27.2.1 Anterior Cingulotomy

In anterior cingulotomy a lesion is made in a region corresponding to Brodmann Area 24 and a portion of the anterior cingulate gyrus. Anterior cingulotomy is useful both in obsessive-compulsive disorder and depression. Clinical outcomes may correlate more with anterior lesion position than with lesion volume and microelectrode recordings can be helpful to identify the dorsal and ventral regions of the gyrus. In a prospective review of thirty-three patients with refractory depression treated by cingulotomy, seventeen patients needed no further treatment. A third of these had at least a 50% reduction in the Beck Depression Inventory and another 42% had reductions of between 35% and 50%.

27.2.2 Subcaudate Tractotomy

In subcaudate tractotomy a lesion is made in the tracts below the caudate nucleus, in the region of the substania innominata. The operation was initially done by craniotomy but the procedure is now done stereotactically and the lesion made using thermocoagulation. In more than a thousand cases performed since 1961, the estimated overall undefined success rate was 40–60%. A 1995 prospective study of 23 patients with either major depression or bipolar affective disorder treated by tractotomy showed lowered Hamilton Rating Scale for Depression Scores (HAMD) at six months that correlated with improved global outcome as measured by multiple scales. Most reports describing this technique are over a decade old, but in a 2017 case report, gamma knife radiofrequency ablation reduced HAM-D scores from twenty-three to four, an improvement that was sustained for 2 years.

27.2.3 Limbic Leucotomy

The combination of anterior cingulotomy and subcaudate tractotomy is known as limbic leucotomy. In a 2002 study of twenty-one patients who had leucotomy for either obsessivecompulsive disorder or major depressive disorder, there was benefit in approximately half of all patients with a few adverse events observed over the two-year evaluation period. In a study of 16 patients who had undergone radiofrequency limbic leucotomy for major depressive disorder over 7 years, depression scores, as measured by the HAM-D or BDI, declined by about 50%.

27.2.4 Anterior Capsulotomy

In anterior capsulotomy, the anterior limb of the internal capsule is lesioned. While primarily described for the treatment of obsessive-compulsive disorder or anxiety disorders, there have been a few reports on the use of anterior capsulotomy for the treatment of depression. In a 2011 study, twenty patients treated with anterior capsulotomy were evaluated for a mean of seven years. Half of the patients had at least a 50% reduction in HAM-D scores.

27.3.1 Subcallosal Cingulate

The subcallosal cingulate (SCG) region was the first identified potential target for deep brain stimulation of medically refractory depression. Patients who responded to antidepressant medications also had increased anterior cingulate gyral glucose metabolism. Those who did not respond had an inverse metabolic pattern. PET studies identified the subcallosal cingulate region (including Broadmann 25) as hypermetabolic in normal subjects in a transient sad state as well as in treatment responsive depression patients. A similar decrease in metabolism within this region was found following electroconvulsive therapy. In depressed patients that benefitted from anterior cingulotomy, improvement in BDI correlated with pre-operative level of metabolism in this subcallosal cingulate region. Treatment with the selective serotonin reuptake inhibitor paroxetine was associated with a decrease in subcallosal hypermetabolism in treatment responsive depression patients, a finding that was not present in patients who were responsive to cognitive brain therapy.

Some of this work spurred the use of SCG as a DBS target. In 2005, six patients with treatment resistant depression underwent a six-month trial of chronic stimulation with electrodes implanted in the SCG. In these subjects, presurgical PET imaging revealed a pattern characterized by elevated blood flow in the subgenual region and reduced flow in the dorsolateral prefrontal cortex. Four of six (66%) patients responded to treatment (≥ 50% reduction in HAM-D scores compared to baseline). Postoperative PET imaging studies at 3 and 6 months in treatment responders also showed a reversal in the pattern of blood flow observed in the preoperative period.

Several ensuing case reports demonstrated benefit. A 2008 case report described a long-term benefit in a patient with medically refractory depression who had been previously treated with radiofrequency cingulotomy. A clinical benefit in a 2010 study following right-sided SCG DBS, prompted the study of asymmetrical effects of right versus left hemispheric stimulation. Lozano, Kennedy and colleagues published long-term follow up data on 20 patients implanted with SCG DBS electrodes. Improvement at 1–3 years ranged from 45–75%. Holtzheimer et al., reported their results on 7 patients with bipolar II disorder and 10 patients with major depressive disorder showing a trend towards an increase in stimulation efficacy over time, with 36% remission and 36% response rate at 1 year and up to a 58% remission rate and a 92% response rate after 2 years. Lozano et al., also published initial results of a three center prospective open-label trial, with a 57% response rate (> 50% decrease in HAM-D scores) at 1 month, a 48% at 6 months and a 29% at a year. When responders were defined as patients having > 40% reduction in HAM-D, response rate at one year increased to 62%.

With the success of these initial studies, a multicenter randomized control trial was initiated to study Broadman area DBS. It was discontinued after a futility analysis predicated the probability of success being no greater than 17.2%. Despite these findings, several groups have been conducting clinical trials to improve the therapy. Newly proposed strategies include characterizing predictors of response to SCG DBS, refining surgical targeting and clarification of surgical candidacy. Electrode locations in patients who did or did not respond to surgery are fairly similar. In a recent study, however, diffusion tensor imaging (DTI) and the volume of tissue activated by stimulation revealed that DBS responders shared bilateral pathways from their activation volumes to the medial frontal cortex, rostral and dorsal cingulate cortex via the cingulum bundle, and subcortical nuclei (▶ Fig. 27.1). In a 2015 trial, 8 patients were implanted with SCG electrodes. Five responders were randomized to undergo a double-blinded active vs. sham stimulation study. In these subjects, active stimulation was shown to be more efficacious than sham, suggesting that in candidates who respond to the therapy DBS may indeed be exerting a beneficial effect.