatment-resistant depression. Other strategies that target the brain more directly, such as transcranial magnetic stimulation (TMS), magnetic seizure therapy (MST), and DBS, are currently being researched.
Medscape: Have you seen any adverse reactions in your patients thus far?
Dr. Mayberg: We saw no short-term or long-term adverse effects from the high-frequency DBS used in our study. Given the potential involvement of hypothalamic and insular fibers influenced indirectly by the stimulation, we carefully monitored blood pressure, pulse, temperature, and gastrointestinal effects, but observed no autonomic changes. Acute testing of individual contacts in the operating room demonstrated transient lightheadedness at high amplitudes that resolved quickly with reduction in voltage settings. Mental slowness was described by some patients when the most superior contacts, closest to the corpus callosum, were tested. Again, such behavioral effects resolved quickly when the contact was changed. We had no reports of hypomania or elation, agitation or anxiety, or motor or sensory changes with stimulation of any contact either acutely or chronically.
Medscape: Can you explain how the deep brain stimulator works, both mechanically and mechanistically?
Dr. Mayberg: The exact neurobiologic mechanisms mediating clinical changes with DBS are unknown for any disorder. Electrophysiologic studies suggest both excitatory and inhibitory effects, depending on whether gray or white matter is targeted. Current evidence suggests that high-frequency DBS activates white matter, although the nature of the fibers being stimulated is critical to understanding whether the net effects are excitatory or inhibitory. Other data demonstrate that DBS results in inhibition of neurons. Change in network oscillations is an alternative possible mechanism. Our own studies have measured chronic changes in regional blood flow using positron emission tomography (PET). Although this approach can identify which regions are affected by the chronic stimulation, it does not further elucidate the mechanisms mediating such changes. Bottom line, we don't really know how DBS works. The converging evidence implicates a combination of local and remote chemical and electrophysiologic effects.
Our original hypothesis was that stimulation of the subgenual cingulate region would disrupt activity in the subgenual cingulate cortex and produce secondary remote effects in brain regions functionally linked to this region via adjacent white-matter fibers. On the basis of these known connections, we anticipated potential changes in the brain stem, hypothalamus, nucleus accumbens, and various regions of the orbital, medial, and prefrontal cortex.
We also had previous imaging evidence that the activity in this multinodal depression "circuit" was dysfunctional. We therefore saw DBS as a means to influence the balance between this highly interactive set of brain regions at the level of the subgenual cingulate.
Medscape: You've just mentioned that the stimulator is implanted in the subgenual cingulate region. What evidence implicated this region as an important site in the pathophysiology of depression?
Dr. Mayberg: There are a number of converging lines of experimental evidence. Both Cg25 [cingulate area 25] and the prefrontal cortex have emerged as critical regions mediating depression remission. A series of PET experiments have demonstrated both decreased subgenual cingulate activity and increased prefrontal activity with successful antidepressant treatment. Of interest, although frontal changes appeared to be a correction of baseline underactivity, the subgenual cingulate changes are decreases below normative levels. The subgenual cingulate changes are seen not only with antidepressant medication, but also with response to ECT and even to placebo medication, suggesting an important role in clinical recovery. In fact, patients in our study who failed to respond to treatment showed no subgenual cingulate changes. In addition, subgenual cingulate activity has shown marked increases in activity during states of profound negative mood (ie, sadness) in nondepressed volunteers, suggesting a further critical role in regulating acute and chronic negative mood states in both healthy patients and those with disease. We postulated a reciprocal set of changes in cortex and subgenual cingulate with DBS, namely, suppression of area 25 and disinhibition of frontal cortex, consistent with past findings of effective response to other antidepressants.
Medscape: How do you think that your background as a neurologist has influenced your research interests in psychiatry?
Dr. Mayberg: Neurologists are trained to think about behavioral syndromes from the perspective of brain circuits. That training in neuro-localization is at the core of all of our studies of major depression over the years; in essence we have strived to integrate ongoing progress from studies of neurochemical systems in major depression within an anatomical framework. Defining the regions of importance was a first step; but the most critical studies were those working to define regional interactions within specific circuits. As in Parkinson's disease, it isn't just where and what chemicals, but also how the rest of the relevant circuits have adapted, either good or bad, to these primary changes over time. Working to understand the dynamics of these mood circuits was greatly influenced by ongoing advances using DBS in the Parkinson's disease research community.
Medscape: Is this the first example of a directed intervention for depression?
Dr. Mayberg: Not exactly. I think that both TMS (targeting the prefrontal cortex) and VNS (targeting the vagus nerve) are directed interventions. The primary difference between these more empiric interventions and our DBS approach is that our previous imaging findings provided an evidence-based rationale for both electrode targeting and the desired physiologic change effects.
Medscape: Do patients get lesions from device implantation?
Dr. Mayberg: We don't have evidence of that on postoperative MRI scans of our patients, although a micro-lesion is certainly a possibility. Micro-lesions are less likely when electrodes are placed within white matter than when they are placed within gray matter, especially when they are inserted in a single pass. Insertional effects (ie, behavioral changes prior to turning on the electrical stimulation) can be seen even without a micro-lesion. One theory is that there is local edema at the target site.
Medscape: How did you control for that?
Dr. Mayberg: There's no way to control for it, per se. One can, however, document that it has occurred by observing behavioral changes prior to turning on the stimulator, or by noting continued behavioral changes with cessation of the stimulation. True micro-lesions would be expected to result in sustained behavioral improvements (or deficits) over time, even in the absence of electrical stimulation. Although we have observed positive insertion effects in several subjects, the effects were not sustained. Improved behavior required chronic stimulation.
Medscape: So, is DBS in any way similar to a pacemaker in a heart patient?
Dr. Mayberg: That is not a bad metaphor, although we don't have physiologic evidence to that effect, such as recordings demonstrating firing rate or field potential abnormalities in area 25 or its targets. We also have no direct evidence that we have introduced a more "normal" rhythm or a new pacemaker with chronic DBS. That said, it is an appealing explanation for the sustained behavioral changes seen in these patients, including their improved responses to everyday emotional stressors. We can theorize that the acute stimulation effects seen in the operating room reflect the acute reversal or disruption of a chronic aberrant rhythm, while the chronic DBS might be establishing a new firing pattern, thus preventing re-emergence of the previous abnormal default state. Such a hypothesis will require investigation.
Medscape: One of the major differences between what you're seeing here with DBS and what is observed with other treatments for depression is the acute effects. Can you describe some of the acute effects of stimulation?
Dr. Mayberg: The acute effects in the operating room were unique for each patient, but all shared certain features. In general, patients described a sudden disappearance of something negative, which was more often than not a change in a visceral state: a sudden sense of intense calm and relief, clearing of mental heaviness, lifting of a black cloud, the disappearance of a void, fading of a burrowing dread in the pit of the stomach, are some examples. Of interest, the turning off of these negative sensations was followed almost immediately by a change in attention and interest with objective evidence of increased spontaneous speech and motor speed. Such effects, when present, were contact- and dose-specific and could be reproduced in a blinded fashion with repeated testing. Their time course was quite rapid, occurring approximately 15-20 seconds after initiating stimulation at the specific electrode contact.
Importantly, the mood effects were quite specific. Patients did not experience positive mood effects; rather, their chronic negative mood was attenuated. The patients were quite explicit: something was shut off, nothing was added. And once something was taken away, they were able to better attend to the environment around them. Many, in fact, described renewed interest in starting activities that had been previously impossible to plan or initiate. You can imagine our surprise at having patients respond to the question, "If you were home right now, what can you imagine yourself doing?" with comments like, "I've got gardening to do, there's all these leaves and it's such a mess." Or, "I've been meaning to clean out my garage." All of a sudden they were interested in activities -- and especially activities involving social interactions, whereas previously they had been apathetic, disinterested, and inactive. One patient described it as: "I have been so totally preoccupied with this overwhelming negative state of the body that I have nothing left for anything else. Well, I've just somehow been freed to go about my business." To me, it's as though the overactive subgenual region was acutely inhibited, releasing action-oriented systems in the basal ganglia and frontal cortex to engage more normally with stimuli in the environment.
Medscape: In the paper you describe that your patients find relief from a feeling of "void" or "painful emptiness." What do you think is the neuroanatomical basis for this sudden change to having an interest in action?
Dr. Mayberg: I think that the first thing that happens is an abrupt change in activity in the subgenual cingulate. It makes the most sense since that is the immediate target of the stimulation. The change in interest that occurs next most likely reflects secondary changes in subgenual cingulate efferents such as the basal ganglia or medial frontal cortex. This could result from direct activation along the white-matter tracts that are being stimulated or via trans-synaptic effects following initial changes in area 25. We don't know, since we are not measuring physiologic changes occurring with acute stimulation. It is definitely an important area for future research.
Medscape: After observation of these initial acute effects, can you describe the long-term effects and how you measured them?
Dr. Mayberg: We used standardized psychiatric rating scales classically employed to evaluate the efficacy of antidepressant interventions. Our primary endpoint was the Hamilton Depression Rating Scale. We kept the stimulation parameters constant following testing to determine the optimal settings. Patients were then followed weekly for 6 months. Clinical improvement was documented by a 50% drop in the Hamilton Scale. Four of the first 6 patients met this response criterion at 3 months, and the response was sustained at 6 months. These same 4 patients met remission criteria at 1 year. The DBS remained at the same stimulation parameters throughout, without need for dose increases or decreases. Medications were kept at stable doses in all patients up to 6 months, although doses were decreased in many cases thereafter. Some patients actually required dose decreases earlier in the study because of obvious drug-related side effects.
Medscape: That brings up an interesting point about the differences between DBS and pharmacologic treatments. You looked at your patients in these studies using PET scans. Did you see any differences in the changes with DBS as compared with the observed changes with drug treatments?
Dr. Mayberg: Scans were acquired at baseline and after 3 and 6 months of chronic DBS without any changes in the medications. Basically, we saw what we had hypothesized: limbic and subcortical decreases and cortical increases. Specifically, decreased activity relative to baseline was seen in area 25, the hypothalamus, and the orbitofrontal and medial frontal cortex; increases were seen in the brainstem, prefrontal, parietal, and dorsal cingulate cortices. This constellation of regional brain changes strongly suggests that DBS impacts the entire depression circuit and not just a subset of regions as we saw previously with pharmacotherapy and cognitive behavioral therapy (CBT).
The brain changes with DBS in regions mediating CBT effects (dorsal cingulate, medial frontal cortex) were especially interesting since these patients were consistently unable to engage in such therapy prior to DBS. They are all now learning CBT techniques and are finding it very useful. This brings up a critical point about this new treatment. DBS is not a cure-all, despite how robust the clinical responses appear to be. The DBS starts the process by normalizing a very dysfunctional circuit. For full functional recovery, you also need get adequate rehabilitation, as provided, for instance, by CBT. This is in many ways analogous to ensuring an optimal functional recovery after hip or knee replacement surgery by requiring a course of physical therapy. I think we are going to need to actually study the synergy between DBS and CBT in these patients more formally.
Medscape: To facilitate this process, do you have the psychiatrist working in conjunction with the surgeon and the neurologist?
Dr. Mayberg: Absolutely, this is a multidisciplinary team effort. There is the monitoring of the DBS stimulation parameters, psychopharmacologic management of emergent side effects and drug discontinuation if indicated, as well as continuity of care by the patient's personal psychiatrist. Practically speaking, the treating psychiatrists know the patients the best, and they are often able to see the more subtle changes in behavior facilitated by the DBS.
Medscape: What do you think is the future of DBS for patients with depression? Psychiatrists today deal with the fact that a third of their patients have a good response to drugs, a third of their patients have a mediocre response, and a third of their patients don't respond. Currently, people have to go through several treatment regimens before they can turn to alternatives.
Dr. Mayberg: I think that DBS certainly needs to be further studied. These first results are very encouraging: 4 out of the 6 patients met response criteria at 6 months, and have since met criteria for remission at 1 year; 2 of the 4 are out to 2 years and continue to be well with chronic stimulation. We are seeing a similar rate of response in our second set of 6 patients, although we do not yet have 6-month outcome data in this second group. A definitive double-blind, placebo controlled study is now needed. From a research perspective, we are also examining brain markers that might identify which patients might best benefit from such a procedure. Similarly, we don't know whether this treatment is efficacious for other subtypes of major depression such as bipolar, as we have studied only unipolar patients thus far. Bottom line, we need to better understand the underlying pathophysiology of the disorder and work toward developing biological markers that help us to optimize treatment for individual patients, be it medication, therapy, or DBS.
Medscape: Is there anything else that you'd like to add?
Dr. Mayberg: I think these are early and promising results, and we are looking forward to studying additional patients in Toronto and hopefully soon in Atlanta. More broadly, this experiment defines a potential paradigm shift in the way we think about antidepressant mechanisms of action since, unlike most other treatments, Cg25 DBS produces acute antidepressant effects. Development of new medications that might mimic these effects is an obvious potential new focus of research. What is very gratifying is that basic scientists are now showing more interest in the subgenual cingulate region and its involvement in more classic antidepressant treatments. It is an exciting time to be working in this field. I hope we can continue to make further progress in understanding and treating this serious and debilitating illness.
This interview is published in collaboration with NARSAD, The Mental Health Research Association.