Introduction
Neurosurgical interventions for the treatment of psychiatric illnesses have been used since the dawn of the somatic treatments in neuropsychiatry ( ). The use of surgery in psychiatry existed before there were effective pharmacological strategies, such as antidepressants or antipsychotics ( ). Egas Moniz, a Portuguese neurologist, partnered with neurosurgeon Almeida Lima to perform a frontal leucotomy in 1935 in a 63-year-old woman suffering from depression, anxiety, paranoia, hallucinations, and anxiety. It was for this work, described as “one of the most important discoveries ever made in psychiatric medicine,” that he received the 1949 Nobel Prize for Physiology or Medicine ( ). American neurologist Walter Freeman, with neurosurgeon James Watts, categorized the different types of operations, delineating specific landmarks and selecting the techniques for the lesions. A “minimal approach” involving more anterior lesions was performed in patients with affective disorders, while patients with schizophrenia and more severe symptomatology were given a “radical lobotomy,” usually more posterior and extensive ( ). Case reports were inconsistent in their methodological reporting, but would estimate “positive responses” in 30%–70%, and techniques were varied: patients with for melancholic features would receive anterior cingulotomy, stereotactic subcaudate tractotomy, limbic leucotomy, and anterior capsulotomy ( ; ). From today’s perspective, it may appear that these interventions were unsafe, but they were in many cases interventions of last resort to bring relief to patients when there were no other available options, as antipsychotics only became available in the 1950s, and antidepressants after that. Since early stages, psychosurgery discussions have invoked controversy, as the widespread and indiscriminate use of the transorbital lobotomy in the mid-20th century resulted in profound ethical ramifications that persist to this day ( ). The emergence of psychopharmacology contributed to a less invasive approach to the treatment of psychiatric disorders, and for a number of decades, neurosurgical interventions fell out of favor, with both societal and professional criticism regarding the significant and largely underreported adverse events, and the lack of objectivity and scientific rigor ( ).
However, there are patients for whom standard treatments with pharmacology, psychotherapy, and noninvasive neuromodulation are not effective. A new paradigm in the conceptualization of neuropsychiatric disorders as dysfunctional brain networks, advances in functional stereotactic neurosurgery, and successes in treatment of neurological disorders such as Parkinson’s disease made the exploration of neurosurgical interventions for severe depression possible again. Neuromodulation techniques, as opposed to lesions, have the possibility of reversibility of side effects. New neuroimaging methods, identifying structural and functional interconnectivity of relevant brain areas allowed the progress beyond a static lesion model ( ). Recognition of these cortical and subcortical nodes, the pathways between them, functional changes observed in pathological states, and mood changes when these areas were targets of surgical ablation for other neuropsychiatric disorders opened the tangible possibility of implementing invasive neurostimulation in the form of deep brain stimulation (DBS). Brain regions for invasive and noninvasive stimulation are located in the same networks across psychiatric and neurological diseases. From there, the concept framing for understanding brain stimulation as a network phenomenon has generated specific hypotheses regarding optimization of brain stimulation therapies that are being tested ( ).
In DBS, electrodes are implanted surgically through small holes in the skull in specific areas of the brain (usually in both hemispheres), depending on the desired symptoms targeted. In Parkinson’s disease, for example, the most common sites for implantation are the subthalamic nucleus and the globus pallidus. Stereotaxy is used to determine the final location of the electrode, as well as the trajectory of the lead, and the surgery is planned with the aid of neuroimaging that is acquired in advance. Once implanted, the electrodes are connected, via extension cables that travel under the skin, to a programmable pacemaker device. Once the stimulation is turned on, this battery sends electrical pulses that modulate the local region as well as the neural circuits that communicate that area to the rest of the regions involved in the functioning of that circuit. The programming allows for multiple parameter settings, as each of the leads has multiple contacts (usually separated by a few millimeters), as well as voltage or current, frequency, and pulse width ( ).
DBS acts on the cells and fibers located closest to the implanted electrode, in most cases inhibiting cells and exciting fibers ( ; ). DBS has electrical, chemical, and other neural-network influences on brain tissue. Once modulation of pathologically functioning neurocircuits was introduced and the physiological basis of depression started to be understood, treatment-resistant depression emerged as a candidate to develop treatments. Mood neurocircuitry is located throughout cortical and subcortical areas, with different nodes and hubs. Therefore, it is not surprising that DBS for depression has been explored in multiple different targets. While the exact mechanism of action of DBS is still unclear, it has become clear that it involves modulation of pathologically functioning circuits. And despite the “connectomic” framework of the development of DBS for mood disorders, targets are still described as anatomically located. These include the subcallosal cingulate white matter (SCC), ventral capsule/ventral striatum or anterior limb of the internal capsule (VC/VS or ALIC), nucleus accumbens (NAcc), the supero-lateral medial forebrain bundle (MFB), the inferior thalamic peduncle (ITP), and the lateral habenula (LHb).
Worldwide, several groups have explored DBS for depression in these targets. The initial publication documenting DBS in depression came out in 2005. More than 15 years later, there have been open-label series and clinical trials with varying results, but advances in the mechanisms of antidepressant effects, newer technologies to deliver and sense stimulation as well as imaging have moved the field forward although it is still considered experimental ( ). Considering the prevalence of depression, the levels of treatment resistance, and the continuing high rates of suicide, the total number of patients who have received DBS for TRD remains in the low hundreds, while numbers in several orders of magnitude could potentially benefit from this intervention ( ). The pattern that happened in many of these targets started with initial promising results of open-label trials that were not successfully replicated in randomized, sham-controlled, double-blind studies. There are several reasons that can explain this discordance. Importantly, there may be a number of explanations that are related to study design, patient selection, or lack of clear biomarkers that would define this clinically diverse syndrome. The enthusiasm to replicate initial open-label findings pushed the scientific community to implement clinical trials that did not account for many variables that were (and still are) unknown, for example in patient, target and parameter selection, as well as trying to imitate outcome measures that are better suited for pharmacological trials. Something similar happened in vagus nerve stimulation, where in spite of having shown treatment efficacy and received Food and Drug Administration approval, has not been covered by healthcare companies and agencies ( ). The cumulative evidence that has been generated in the last decade will hopefully give the clinical trials that may be conducted in the future a better chance of success, as several aspects involving neurosurgical refinement of the techniques have advanced, trial design has been critically discussed, and the promise of biomarkers appears closer to be fulfilled ( ) ( Table 22.1 ).
Study | Target | Subjects | Design | Follow-up period | Results | Impact |
---|---|---|---|---|---|---|
SCC | 6 | OLS | 6 months | 66% response, 50% remission | First DBS for depression study. Positive clinical results, PET changes in local and remote areas | |
SCC | 20 | OLS | 1 year | 55% response, 33% remission | Showed sustained mood improvement at 1 year | |
SCC | 20 | OLS | 3 years | 64% response, 43%–50% remission | Long-term stimulation is safe and provides sustained efficacy | |
SCC | 8 | OLS | 1 year | 62.5% response, 50% remission | Second independent study to show efficacy of SCC-DBS | |
SCC | 17 (seven bipolar 2 patients) | OLS | 2 years | 41% response at 6 months, 92% response at 2 years (11/12 patients) | Showed long-term efficacy and safety of SCC-DBS | |
SCC | 4 | OLS | 6 months | 50% response | Longer pulse widths may have a role in antidepressant effects | |
SCC | 6 | OLS | 24–36 weeks | 33% response, 33% remission | SCC-DBS causes acute and chronic antidepressant effects | |
SCC | 5 | COS | 6 months | Active phase: 4/5 sustained response Sham phase: 2/5 relapsed | Continuous electrical stimulation is necessary to avoid relapse. Slow return of symptoms | |
SCC | 5 | OLS | 24 months | 20% response | Posterior gyrus rectus is a viable target for DBS in MDD (more ventral than SCC) | |
SCC | 90 | RCT | 6 months double-blind, then open-label follow-up | Primary endpoint: Response: 20% (active) vs 17% (sham); Remission: 5% (active) vs 7% (sham). 30 month response rate: 48% | Not clinically significant at primary endpoint. Increased response rates over long-term open-label phase | |
SCC | 8 | RCT then OLS | 24–48 months | 37% response at 6 months, 51% response (average), 33% remission in long-term follow-up | No clinical significance during double-blind phase (8 weeks); long-term treatment with significant response | |
SCC | 9 | RCT-COS | 13 months | 44% response | Long-term high-frequency stimulation appears to be better than low frequency | |
SCC | 11 | OLS | 1 year | 81.8% response, 54% remission | Tractography-based target selection DBS improves outcomes | |
SCC | 28 | OLS | 8 years | Response > 50%, remission > 30% between years 2–8. 75% were responders for more than half of their participation | Treatment response to SCC DBS is sustained over time. Longest follow-up period published | |
VC/VS | 15 | OLS | 1 year | 53% response; 40% remission | Significant improvement in depressive symptoms | |
VC/VS | 17 | OLS | 14–67 months | 71% response at last follow-up, 35% remission | Long-term sustained improvement in depressive symptoms | |
VC/VS | 30 | RCT, then OLS | 16-week RCT, then 24-month follow-up | Primary endpoint: 20% (active) vs 14.3% (sham); long-term follow-up: 20%–26.7% | First RCT for DBS in depression | |
vALIC (VC/VS) | 25 (OLS); 16 (COS) | OLS then RCT-COS | 52 week optimization phase (OLS), then 2 week COS | 40% response (OLS phase); 16 patients on the COS had lower HAM-D ( P < .001) during active DBS compared to sham | vALIC DBS showed significant decrease of depressive symptoms. Discontinuation of stimulation was followed by rapid return of symptoms | |
NAcc | 11 | OLS | 48 months | 45% response | Response found in patients with long-term follow-up | |
NAcc | 4 | OLS | 6 months | 50% response during extended stimulation | NAcc appears more promising target than caudate nucleus | |
MFB | 7 | OLS | 12–33 weeks | 86% response, 57.1% remission | Rapid reduction of symptoms within 2 days, response with long-term treatment | |
MFB | 4 | OLS | 26 weeks | 75% response | Rapid reduction of symptoms within 7 days and response with long-term treatment | |
MFB | 6 | OLS | 1 year | 80% response (4/5, one withdrawal, one lost to follow-up) | Expansion from previous study with longer follow-up describing durable response | |
MFB | 16 | 2 month RCT, then OLS | 1 year | 100% response, 50% remission at 1 year, 10 achieved response at 1 week | 2-Month blinded phase did not show difference in sham vs active stimulation. Sustained responses starting after surgery | |
ITP | 1 | CR | 18 weeks | HDRS-17 scale decrease from 42% to 6. 100% remission | ITP DBS with promising antidepressant effects | |
ITP vs vALIC (VC/VS) | 7 | COS | 3–8 years | Response in both targets | 6/7 Participants preferred vALIC stimulation over ITP. 2 suicides | |
LHb | 1 | CR | 4 months | Remission | Highlighted antidepressive effects of LHb DBS; cessation of DBS current resulted in return of symptoms |
Targets for DBS in treatment-resistant depression
Subcallosal cingulate white matter
The anterior cingulate cortex plays a crucial role in the pathophysiology of depression. This region’s involvement has been verified through physiology, and functional and structural imaging data ( ). The subcallosal aspect of the anterior cingulate is a critical node in mood regulation networks involved in negative mood and antidepressant treatment response ( ). Neuroimaging studies demonstrated that the SCC is activated during sadness induction in healthy volunteers, the SCC is hyperactive in patients with depression when compared with healthy volunteers, and successful treatment of depression is associated with normalization of SCC function.
The metabolism in the SCC (studied mostly through positron emission tomography) is positively correlated with depression and anxiety severity ( ; ; ). When normal controls underwent a sadness induction experiment, increases in blood flow in the area were documented ( ). Patients who responded to antidepressant therapy had a decline in metabolism from an abnormal elevation toward normality ( ). These changes observed in the SCC were not isolated, and other brain region changes in treatment supported the concept of neurocircuitry based changes in mood states. Resting state functional connectivity between SCC and thalamus within the default mode network (DMN) is significantly greater in depressed subjects. The length of the depressive episode is positively correlated with functional connectivity in the SCC in depressed subjects ( ). Meta-analytic findings show reliably increased functional connectivity between the DMN and SCC predicting levels of depressive rumination ( ; ). Other targets for DBS were originally designed imitating the lesion model (i.e., pallidotomy and globus pallidus stimulation in movement disorders, or capsulotomy and ventral capsule DBS in psychiatric illnesses). The SCC, on the other hand, was not considered a target for ablation previously (it is more medial than the subcaudate tractotomy lesion target). Functional imaging highlights this region as a primary dynamic modulator within a larger, multicomponent mood regulation system ( ).
Clinical studies
The first publication of DBS in depression was published in 2005. Six severely treatment-resistant depressed patients were implanted in the SCC. After 6 months of stimulation four of the six patients responded (50% decline in depression severity from baseline), with three of them achieving symptomatic remission. The Hamilton Depression Rating Scale (HDRS-17) was reduced in 71% ( ). That original cohort of six patients was expanded to 20 patients. One month after surgery, 35% of patients met criteria for response with 10% of patients in remission. After 6 months, 60% of patients were responders and 35% met criteria for remission. Notably, the response was largely maintained at 12 months and beyond ( ). After 1 year of stimulation, 62.5% of patients were responders, and the response rate after 2 years was 46%, with 75% response rate after 3 years of stimulation. The baseline severity of patients included in these studies was very high and with long duration in the index episode, approximating seven years. Only 10% were employed and had previously tried and relapsed after ECT. SCC DBS did not only generate a sustained symptomatic improvement, but patients regained overall function in physical health and social functioning, although two patients died of suicide during depressive relapses ( ). After these initial promising reports, several single and multicenter studies were published, demonstrating comparable degrees of efficacy in open-label designs ( Table 22.1 ). Seventeen patients (seven of them with chronic depression in bipolar 2 disorder) were implanted at Emory University. After 6 months of stimulation, the response rate was 41% (7/17), and 92% after 2 years of stimulation (12 of the 17 patients having reached the latter time point by the time of publication) ( ). Both patients with unipolar and bipolar 2 depression responded similarly. Again, no side effects were attributable to stimulation, such as mania or cognitive changes ( ). Other centers have described similar outcomes, with many case series ( ; ; ; ). Puigdemont et al. reported outcomes in eight patients with severe TRD with 6 months response and remission rates of 87.5% and 37.5%, respectively ( ). These dramatic improvements were sustained after 12 months, with 62.5% response and 50% remission rates. Another group in Germany implanted six subjects and explored acute effects of stimulation, but also described long-term antidepressant effects, with two of the six patients in remission of depression after 6 months of stimulation. As described in the other case series in the SCC, high voltage stimulation did not cause side effects ( ). An early metaanalysis of four studies by Berlim et al. confirmed the sustained positive results up to 1 year, with response and remission rates of 36.6% and 16.7%, 53.9% and 24.1%, and 39.9% and 26.3% at follow-up endpoints of 3, 6, and 12 months respectively ( ). There was an additional multicenter study conducted in three different sites in Canada that implanted 21 patients ( ). Forty-eight percent of patients were responders at 6 months.
An industry-sponsored, double-blind, randomized controlled multicenter study was conducted, with the initial intention of recruiting 200 patients in North America. The study was halted after a futility analysis determined that the likelihood of it achieving its primary outcome was low ( ). Ninety patients had been implanted by the time the study was stopped. Its primary outcome was response (40% reduction in Montgomery–Äsberg Depression Rating Scale (MADRS) from baseline) averaged over months 4–6 of a double-blind phase (24 weeks). Participants were 2:1 randomized to either active ( n = 60) or sham ( n = 30) stimulation for the initial 6 months, then all participants received active simulation. There was no statistically significant difference in response during the blinded phase (twelve (20%) patients in the stimulation group vs five (17%) patients in the control group). These results were lower than the reports in the prior studies, but interestingly the long-term (open-label) follow-up phase described a gradual increase in response to treatment with half of the patients endorsing positive responses of chronic DBS.
Long-term sustained antidepressant effectiveness has been demonstrated in other groups as well ( ). A case series long-term report with up to 8 years of follow-up described that in 28 patients implanted at a single center, response was ≥ 50% and remission rates were ≥ 30%, after the second year since surgery. Crowell et al. reported that three-quarters of all participants met the treatment-response criterion for more than half of their duration of participation in the study, with 21% of all patients demonstrating continuous response to treatment from the first year onward. There were three patients who dropped out, and there were no suicides during the follow-up period ( ). Stimulation appears to be most effective with high frequency parameters, and delivery of stimulation needs to be uninterrupted, with return of symptoms over periods of weeks if it were to be stopped ( ).
The realization that variability in the surgical implantation was crucial generated a change from a standard anatomical coordinate-based to a connectomic approach. The use of tractography-based target selection was derived from the initial analysis of white matter structural connectivity in responders to SCC DBS, and then was implemented prospectively ( ). Up until then, the SCC target had chosen the surgical region for implantation of the DBS leads extrapolating the functional imaging findings that implicated the subcallosal region and Brodmann Area 25 in depression, but lacked precision, especially in an area with high anatomical variability. Knowledge of the white matter fibers and the network that were stimulated in the SCC became more apparent when newer methods combining tractography imaging and engineering methods that estimated the volume of activated tissue were combined ( ). Small differences in electrode location caused substantial differences in the activated pathways and confirmed widespread network changes associated with DBS induced antidepressant effects ( ). Using models that calculated volume of stimulation with individualized stimulation parameters, each contact had a unique set of white matter fibers. All the DBS responders shared a combination of white matter tracts connecting the SCC to the rest of the cingulate cortex (via the cingulum bundle), bilateral medial frontal cortices (through the forceps minor), subcortical nuclei and the thalamus (via uncinate fasciculus and frontostriatal fibers). With this response fingerprint, it became possible to test the hypothesis prospectively. Eleven subjects were implanted using target selection for the DBS that was based on the connectivity map that was present in responders ( ). The response rate increased, with 8/11 (72.7%) of patients improving by more than 50% from baseline after 6 months, with an additional subject becoming a responder at the 12-month time point (9/11, 81.8% response rate). Prospective targeting allowed for personalized, patient-specific, target selection. This targeting method confirmed and validated the conceptualization of a network model with the cingulate as a hub, where engagement of remote areas of the depression network is needed for the adequate antidepressant effect. Furthermore, there have been additional reports that confirmed the network model rationale behind the SCC DBS. Distinct patterns of white matter activation have been found to be related to the intraoperative responses when there are changes in autonomic behavior (heart rate elevation) as well as positive antidepressant responses ( ; ). Tractography-based targeting in the SCC not only resulted in better clinical outcomes in the months after implantation, but has also resulted in faster and more robust acute behavioral responses in the operating room ( ). It has also allowed collecting more reliable electrophysiological signals, derived from a certainty of the ideal location of the stimulating contacts ( ).
Ventral capsule/ventral striatum (ventral anterior limb of internal capsule)
The ventral capsule/ventral striatum (VC/VS), also referred to as the ventral anterior limb of the internal capsule (vALIC), has been identified as another target for both depression and anxiety. For many years and still in use, ablative surgery in the form of anterior capsulotomy has been an effective treatment for treatment refractory psychiatric disorders since 1949 ( ; ). Recognizing the marked improvement in depressive symptoms in open-label trials of VC/VS DBS for OCD, patients with TRD were enrolled in studies. Over the years, the VC/VS target has migrated posteriorly, almost to the level of the anterior commissure, based solely on clinical experience of better outcomes associated with more posterior stimulation ( ; ). While initially replicating the old ablative approach, newer studies have demonstrated that stimulation in different contacts of the DBS leads along the span of the capsule generated distinct patterns of activation along the cortico-striatal-thalamic-cortical network ( ).
Clinical studies
The surgical technique for VC/VS DBS involves stereotactic anatomic targeting, using high-resolution volumetric magnetic resonance imaging for planning. The anterior limb of the internal capsule and the VS can be easily visualized on T2 and inversion recovery images for direct targeting. Typical coordinates are 4–10 mm lateral to the midline, 3–5 mm ventral to the anterior commissure, and 1–3 mm anterior to the posterior border of the anterior commissure. DBS electrodes are implanted bilaterally through the shaft of the internal capsule with the most ventral aspect in the NAcc ( ; ). In recent years, the introduction of tractography in this target for OCD, and in other targets for depression, has changed the older standard anatomical approach ( ). The first open-label study commented on VC/VS-DBS of 17 TRD patients and found response rates of 53% at 12-month follow-up and 71% at the last follow-up after 14–67 months (and remission in 40%) ( ; ). Such open-label results were promising, and a multicenter randomized clinical trial was designed with the goal of providing a higher level of evidence supporting this target for treatment in TRD. Importantly, advanced targeting technologies that would be considered essential for the surgery were not applied. DBS for OCD had already received a humanitarian device exemption in 2009 ( ; ). A 16-week, randomized, sham-controlled trial in the United States did not find clinical significance in treatment response rates. Only 3 of the 15 patients randomized to active stimulation (20%) had achieved response, while 2 of the 14 (14.3%) who received sham therapy responded. The response rates in the open-label phase of 24 months of follow-up were also low, with 20%–26.7% achieving response at any time during that period ( ).
A different study, designed and conducted in the Netherlands, had better results although they were not directly comparable to the initial clinical trial. Patients had an initial open-label optimization phase that lasted 52 weeks. This phase described a 40% overall response rate in 25 patients. Mean depression scores decreased 28.3% (HDRS-17) and 30% (MADRS). Of these 25 patients, 16 (9 responders and 7 nonresponders) were entered in a randomized crossover period (active-sham vs sham-active). All responders had a return of symptoms within less than 2 weeks when stimulation was discontinued ( ). There are reasons to think that different targets may have variable times to have relapse in symptoms when stimulation is stopped ( ). Of the original 25 patients who had entered the clinical trial, 21 entered and 18 completed the maintenance phase for the following 2 years. 44% of patients were classified as responder. Patients who had not responded during the initial optimization phase did not become responders afterwards ( ).
Studies of DBS for OCD in this same target have started to identify neuroimaging techniques such as tractography, identifying certain fibers that are responsible for response in patients ( ; ). In OCD, active stimulation of the capsule fibers closer to the MFB than the anterior thalamic radiations was associated with better treatment outcome ( P = .04; r 2 = 0.34). Confirming the differences in tractography imaging and standard anatomical imaging (like in SCC), stimulation sites were largely overlapping and could not differentiate responder status, suggesting response is independent of the anatomically defined electrode position. As it was discussed earlier, the concept of the optimal target has evolved, from thinking of the target as a coordinate-determined gray or white matter structure, to conceiving of the target as “tapping into” a circuit connects to several regions of the symptomatic network ( ). Innovative trial design, introduction of newer imaging methods, and engagement of specific biomarkers, whether physiologic, imaging, or neuropsychological, will continue to elucidate the mechanisms of action of DBS and making this target a viable therapy for patients with TRD ( ).
Nucleus accumbens
The nucleus accumbens (NAcc) has been implicated as a neuromodulation target since the earlier days of this technology ( ). It is known to play key roles in the cognitive processing of motivation, reward (i.e., incentive salience, pleasure, and positive reinforcement), and reinforcement learning ( ). Preclinical animal studies have long described the antianhedonic effects of electrical stimulation of the accumbens ( ). In animal models of depression, the reward system is dysfunctional, and is reset by chronic administration of an antidepressant ( ).
Clinical studies
While septal stimulation had been conducted many decades ago, the “modern” beginnings of DBS in NAcc started when a group in Germany implanted three patients with severe refractory depression ( ). The three participants improved “immediately” in their depression when the stimulator was on, and worsened in all three patients when the stimulator was turned off. Using FDG-PET, significant changes in brain metabolism as a function of the stimulation in fronto-striatal networks were observed. The cohort was extended to 10 participants. After 1 year of stimulation, half (50%) were responders and three patients were in remission ( ). Similar PET results were seen in this larger cohort, with decreased metabolism in the SCC and in prefrontal regions including orbital prefrontal cortex. NAcc DBS also has sustained and durable antidepressant effects, with the same open-label cohort describing response rates of 45% (5 of 11) at 48 months ( ). A different group in France implanted four subjects with the intention of doing a pilot multicenter prospective, noncomparative, and open trial. Patients initially received caudate stimulation, and after lack of antidepressant response, accumbens stimulation. This change in the DBS stimulation target caused that three of the four subjects had positive changes in mood ( ). No cognitive or other major adverse effects were reported in either trial ( ). The literature provides promising evidence of NAcc DBS being a treatment for TRD; however, small samples have prevented definitive conclusions regarding its antidepressant efficacy.
Medial forebrain bundle
The MFB is a part of the mesolimbic-mesocortical dopamine reward system ( ). Researchers have hypothesized the role of MFB stimulation as either a pathway to regulate descending glutaminergic fibers from the mPFC to the VTA and modulate dopamine and stimulate cortical brain regions. The MFB has been considered for a long time as an essential structure related to psycho-behavioral functioning in both animals and human subjects ( ). There have been descriptions of its function involving affect regulation, as well as the reward-seeking system ( ). The MFB, with its fibers traveling between the ventral tegmental area and the NAcc and structures beyond the reward-seeking system, appears to be involved in the pathophysiology of MDD. Interestingly, while other targets within the reward system (ventral striatum and nucleus accumbens) had already been tried, the difficulties identifying it in standard imaging, had delayed its potential target for DBS in depression ( ).
Clinical studies
The surgical technique of DBS in MFB invariably requires of deterministic tractography to individually map the target area. The MFB is not visible in standard neuroimaging, instead requiring the acquisition of special tractography sequences. This apparent disadvantage in the target selection resulted, in the end, in avoiding the pitfalls that both SCC and VC/VS had, when the initial clinical trials were guided by less precise implantations.
The original pilot study in Germany assessed safety and efficacy of DBS in MFB in seven patients with TRD ( ). Strikingly, the antidepressant effects were very rapid in their onset, even faster than NAcc previously described. The authors described instant intraoperative antidepressant-like effects such as appetitive motivation. In the acute intraoperative reports, MFB stimulation usually causes increased vigilance, eye contact, and engagement in conversation, as well as self-reported feelings of energy and motivation concordant with mood improvement ( ). Within the first week of stimulation, patients already had significant responses, and response and remission rates of 86% and 57.1%, respectively. Not only the antidepressant effects were evident early on, but they were sustained in time. Half of those patients continued to have sustained remission at 1-year which continued until the 4-year follow-up ( ). A separate group in the United States replicated the early effects. Three of six patients had > 50% decrease in depression scores after a week poststimulation initiation relative to baseline ( ). An interesting fact in these two case-series is that the response to DBS relies on the preservation of the anatomical target. In the original cohort, the patient who did not respond to DBS had a minor intracranial hemorrhage in the trajectory of the lead, therefore irreversibly lesioning the intended target of stimulation. In the second cohort, the patient that did not respond to DBS had reduced frontal connectivity to the MFB when the DTI was analyzed. Both centers have published their long-term results, and the antidepressant effectiveness is sustained, and the neurocognitive tests did not find changes in cognition or impulsivity ( ; ). Due to its proximity to oculomotor control areas in the midbrain, strabismus and double vision are the most significant stimulation related adverse effects of DBS in this target were blurred vision and strabismus. Similarly to the rapid onset of antidepressant effects, there seems to be an abrupt return of depressive symptomatology if stimulation is discontinued ( ).
More recently, a clinical study with a randomized-controlled onset of stimulation was reported ( ). Sixteen patients were implanted in a double-blind randomized-control (DBS active vs sham) condition for the initial 8 weeks after surgery, at which point blinding was lifted and all patients received active stimulation. Similar to the first study, all 16 patients reached the response criterion, and most patients ( n = 10) responded within a week; 50% of patients were classified as remitters after 1 year of stimulation (MADRS < 10). Both groups (active/sham) demonstrated an antidepressant effect. Thus, it appeared that the sham-stimulation phase of 2 months was not long enough to separate treatment from other effects. The study reached its primary outcome at 12 months of stimulation, with all participants responding to DBS and a 56% mean decline in MADRS (50% of patients in remission). This lack of difference at this endpoint highlights the difficulties in trial design for DBS. It would be hard to justify that a trial with the sustained antidepressant results as these have reported would be due to placebo effects. Patients with TRD usually have little response to antidepressant interventions, and these are usually short lived. But any regulatory agency who would have asked for a sham versus active trial as the primary efficacy outcome would have deemed this study inconclusive. The authors of this trial rightfully comment that slow, careful, and adaptive study development in DBS for depression is appropriate.
Inferior thalamic peduncle
The ITP is part of the interplay between the dorsomedial thalamus and the orbitofrontal cortex ( ). Depression models have shown a dysregulation in this connection ( ). A case report regarding ITP DBS showed a decrease in depression scores early after surgery, and sustained after 8 months of stimulation using high frequency DBS and very large pulse widths (3.5 V, 450 μs pulse width) ( ). There was a return of depressive symptoms when stimulation was interrupted, and the antidepressant effects were recaptured after stimulation was resumed with sustained effects ( ). One trial attempted to evaluate the difference between stimulation in the internal capsule and the inferior thalamic peduncle. The group consisted of seven patients with TRD who were implanted and underwent blinded cross-over periods of 2 months per target. Due to low number of participants, it was not possible to determine superiority of one target over the other. All patients ( n = 7) were followed up for at least 3 years (3–8 years) after implantation. Six patients completed the first crossover and five patients completed the second. Two participants died of suicide. Numerically, it appeared as if depression scores were lower for capsule stimulation. Three out of five subjects had response to ITP stimulation. Patients preferred the ALIC/BNST target with no major adverse effects ( ). Further clinical studies are needed to further validate the ITP as a DBS target for depression.
Lateral habenula
The LHb is an epithalamic structure that regulates serotonergic raphe nucleus activity and modulates dopaminergic midbrain functions ( ). Increased activation of the lateral habenular nucleus leads to the down regulation of the serotonergic, noradrenergic, dopaminergic systems and stimulation of the hypothalamic-pituitary-adrenal (HPA) axis ( ). This overactivity in the habenula in depressive states may be counteracted by functional inhibition of the lateral habenula with DBS. The hypothesis is based on the findings of a clinical imaging study examining the habenula after tryptophan depletion and several animal models of depression ( ). The acute antidepressant properties of ketamine (a rapid acting antidepressant) may be mediated through the habenula ( ).
Clinical studies
Despite its promising neurobiological support, there have only been two case reports in the literature ( ). In one case, the authors reported remission of depressive symptoms after 4 months of habenular stimulation. Interestingly, cessation of DBS current resulted in the return of depressive symptoms ( ). Further clinical trials, case series, and studies of comparison between targets are under way to further examine the feasibility as a DBS target.
Conclusions
Psychiatric disorders are complex, with a constellation of symptoms and signs that are manifestations of multiple interconnected relevant circuits (mood, reward, anxiety/fear, homeostasis, cognition, etc.). Functional neurosurgery has been at the forefront of the advances in clinical neurosciences in the last couple of decades. Newer surgical techniques allow for more precise implantation, minimizing complications, and directly monitoring the physiologic changes caused by stimulation in the affected neurocircuitry ( ). The progress in DBS for depression will come not from a single discovery or breakthrough, but with a concerted effort by all the parties involved (basic scientists, neurosurgeons, psychiatrists, computational scientists, and biomedical engineering, to name some of them). Identification of biomarkers of illness, response, and change will play a role in the design of more precise targets for engagement ( ; ). Likewise, this will impact patient selection and trial design. The new concept of “connectomics” aims to map the structure of the brain at several levels from individual neurons to nodes and networks, and this framework is well suited to investigate key questions on the complex functions of the brain ( ). The refinement of patient selection, and biomarker engagement with therapy, has evolved with incremental success in the field of Parkinson’s disease, even aiding in the determination of target selection depending on clinical characteristics ( ). The field of neuromodulation in psychiatry is ripe for interventions that bring hope for many patients with severe, treatment-resistant disorders. The initial enthusiasm generated by small, open-label and mostly single-center studies was followed by a “loss of innocence,” doubt and pessimism when the results of multicenter, randomized, double-blind trials did not replicate the positive results ( ; ). In the end, strong clinical evidence will be needed to justify the invasiveness of these interventions for a large portion of patients with TRD who have not responded to other treatments. While initially disappointing in their primary outcomes, several cohorts of patients who received DBS in different targets have shown that when patients respond, they have sustained antidepressant effects. An exploratory metaanalysis published in 2014, gathering data from the DBS case series published to that date, estimated that DBS was 71% more likely than sham treatment to be of benefit for patients with TRD ( ). However, it only included a total of 125 patients from eight different studies (only one randomized double blind control study in VC/VS). Another study that selected 10 clinical trials (with only two RCTs) combined a total of 190 patients receiving DBS in different targets. Patients on active treatment had a significantly higher response rates than sham stimulation (OR = 5.50; P < .0001) and reductions in mean depression score (SMD = − 0.42; P = .006).
For a large number of patients with chronic depression, the endless cycle of response and relapse is disheartening and contributes to lesser engagement in functional rehabilitation. The sustained responses in DBS and other surgical interventions such as VNS are one of the justifications for the higher initial surgical risk, and possibly the financial costs of the interventions ( ).
Advanced neuroimaging techniques are changing the clinical practice of psychiatric neurosurgery. DTI targeting methods are being used routinely in SCC, VC/VS, and MFB DBS not only in MDD but in a majority of conditions explored. A connectomic approach to DBS surgery opens up the reality of personalized treatment, where a particular target is decided on the involvement of certain white matter structures and symptoms that respond to specific circuit modulation. A notable example happened with medial prefrontal cortex/uncinate fasciculus DBS. Researchers intentionally steered the current in the DBS lead to stimulate the uncinate fasciculus, resulting in a dramatic reduction of posttraumatic stress disorder symptoms. The rationale for selecting this target and electrode contact configuration had a strong translational component, as this white matter bundle has an important role of modulating the basolateral amygdala.
The keys for success in the near future of DBS for depression will rely on the integration of advances in imaging, neurophysiology, and clinical expertise to plan new multicenter trials that will replicate, on a larger scale, the observations of different research groups, thus ensuring a safe and long-lasting treatment option for the TRD population.