Surgical treatment of major depression has been performed for the past several decades using precise stereotactic targeting to lesion select sites in the frontal lobes and in various deeper subcortical structures. These procedures have been reserved for only the most severely depressed and otherwise unresponsive patients. Targets for intervention have included the anterior capsule, the substantial innominata/subcaudate white matter and the caudal anterior cingulate gyrus. Of these, cingulotomy has seen the greatest application, with over 500 procedures reported (1–4).

In the past several years, there has been increasing enthusiasm for the application of deep brain stimulation to the treatment of major depression. Here, too, multiple targets have been suggested, including the subgenual cingulate gyrus (5), the inferior thalamic peduncle (6), the anterior capsule (7), and the subthalamic nucleus (8). Deep brain procedures hold several principal advantages. First, the treatment is nonablative and therefore reversible if it is performed without complication. Furthermore, the parameters of stimulation can be adjusted, and stimulation can be increased or decreased over time. This is of particular importance in treating a disease such as depression in which the disease anatomy is still poorly understood and the symptoms are not easily quantified or measured and may respond over months rather than minutes.

In this article, we describe the case of a patient who, under the direction of a multidisciplinary case committee, underwent both an ablative cingulotomy and subsequent bilateral deep brain stimulation placement in the Cg25 area. Review of this case provides a means of comparing the two techniques and of illustrating what we feel are some important advantages to using stimulation in the treatment of major depression. This report also provides potential insight into common and unique mechanisms mediating the two procedures.

Cingulotomy

Deep Brain Stimulation

Our experience with this single patient is valuable for the insight it can provide on ablative and novel stimulatory therapies for major depression. The mechanisms by which these procedures affect mood is a matter that currently draws much study and interest. The individual therapies are discussed below, followed by some conjectures on their interrelation in this novel case. Like all case studies, it is limited in its scope. It is hoped that ongoing trials and research to clarify the role of the Cg25 region will eventually elucidate the role of this region in major depression.

Lesional Cingulotomy

Whitty and colleagues first reported cingulectomy in 1952. Based on observations by Friedman and Watts that transection of cingulate fibers decreased psychic tension and were an important component of successful leucotomies for affective disorders, they performed open bilateral cingular resections (15). Ballantine refined the procedure considerably by performing stereotactic lesioning of the cingulum guided by air ventriculography. Between 1962 and 1982, he performed cingulotomies on 465 patients for severe and treatment-resistant psychiatric disorders and for intractable pain. In 1987, he and his colleagues reported the results on 120 of these patients who had undergone cingulotomy for major affective disorders. Of this group, 64% were substantially improved at 2–9 years of follow-up. Sixteen percent demonstrated complete remissions and were able to discontinue all medications. An additional 12%, however, committed suicide in the years after their surgery. Notably, assessments were not blind, and for ethical reasons, random assignment was not possible (3). Also, evaluations with standardized rating scales were not performed. Instead, patients were placed in one of seven categories that graded their status from suicidal to in remission. This makes interpretation and comparison with more recent studies difficult.

A later study from the same institution evaluated the use of MRI frame-based guidance and estimated that 33% of the patients treated for major depression were substantially improved. They also reported that many patients in this protocol required numerous repeat surgeries to expand the lesions anteriorly and posteriorly before benefit was achieved. Forty-five percent of the patients in this study required a repeat procedure. It is supposed that broader lesions of the cingulum are more effective (1). A later study used the somewhat more objective Beck Depression Inventory (BDI) as the primary outcome measure. In a group of 13 patients, only four of 13, or 31%, demonstrated a decrease of 50% on their BDI. This group of patients also underwent positron emission tomography (PET) imaging prior to their procedure. A subsequent correlational analysis relating percent change in the BDI to baseline levels of regional cerebral metabolic rate for glucose demonstrated two regions of significant correlation. These were the subgenual cingulate cortex and the posterior thalamus, where higher baseline activity correlated with better outcome to cingulotomy (16). Of interest, both areas have been independently demonstrated to have decreased activity in depressed patients and then to normalize with successful antidepressant medication treatment (17–19). These modern assessments of cingulotomy as a treatment for major depression suggest that it is effective but imperfect. An efficacy rate of 31% in a population resistant to all modes of pharmacologic therapy and to ECT would represent a considerable success, although it has not been tested in blind randomized fashion. Furthermore, the fact that response correlates with activity in the thalamus and in a distinctly separate portion of the cingulate gyrus, which is not immediately adjacent to fibers targeted for ablation, suggests that the treatment succeeds by disrupting a segment of a more complex network.

Deep Brain Stimulation for Major Depression

As noted above, there are considerable data from functional neuroimaging that implicate the subgenual cingulate in the physiology of major depression (16, 17, 20). Several studies have identified increased metabolism in the subgenual cingulate (Brodmann’s area 25) as an important correlate of depression (21). Based on the supposition that deep brain stimulation focally suppresses activity in this area and might directly reverse the aberrant physiology of depression, a series of patients at our institution have undergone electrode placement bilaterally in the subgenual cingulate to treat their refractory depression. A pilot study of six patients who underwent the procedure demonstrated substantial improvement in four of six patients (66%) with decreases of 50% or greater in their HAM-D scores (5). The successful application of deep brain stimulation to treat psychiatric disease would represent a major breakthrough in modern functional neurosurgery. The high incidence of these disorders in the general population and the large percentage that are refractory despite medical treatment make this an important area for research and clinical development.

This case report is of interest because it demonstrates the potential advantages of the newer technique of deep brain stimulation surgery over the more extensively reported ablative cingulotomy. This patient, who underwent both procedures in succession, was able to gain prolonged benefit from Cg25 deep brain stimulation despite no improvement from previous ablative therapy. Cingulotomy produced remission for only 6 months. The subsequent deep brain stimulation procedure continues to be beneficial at 30 months after implantation.

There are several possible causes for the patient’s improvement. The patient was not blind to the procedure or to subsequent stimulation settings. As such, it is possible that the derived benefit is secondary to placebo effect, either from the surgery or from the periodic visits and adjustments that are necessary for programming the deep brain stimulation system. Indeed, the patient had a significant, but unsustained, benefit from her initial ablative surgery, which might also have been a placebo effect. We are, however, encouraged that benefit after deep brain stimulation surgery has continued for 2.5 years, significantly longer than after her previous surgery. She had also failed to have similar transient benefit from either ECT or from any of the nearly 20 medications with which she had been treated in the last decade. Her response, as measured on the 17-item HAM-D, has also improved progressively over the past year. A pure placebo response might be expected to have the greatest effect shortly after surgery and then progressively return to baseline. The opposite has been evidenced.

As noted in the studies above, a large percentage of cingulotomy patients relapse after their first surgery and have found benefit with further lesioning of the caudal anterior cingulum. Indeed, the timing of her initial failure is similar to that suggested by prior investigators performing cingulotomy. It is possible that this patient’s deep brain stimulation procedure has accomplished the same effect simply by expanding the portion of the cingulum that is functionally lesioned. A second cingulotomy was considered in this patient; however, because the first procedure included lesioning at multiple positions bilaterally and because the postoperative imaging demonstrated that large areas had been lesioned, we did not consider that further ablation of tissue in that region would be of benefit. Whether stimulation in the Cg25 region simply expands the area of effective lesion or acts by a separate mechanism remains a matter for research.

The Cg25 region seems to play a role both with the traditional cingulotomy and with the new deep brain stimulation procedure. As noted above, elevated activity in the Cg25 region preoperatively was predictive of success in a series of cingulotomy patients. The same increase of activity in Cg25 noted in depressed patients more broadly was the principal impetus for suggesting deep brain stimulation treatment of this target. The presumption in both cases is that ablation of the caudal anterior cingular gyrus or direct electrical stimulation of the Cg25 region suppresses activity, by direct or indirect means, of the Cg25 region and thus restores a more normal physiology. Although there are direct connections between the subgenual cingulate and mid-cingulate regions through the cingulum bundle, their patterns of cortical connectivity are quite distinct. The subgenual cingulate is connected by unique monosynaptic pathways to the orbitofrontal cortex, striatum, amygdala, hypothalamus, and brainstem. These areas are not directly affected by the caudal cingulotomy procedure. These differences may help to explain transient but unsustained effects with cingulotomy and more sustained effects with deep brain stimulation because the latter procedure may more directly affect regions that typically demonstrate abnormal metabolism in depression. Further studies are needed to fully characterize the necessary and sufficient pathway effects mediating a sustained antidepressant response.

As in deep brain stimulation therapy more broadly, there remains uncertainty on the mechanism of high-frequency stimulation. The use of deep brain stimulation in the globus pallidus or subthalamic nucleus is typically presumed to create a functional lesion of the nucleus. This is presumed only because the global effect of high-frequency stimulation in movement disorder surgery is similar to the effect demonstrated when the nucleus is lesioned due to the similarity of its effect that was obtained in lesioning the same nuclei. This matter is still hotly debated. The substructure of the globus pallidus or subthalamic nucleus is certainly quite different from that of the subgenual cingulate gyrus. Thus we can presume little about the effect of high-frequency stimulation on the myriad connections to and from this region.

Although PET scanning was not performed on this patient, in the first cohort of Cg25 stimulation patients, there were increases in the mid-cingulate after chronic stimulation of the Cg25, whereas the subgenual cingulate itself showed decreased activity. This again suggests an important connectivity between these two areas of the cingulate cortex and supports the idea that the two procedures have worked synergistically. This case report is perhaps most interesting in that it demonstrates that the two procedures can work in concert to control a patient’s depression.

The deep brain stimulation procedure does, however, have some advantages over cingulotomy. If performed without complication, it is a reversible procedure that does not involve the permanent destruction of brain tissue. The effect is also titratable. Thus, the degree of stimulation or the region of effect (altered by changing electrode contacts) can be adjusted, if clinically indicated, without further surgery. If the results of the deep brain stimulation pilot study and the evidence provided by this patient are substantiated by further evidence supporting the effectiveness of Cg25 deep brain stimulation, we expect the procedure to see greater application in the coming years.

This case report suggests that patients who have achieved suboptimal antidepressant effects after a cingulotomy may expect a similar degree of antidepressant efficacy after Cg25 deep brain stimulation as patients who have not received an ablative procedure.