Deep brain stimulation for treatment-resistant depression

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 ).

Targets for DBS in treatment-resistant depression

Fig. 22.1 .