Deep Brain Stimulation for Intractable Psychiatric Illness

Introduction

The burden of psychiatric disease in the general population is substantial. Consider just two of the more common diseases. Major depressive disorder (MDD) is thought to affect nearly 17% of the world’s population, and the lifetime prevalence of obsessive-compulsive disorder (OCD) is estimated at 3%. Although there are a variety of therapies available, a large proportion of patients remain refractory to standard behavioral and pharmacologic treatments. ^, Advances in neurobiology and imaging have strengthened the theory that many of these illnesses involve aberrant brain circuitry, likely due to dysfunction at the level of receptors, synapses, and electrical transmission. Neurosurgical techniques that modulate these networks, such as deep brain stimulation (DBS), may be uniquely positioned to offer new solutions and insights for the treatment of these disorders. In this chapter, we begin by reviewing the history of DBS in psychiatric illness. We then focus in detail on the most robustly studied indications: treatment-resistant depression (TRD), OCD, and Tourette syndrome (TS). We recognize that this is a rapidly growing subfield within neurosurgery, and that out of necessity we must exclude discussion of many other psychiatric disorders that have been investigated. In the concluding section we therefore point the reader to other resources and include a discussion of future undertakings and considerations.

The development of frame-based stereotaxy for human neurosurgery in the 1940s by Spiegel and Wycis, along with the development of stereotactic atlases, allowed surgeons to make discrete lesions in the brain accurately and reproducibly. The first such reported procedure in humans was a medial thalamotomy performed for a behavioral/psychiatric indication (“emotional reactivity”). Procedures such as anterior capsulotomy, subcaudate tractotomy, cingulotomy, and limbic leucotomy were successfully developed and implemented over the following decades. Concurrently, the field of psychiatry continued to mature, with major pharmacological discoveries as well as improved precision in characterizations and definitions of the various disorders being treated. The recent resurgence of interest in neurosurgery for psychiatric disorders was brought about largely by the availability of DBS in the 1990s, following its success for movement disorders starting in the previous decade. In addition, the development of functional imaging and biochemical analysis allowed researchers to discover brain networks involved in diseases like OCD and depression and has translated directly into identifying targets for DBS. ^{, ,} Finally, there has been a definite shift in the last decade toward regarding these illnesses as systems-level disorders of specific neuronal circuits, subcortical and cortical in nature. This view is analogous to that in Parkinson disease (PD), where a circuit abnormality underlies the movement disorder. Thus, the hypothesized consequence is that targeted modulation of these affected circuits may effectively treat the disorder.

DBS has become the mainstay of surgical treatment of movement disorders such as PD, tremor, and dystonia. According to reports from one of the DBS manufacturers, as of 2015, over 135,000 people have had DBS surgery for PD alone. Because of the nondestructive nature of electrode implantation and the ability to alter multiple stimulation parameters via an implanted pulse generator, DBS therapy is adjustable and reversible. In recent years, there has been an increasing interest in the application of DBS to treat patients with severe psychiatric illness, in part due to these advantages of stimulation over lesioning. ^{, , ,} However, as more data have accrued, lesioning techniques refined, and radiosurgery mechanisms understood, it is becoming clear that DBS and lesioning both play a role in modern neurosurgical interventions for psychiatric illness. For instance, in lesioning, the lack of necessity for programming adjustments and battery replacements permit patients freedom from “tethering” to a clinical site capable of managing a DBS device. Stereotactic lesion surgery also can be considered in resource-limited locations where providing DBS equipment or the requisite support team is infeasible. Likewise, the nonsurgical nature of radiosurgery is helpful in patients who cannot or will not tolerate surgical procedures. ^, To maintain focus, however, we limit our discussion in this chapter to DBS procedures.

Given that specific circuits seem to underlie these disorders, one significant challenge to the psychiatric application of DBS is deciding exactly where, anatomically, to place electrode leads. ^{, , , , ,} The use of DBS in PD benefited from the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine primate model that allowed researchers to gain insight into the underlying motor circuits and predict the outcome of therapeutic stimulation in humans. ^, Even with this model, DBS target selection in PD and other disorders such as essential tremor was based, in part, on historical experience with lesioning procedures such as pallidotomy and thalamotomy. The limbic disorders do not yet have as robust animal models that can be used to inform target selection. Instead, targets for DBS have been selected based on empirical experience from lesioning procedures, observations made while using DBS to treat other disorders, and, to a limited but recently increasing extent, neuronal circuit study using noninvasive methods in humans. ^{, ,}

Obsessive-Compulsive Disorder

OCD is a challenging illness characterized by unwanted and intrusive thoughts (obsessions) as well as repetitive and even ritualistic behaviors (compulsions). The obsessions vary and can span a variety of dimensions, such as cleanliness, symmetry, scrupulosity, or concerns about safety, security, or discarding valuables. ^, Patients’ subsequent compulsions are related to their obsessions and include actions such as cleaning, arranging, checking, and seeking reassurance. These thoughts and actions can be so consuming that patients may become physically unable to engage in normal activity or may even injure themselves. ^{, , ,} OCD frequently occurs in combination with other psychiatric disorders such as TS, MDD, and other anxiety disorders. ^, The pathophysiology underlying OCD is far from completely understood, although abnormalities in serotonin regulation have been implicated as a potential contributor. ^, Among the most effective medical treatments is administration of selective serotonin reuptake inhibitors (SSRIs), which further supports the theory that the disorder involves a deficiency of serotonin at the synaptic level. ^, Often, combinations of SSRIs with other agents are required. One frequently employed tool is cognitive behavioral therapy (CBT), which aims to expose the patients in a controlled manner to provoking stimuli and teach them how to handle the evoked feelings. This OCD-specific form of CBT is called exposure and response prevention (ERP). ^{, ,} Surgery has been historically reserved for only those patients with the severest symptoms and who are refractory to medical therapy and expert ERP therapy. ^, Disease severity in OCD is often determined by a clinical rating scale, the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). In general, “response” to treatment is defined as a reduction of at least 35% in Y-BOCS score. ^,

Advances in neuroimaging have helped develop network-based theories of OCD, better informing neurosurgical targeting. In particular, the concept of the so-called cortico-striato-thalamo-cortical loops has proven a useful paradigm for framing the illness. According to this theory, input from the frontal cortex travels to the thalamus through the striatum and basal ganglia and then, subject to processing all along the way, completes the loop by returning to the frontal cortex. Functional imaging of OCD patients has shown that these cortical and subcortical regions are often hyperactive at rest, worsen during known OCD provocations, and can approach normal with successful treatment. ^{, , ,} It is thought that hyperactivity in this loop can lead to an inability to inhibit behavioral responses to unregulated, anxiety-provoking stimuli, generating the clinical picture of obsessions and compulsions.

The fact that some patients remain refractory to therapy, SRIs, and neurosurgical intervention exemplifies the incompleteness of our still nascent understanding of the implicated circuitry. Recent research has shown a number of regions and factors whose importance is yet to be fully determined and delineated. For instance, the lateral and medial orbitofrontal cortices (OFCs) have been implicated in reward processing and affect regulation. There is some evidence that the lateral OFC responds to negative valence and is hyperactive in OCD, leading some to postulate that deficient fear extinction can lead to the obsessions and compulsions of OCD. This theory of deficient fear extinction is further supported by data demonstrating abnormalities in amygdala functioning in OCD patients, specifically hyperactivity during exposure to OCD-specific obsessions, and hypoactivity during exposure to general novelty. ^, The dorsal anterior cingulate cortex (dACC) has also gained recognition as a critical player in OCD pathophysiology. The dACC is theorized to integrate external stimuli with long-term goals. It acts as a gatekeeper that, based on previous knowledge and new information, determines if and how behavioral regulators should be signaled to act. It is thought that in OCD, improper attribution of salience to external or internal stimuli may give rise to obsessions, and inextinguishable signals to act cause patients to repeatedly perform fruitless compulsions. OCD is a heterogeneous disease with dysfunction potentially involving several brain regions and networks.

Although multiple target areas have been explored, many researchers have focused on the anterior limb of the internal capsule (ALIC), the target for the capsulotomy lesion procedure ( Table 110.1 ). ^{, , , ,} The first published series of OCD patients treated with DBS was reported in 1999 by a group of researchers from Belgium, who continuously stimulated the ALIC bilaterally in four patients using a target similar to that used for capsulotomy. They described their results in general terms, but reported “some beneficial effects” in three of the four patients. In 2003, after the addition of two further patients, the group published updated results. Of these six patients, four entered a cross-over phase in which they were stimulated for 3 months and then their devices turned off for 3 months. The mean Y-BOCS score with stimulation was 19.8 ± 8.0 (considered “moderate severity”), compared to 32.3 ± 3.9 (“extreme severity”) without stimulation. Relatively high stimulation parameters were needed to achieve benefit, with pulse generator replacements required every 5 to 12 months.

The first Class I evidence for DBS in OCD came a few years later in a randomized, double-blind, crossover study in France of associative-limbic subthalamic nucleus (STN) territory stimulation versus sham stimulation in 16 OCD patients. In this trial, after surgery and a period of parameter optimization, patients were assigned to either active stimulation or sham for 3 months, with a 1-month “washout period” between the crossover. The trial showed lower Y-BOCS scores with active treatment (19 ± 8) than with sham (28 ± 7) stimulation ( P = .01). Moreover, efficacy was achieved at substantially lower stimulation amplitudes than in the prior report (2.0 ± 0.8 vs. 7.6 V in the 2003 Belgian study). Nevertheless, it is worth noting that a lower cutoff was used to label responders (25% decrease in Y-BOCS rather than 35%).

Groups targeting the ALIC observed that the ventral-most contacts, which bordered the ventral striatum (VS), were usually most effective. They thus began more specifically targeting the nucleus accumbens (NAcc), a major constituent nucleus within the VS known to be involved in reward processing ( Fig. 110.1 ). ^, The NAcc receives input from multiple areas, including the orbitofrontal cortex, amygdala, and caudate, and projects to a similarly diverse set of regions, including the cingulate cortex, striatum, and frontal areas, many of which have been implicated in OCD neuropathophysiology. ^, The term ventral capsule/ventral striatum (VC/VS) has been employed to describe this more ventral target encompassing both the ventral ALIC and NAcc.

A large international study involving 26 patients at four centers in the USA and Belgium investigated stimulation of the VC/VS for severe and refractory OCD. The trial was open-label, and patient recruitment and target selection were similar at all four centers (Leuven/Antwerp, Butler Hospital/Brown Medical Center, Cleveland Clinic, and University of Florida). At last follow-up (mean 24.5 ± 2.5 months; 3 to 36 months), 62% (16/26) of patients were clinical responders, demonstrating a reduction in the Y-BOCS score of at least 35%. Further, analyses over the course of the study revealed that patients with more posteriorly located DBS electrodes (closer to the anterior commissure [AC]) exhibited greater improvement. The authors postulated that the posterior target was more effective for a number of reasons. In addition to stimulating the NAcc, they also noted that the white matter fibers become more compact at this location. Given that DBS typically stimulates a markedly smaller volume than lesioning affects, this tract compaction may enable a more efficient DBS effect. Furthermore, nonhuman primate studies using radioisotope tracers have identified this more posterior region as a node of fibers connecting multiple areas of the medial and orbital frontal cortex with the thalamus, areas whose modulation may be critical to therapeutic effect.

The active leads in this study, now more posterior and closer to the AC, were also near the bed nucleus of the stria terminalis (BNST), a region increasingly seen by developing research as playing an important role in anxiety, stress and compulsive behavior in rodent work, though its role in humans remains unclear. ^, Similar to the previous study, a study from Belgium initially had an ALIC target that gradually migrated posteriorly toward the AC and underlying BNST. ^, This 24-patient study is notable for its design, which consisted of an open-label optimization phase followed by a double-blind crossover withdrawal, rather than an up-front randomization as had been used in previous trials. This study initially targeted the ALIC with the most distal lead extending into the inferiorly bordering gray matter. Seventeen patients completed the crossover study, which consisted of a 3-month ON phase followed by 3-month OFF and vice versa. Although there was some clinical improvement in the OFF group relative to their preoperative Y-BOCS, indicating some level of placebo, there was a median 37% decrease in Y-BOCS when comparing the ON group to the OFF group. Additionally, when analysis was performed comparing lead location and clinical response, the 15 patients with primarily BNST stimulation responded significantly better than did patients who received primarily ALIC stimulation. Thus, like the previous US/Belgian study, this one also noticed improved efficacy with a more posterior target. Whether the BNST is the actual symptomatic region or simply a good landmark that can be used to position the electrode remains to be determined. The latter hypothesis, which is gaining acceptance, conceives of the “target” not as a gray matter region, but rather as a white matter bundle. The effect of stimulation may be transmitted through this bundle to a variety of cortical and subcortical regions to achieve modulation within a broad symptomatic network.

Results from the US/Belgian study with DBS in the VC/VS led to a Humanitarian Device Exemption (HDE) approval by the US Food and Drug Administration (FDA) in early 2009. Although the HDE requires local Institutional Review Board approval and does not guarantee insurance reimbursement, the approval nevertheless represented an important event in modern-day psychiatric neurosurgery in the United States.