11 Deep Brain Stimulation for Obsessive Compulsive Disorder

11.1 Introduction

Obsessive-compulsive disorder (OCD) produces recurrent thoughts, images, feelings, and behaviors that persist despite attempts to eliminate them and are accompanied by marked and often overwhelming anxiety.1 The disorder leads to significant and dramatic impairment in social and occupational functioning. OCD has a lifetime prevalence of 2 to 3%, and it is estimated that 1.2% of the population has suffered from OCD symptoms in the last year.² Current first-line treatment consists of a combination of behavioral therapy and pharmacological agents; however, even with access to best available medication and behavioral therapy, 10 to 20% of patients will remain severely disabled by the disorder. This statistic is worsened further by the fact that even when properly treated, many patients stop their medication due to unwanted side effects.³ Thus despite advances in pharmacotherapy and behavioral therapy, a large number of individuals still suffer from severe and under-treated OCD. Therefore, patients with severe and refractory OCD may benefit from consideration of surgical intervention.

11.2 Development of Stereotactic Neurosurgery for OCD

The first stereotactic neurosurgical procedure in humans, a medial thalamotomy, was performed for psychiatric/behavioral reasons. Neurologist Ernst Spiegel and neurosurgeon Henry Wycis modified the Horsley–Clarke apparatus, devised four decades prior for targeting specific regions within animal brains, to create a human stereotactic system. They reported the technique and a brief description of the indications and results in one patient with “emotional reactivity” in their landmark 1947 monograph.4 The next two decades witnessed the development of other lesion procedures for psychiatric indications, including the capsulotomy, cingulotomy, and subcaudate tractotomy.

Following on the heels of the Spiegel and Wycis report, psychiatrist/neurosurgeon Jean Talairach stereotactically targeted the anterior limb of the internal capsule (ALIC), thereby performing the first capsulotomy.⁵ Talairach’s capsulotomy, like Wycis’s thalamotomy, was created by surgically introducing a radiofrequency electrode into the target and thermocoagulating the tissue. A few years later, neurosurgeon Lars Leksell performed the first capsulotomy using stereotactically targeted radiation, thereby creating the field of stereotactic radiosurgery.⁶ The capsulotomy is thought to exert its effect by altering communication between thalamic nuclei and prefrontal cortical (PFC) regions, especially orbital and medial PFC. Specialized centers continue to perform capsulotomy procedures to this day, with response rates (≥ 35% decrease in Yale–Brown Obsessive-Compulsive Scale [YBOCS]) ranging from 40 to 70%.^7,8,9

Cingulotomy involves the creation of a lesion in the dorsal anterior cingulate cortex and cingulum bundle. Foltz and White first described the procedure in 1962,¹⁰ and Ballantine subsequently performed and studied it extensively.^11,12 The rationale for targeting this region was based on the work of Papez, in which he described a circuit from the hippocampus to the mammillary bodies, including the cingulate cortex that was important for processing emotion and anxiety.¹³ Recent series of cingulotomy for OCD have demonstrated response rates of 30 to 50%.^14,15

The subcaudate tractotomy consists of creating a lesion in the frontal white matter inferior to the caudate head, designed to disrupt frontothalamic connections. Knight first performed these procedures in the early 1960s using stereotactic placement of ytrrium-90 radioactive seeds to produce a focal lesion.¹⁶ There has been little outcome data from this procedure in the era of YBOCS measurements (> 1990), and in modern practice it is rarely performed as a standalone procedure.

The combination of cingulotomy and subcaudate tractotomy is termed the limbic leucotomy, and was introduced by Kelly in the early 1970s.17 This procedure may be performed as a single surgery¹⁸ or as a staged procedure, where the subcaudate tractotomy is performed on patients not responsive to cingulotomy.^14,19

Since the early days of human stereotactic neurosurgery, brain stimulation existed side by side with lesion procedures as another tool for treating psychiatric disorders, but did not gain traction for the first few decades due to limitation in device technology. In 1954, Pool described implanting an electrode and stimulating the caudate nucleus of a patient with severe depression, leading to an improvement in appetite and mood.²⁰ Deep brain stimulation (DBS) in its modern form was developed in the 1980s by Benabid²¹ and became an extremely valuable addition to the neurosurgical armamentarium for treating movement disorders. It was first applied for psychiatric disorders in 1999, when Nuttin reported the first cases of DBS for OCD, finding that three of four implanted patients demonstrated clinical response to stimulation of the ALIC.²² Although at that time DBS was widely considered to operate as a functional lesion, later research has indicated a more complex effect of stimulation,^23,24,25 calling this putative mechanism of action into question.

11.3 OCD Pathophysiology

The mid 1980s witnessed the development of key insights into the organization of cortical and subcortical circuitry, as well as their integration for the regulation of behavior. These theories proposed the existence of cortical-basal ganglia-thalamocortical (CBTC) circuits that pass information along loops involving cortex, striatum, pallidum, subthalamic nucleus, and thalamus.26 These distinct but overlapping circuits regulate control over motor actions as well as emotion, mood, and decision-making behaviors. Dysfunction in these circuits can lead to alteration of these behaviors, manifesting as various neuropsychiatric disorders. The important corollary notion is that the identification of the dysfunction opens the door for targeted interventions (such as DBS) to attempt to restore functionality and treat the disorders. Perhaps best understood are the CBTC circuits regulating movement, as evidenced by the success of DBS for movement disorders. Several other circuits encompass regions of the brain governing behaviors that are perturbed due to psychiatric disease, including prefrontal regions such as orbitofrontal cortex (OFC), dorsolateral prefrontal (dlPFC), and anterior cingulate cortex (ACC).

The current prevailing theory regarding the pathophysiology of OCD is based on this CBTC theory and dysfunction within prefrontal circuits.²⁰ One of the implicated circuit loops involves the OFC and the ventromedial caudate and is thought to mediate how a person responds to emotionally salient stimuli. As with all CBTC circuits, it comprises an excitatory direct pathway and an inhibitory indirect pathway that exist in equilibrium in healthy individuals. However, the direct pathway is thought to be pathologically hyperactive in OCD patients, thereby generating an unchecked positive feedback loop in this first circuit.²⁰ This hyperactivity, which has been observed robustly and consistently in OCD patients in functional imaging studies,^27,28,29 has been proposed to manifest as exaggerated attention to perceived threat, thereby contributing to the obsessions of OCD.³⁰ Compulsions may then develop as a means to handle these obsessions, and the temporary relief attained by these compulsions leads to their reinforcement and the entrenchment of the stereotypical behaviors of OCD. Indeed, optogenetic studies in mouse models have demonstrated that chronic activation of pathways between OFC and striatum generates OCD-like repetitive behaviors.³¹

Another implicated CBTC circuit involves the dlPFC and dorsolateral caudate.²² This pathway underpins executive function and facilitates cognitive flexibility. It appears to be hypoactive in OCD patients leading to cognitive inflexibility and rendering them unable to deviate from ritualistic compulsions.^32,33 Along with the aforementioned aberrant CBTC loop, pathologic activity in these circuits generates anxiety-provoking obsessions, abnormal compulsive behaviors transiently relieving this anxiety, and a lack of flexibility needed to abandon these rigid behavioral patterns.³⁴

The ACC has also been implicated in the pathophysiology of OCD. As a hub for cognitive control functions, the dACC integrates with various other involved frontal regions.³⁵ It has extensive reciprocal cortical connections with the dlPFC, and plays a major role in modulating cognitive flexibility and executive function.^36,37 In addition, the ACC has projections to the primary, premotor, and supplementary motor cortices, which theoretically help govern behavior execution and cessation.^27,38 Abnormal activity levels have been seen in the ACC of OCD patients in both resting-state and symptom-provocation functional imaging studies.^39,40,41,42 Moreover, the involvement of ACC in OCD pathophysiology is further supported by the efficacy of cingulotomy in alleviating OCD symptoms.¹⁵

11.4 Development of Targets for DBS for OCD

A variety of targets have been developed for DBS for OCD ( Fig. 11.1). The first and most commonly used target was chosen as a direct extension of the capsulotomy experience, targeting the ALIC.²⁸ Targets within the vicinity of this region have been defined with different names. ALIC refers to the entire white matter structure, as the original capsulotomy studies targeted this entire region. Another widely used targeting term is the ventral capsule/ventral striatum (VC/VS), referring to the ventral most portion of the ALIC and the underlying gray matter of the VS immediately below it. Referring to the target as the ALIC or VC/VS emphasizes the idea that the target may actually be a white matter target, such that the goal of stimulation is to influence the fibers coursing through this region. By targeting these fibers, stimulation can influence the regions they connect, i.e., PFC and subcortical regions, via the CBTC circuit. The emphasis on white matter targeting is becoming the prevailing view in this field.^43,44 Nonetheless, some of the older studies have emphasized the gray matter as the actual surgical target, referring to it as the VS or nucleus accumbens (NAc).

The therapeutic mechanism of DBS within this target region likely extends beyond the creation of a reversible lesion that partially impedes information transfer.^45,46 DBS may also affect white matter pathways by generating consistent axonal activation through supra-threshold stimulation.²³ In addition, stimulation likely affects adjacent gray matter structures such as the striatum; recently it has been posited that VC/VS stimulation effects on the bed nucleus of the stria terminalis may be crucial to the target’s efficacy.⁴⁷

Fig. 11.1 Regions historically targeted for DBS for OCD. The figure presents the portions of respective regions targeted by published studies of DBS for OCD. ALIC, anterior limb of the internal capsule (yellow); BNST, bed nucleus of the stria terminalis (green); ITP, inferior thalamic peduncle (salmon); NAc, nucleus accumbens (cyan); STN, subthalamic nucleus (red); VS, ventral striatum (royal blue).

The subthalamic nucleus (STN) has also been utilized as a target for DBS for OCD. The STN is an essential component of the indirect pathway of CBTC circuits.48 It has multiple subdivisions, including a motor territory (which is a target for DBS for Parkinson’s disease), an oculomotor territory, an associative territory, and a limbic territory.⁴⁹ While the mechanism is only partially understood, electrical stimulation of the limbic territory is thought to modify the STN interaction with the CBTC circuits implicated in OCD and thereby decrease symptom severity.⁵⁰

11.5 Criteria for Candidacy

Candidacy for DBS for OCD follows essentially the same criteria as those adopted for lesion procedures decades ago. The main categories of criteria are diagnosis, chronicity, severity, and refractoriness. The primary diagnosis should be OCD. Additional common diagnoses are mood disorder, anxiety, eating disorders, and others, but these should not be the primary diagnoses. Some comorbidities are exclusions, as exemplified below. Typical chronicity criteria are ≥ 5 years since diagnosis. Some groups also adopt a minimum duration of severe symptoms. Severity is usually measured with the Yale Brown Obsessive Compulsive Scale (YBOCS), a measure of disease severity in OCD.51 Most groups use a minimum score of approximately 28, or approximately 14 if only obsessions or only compulsions are present. Refractoriness is measured relative to pharmacological and cognitive behavioral therapy. Typical requirements are at least three trials of ≥ 12 weeks of maximum tolerated doses of serotonin reuptake inhibitors (selective or not), including one trial with clomipramine, at least two augmentation strategies such as the use of antipsychotic or tricyclic antidepressant drugs, and at least 20 hours of expert OCD-specific exposure/response prevention (ERP) therapy (although shorter participation may be allowed if nonadherence is due to intolerance of therapy). Other typical inclusion criteria are age (18 to 75 years), ability to provide informed consent, and demonstrating appropriate expectations from surgical outcome. Exclusion criteria include comorbid psychiatric disorders with the potential to interfere with treatment, clinically significant conditions affecting brain function or structure, extremely low cognitive ability, current substance use disorder, and recent suicide attempt or active, formed suicidal ideation.

11.6 Efficacy of DBS for OCD

Nuttin reported the first patient series on the efficacy of DBS for OCD in 1999.28 Bilateral electrodes were implanted in the ALIC of four patients with severe OCD. The study reported beneficial effects in three of the four patients, with a self-reported 90% decrease in compulsive and ritualistic behaviors in one patient. The reported results were descriptive, not incorporating measurements using the standard symptom scale, the YBOCS.⁵¹ Nevertheless, it demonstrated the safety and potential viability of DBS for the alleviation of OCD symptoms.

Since this initial report, there have been a number of studies on DBS for OCD, ranging from uncontrolled case series to randomized, blinded trials. Here we highlight results from studies with cohorts of at least six patients ( Table 11.1). We excluded studies whose results are included in a later publication,^52,53 in order to avoid duplication. To date, a total of eight studies have met these criteria.^{28,29,47,50,54,55,56,57} One study used unilateral DBS⁵⁴ and the other seven used bilateral implantation strategies. Six of the eight studies implanted electrodes in the regions of the ALIC or VC/VS, albeit with a variety of nominal target names, including the NAc,^54,55 VC/VS,^56,57 bed nucleus of the stria terminalis (BNST),⁴⁷ and inferior thalamic peduncle (ITP).²⁹ One study targeted the STN,⁵⁰ and the most recent study targeted both VC/VS and STN regions in order to compare efficacy in the two locations.⁵⁸

In 2008, a French consortium published their results studying the effects of STN stimulation in a crossover, double-blind, multicenter study of 16 patients treated with stimulation of the anterior territory of the STN.50 After a 2-month postimplantation recovery phase, investigators tested a range of stimulation parameters across all contacts to establish the optimal parameter set for each individual. Patients were then randomized 1:1 to receive either active stimulation or sham (DBS off) for 3 months, using the individualized parameter set as a starting point. There was then a 1-month washout period (DBS off for both groups), followed by another 3-month period in which each patient crossed over to the other treatment. Thus eight patients were in the on-off group, and the other eight were in the off-on group, with each patient serving as his/her own control. Clinical response was measured at the end of each crossover phase. Of note, the YBOCS criterion for response was a decrease of 25%, a lower threshold than the typical 35% reduction criterion used in most DBS studies. The primary outcome measure of the study was the change in YBOCS score at the end of the stimulation compared to the sham period. The study did indeed meet its primary endpoint, as YBOCS scores were significantly lower (i.e., symptoms were less severe) after active stimulation than they were after sham stimulation (19 vs. 28, respectively, p = 0.01). As secondary assessments, the global assessment of functioning and clinical global impression were also significantly improved during active stimulation, suggesting a significant improvement in both symptom severity and quality of life. Neuropsychological, depression, and anxiety measures did not change significantly with active stimulation. Thus, this trial provides Level I evidence that active stimulation of the STN reduces OCD symptoms.⁵⁹

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