Deep Brain Stimulation for Obsessive–Compulsive Disorder

Introduction

The Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-V) defines obsessive–compulsive disorder (OCD) as a psychiatric disorder characterized by persistent obsessions with intrusive thoughts leading to severe generalized anxiety and/or compulsions in the form of repetitive tasks to relieve this distress ( ). OCD affects approximately 2%–3% of the population, with no gender preference, and is the 10th leading cause of disability worldwide ( ). The symptoms interfere with routine activities, performance at work, and social interactions, leading to an increase in the incidence of suicidal events ( ).

In terms of management, selective serotonin reuptake inhibitors and cognitive and behavioral therapy are the first-line treatment options for patients with OCD ( ). These therapeutic measures provide a 40%–60% reduction in OCD symptoms in approximately 50% of patients ( ). Recently noninvasive neuromodulation options, including transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation, have been explored in the treatment of OCD symptoms. Various rTMS protocols have been used with success in this, with targets including dorsolateral and dorsomedial prefrontal cortices (PFCs), as well as the supplementary motor area (SMA) ( ). Transcranial cathodal direct current stimulation (tDCS) (2 mA/20 min) of the bilateral preSMA region has been shown to decrease Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores after 20 sessions in 12 patients with severe OCD ( ). Similarly, tDCS of the left orbito-frontal region has been shown to reduce Y-BOCS score by 26% after 10 sessions (2 mA/20 min) ( ). However, despite aggressive pharmacotherapy and behavior therapy, 10%–25% of patients have persistent symptoms leading to a significant morbidity ( ).

Surgery is a reasonable option for this subset of patients with treatment-refractory OCD. The surgical treatment of psychiatric disorders dates back to the origin of neurological surgery, but became less well regarded due to a poor understanding of the pathophysiology of psychiatric disorders and the high surgical morbidity/mortality associated with such techniques as frontal lobotomy. Furthermore, variable reporting of surgical outcomes and the advent of the availability of effective medications depreciated surgical therapy. Technological advances and evolutions in brain-imaging techniques not only improved our understanding of the pathophysiology of psychiatric disorders but also led to a renewed interest in the surgical treatment of refractory psychiatric disorders, including OCD. Various targets for ablation and/or neurostimulation have been described; however, owing to its reversibility, adaptability, and the existence of reliable sham conditions, as well as the ability to blind stimulation for research studies, neurostimulation is presently considered to be superior to ablation when treating psychiatric disorders ( ).

The success of deep brain stimulation (DBS) surgery for a variety of movement disorders over the past two decades has led to the exploration of this treatment modality for medically refractory OCD. Both the minimally invasive nature of DBS surgery and its excellent safety profile made it a favorable technique for treating functional brain disorders. Worldwide, more than 100,000 patients have received DBS implants for a variety of disorders, including OCD ( ). Till presented over 100 patients who underwent DBS surgery for medically refractory OCD, which resulted in this therapy receiving a Humanitarian Device Exemption (HDE) status by the United States Food and Drug Administration (FDA) in 2009 ( ). In a last decade use of DBS for emerging applications and under the HDE has grown exponentially at a rate of 36% annually, compared to 7% for approved indications ( ). DBS has also been shown to have a positive impact on the “lived experience” of patients with treatment-refractory OCD ( ).

This chapter highlights the pathophysiology of OCD, indications and outcomes in patients who underwent DBS for treatment-refractory OCD, various surgical targets used, ethical issues, and recent advances, and gives a review of pertinent literature.

Pathophysiology of Obsessive–Compulsive Disorder

While functional brain imaging, animal models, and physiologic and anatomic studies enable us to understand the neurobiology of OCD better, it is understood that mood and behaviors associated with OCD are unique to human beings and so experimental observations in animal models of OCD may not be directly extrapolated to the human disease. There is no one neural “circuit” or “target” that is implicated in the pathophysiology of OCD. Instead, the symptoms of OCD are caused by abnormalities in multiple interwoven neural “circuits” or “targets” that form a complex network controlling mood and anxiety ( ). Consequently, effective neuromodulation for OCD likely requires multiple neural circuits to be impacted via stimulation of anatomical targets that are selected based on a detailed understanding of the basic pathophysiology.

identified multiple parallel basal ganglia–thalamocortical loops (cortico–striato–pallido–thalamocortical loops) that process cortical inputs from the motor, oculomotor, dorsolateral prefrontal, lateral orbitofrontal, and anterior cingulate regions. Each of these circuits includes functionally and anatomically discrete regions of the striatum, globus pallidus/substantia nigra, thalamus, and cortex. In the motor loop, motor and somatosensory cortical areas send partially overlapping projections to a specific region of the striatum. The striatum then sends projections that further converge at the level of the globus pallidus. From the globus pallidus, fully converged fibers project to a specific location in the thalamus. To close the loop, the thalamus projects back to a cortical area that feeds into the circuit. The net result is that several cortico–striate inputs that are functionally related are funneled together to a single cortical region in a feedback loop ( ). While these circuits are anatomically and functionally segregated, there is connectivity between the circuits so that limbic, cognitive, and motor pathways are integrated.

The basal ganglia–thalamocortical loop implicated in the pathophysiology of OCD originates in the PFC and orbitofrontal cortex (OFC). Fibers originating from the PFC and OFC project to the ventral striatum (Vs) through the ventral internal capsule. Specifically, these fibers reach the ventral aspect of the caudate and the nucleus accumbens (NAcc), and are excitatory in nature by means of glutamate and aspartate ( ). This area also receives inhibitory serotonergic input from the dorsal raphe nucleus of the midbrain. From the Vs the fibers project to the ventral pallidum and are mediated by substance-P, enkephalin, and GABA ( ). Inhibitory projections then reach the medio-dorsal aspect of the thalamus. Finally, the thalamus projects fibers back to the OFC. The overall output of this pathway is inhibitory in nature and seeks to dampen the input to the cortex ( ). There is also a parallel circuit originating in the anterior cingulate cortex with projections to the Vs/pallidum and termination in the medio-dorsal aspect of the thalamus. This loop then projects back to the anterior cingulate cortex. The anterior cingulate loop is believed to underlie the anxiety component of OCD, while the circuit originating in the OFC is thought to mediate the core symptoms of OCD ( ). Moreover, while the basal ganglia–thalamocortical loop originating in the OFC is inhibitory in nature, the cortico–thalamocortical circuit originating in the OFC and PFC is excitatory in nature. These loops are also known as the direct and inhibitory pathways, respectively ( ). The positive feedback loop originates in the OFC and PFC and projects to the dorsomedial thalamic nucleus through the anterior limb of the internal capsule (ALIC). In a normal state this excitatory pathway is dampened by the net inhibitory output of the basal ganglia–thalamocortical loop ( ). There is also a net effect of decreased thalamic stimulation of the cortex through pallido–thalamic connections, which are mediated by GABA ( ). It is believed that OCD symptoms arise when the equilibrium between these finely tuned pathways is lost ( ). An additional loop involving the limbic and Papez circuits underlies the emotional aspects of OCD. Widespread connections between the anterior cingulate cortex, OFC, dorsomedial thalamus, NAcc, and Papez circuits may mediate the limbic component of OCD ( ). Obsessive–compulsive symptoms are caused by either decreased activity in the basal ganglia–thalamocortical (striato–pallido–thalamocortical) loops or increased activity in the cortico–thalamocortical (orbito–fronto–thalamic) loops ( ). NAcc DBS causes an increase in striatal dopamine with improvement in reward processing, thereby ameliorating the striatal dysfunction in patients with OCD ( ).

Generally there is increased stimulation of the OFC due to decreased modulation by the cortical–subcortical circuits, resulting in the OCD symptomatology ( ). Also, there is interindividual variability in the morphology of orbito–fronto–thalamic tracts, and the pattern of arrangement of these tracts within the ventral capsule (Vc)/Vs region is complex and unique to an individual, based on diffusion magnetic resonance imaging (MRI) ( ). Thus modulating either of these pathways and Papez circuits could possibly ameliorate the obsessive–compulsive, anxiety, and emotional symptoms associated with OCD ( ).

Based on various electrophysiological studies (e.g., error-related negativity assessed by electroencephalography), dysfunction of the cognitive control network involving the dorsal anterior cingulate cortex (dACC) has been found in patients with OCD. This has led to the hypothesis that the dACC is involved in the pathophysiology of this disorder ( ). Also, disconnection of the hyperactive ventral tegmental area dopaminergic neurons and PFC has been shown to ameliorate OCD symptoms following continuous stimulation of bilateral supero-lateral medial forebrain bundles ( ), thereby implicating the role of reward circuitry in the OCD pathophysiology. Recently, in a large animal model (Göttingen Minipig), fluorogold tracing has revealed inputs from the medial parts of the PFC, subgenual cortex (BA 25), bilateral insula, amygdala, entorhinal cortex, the CA-1 region of hippocampus, subiculum, paraventricular and anterior parts of the thalamus, dorsomedial parts of the hypothalamus, substantia nigra, ventral tegmental area, the retrorubral field, and the dorsal and median raphe nuclei to the NAcc ( ). These connections reiterate the importance of the NAcc as a crucial nodal point for neuromodulation in patients with OCD.

Functional neuroimaging studies using positron emission tomography (PET) and functional MRI (fMRI) report abnormally increased metabolic activity of the PFC, anterior cingulate cortex, OFC, caudate, and thalamus in OCD patients in both neutral and provoked states as compared to healthy individuals ( ). DBS of the Vc/Vs region has been shown to modulate the activity with changes in blood perfusion in different regions of the brain (thalamus, striatum, globus pallidus, and dACC) implicated in the pathophysiology of OCD ( ). Modern neuroimaging has improved the field of psychiatric neurosurgery by providing insights into the pathophysiology and also elucidating the mechanism of action of neuromodulation for a variety of these disorders ( ). A recent tractography study showed increased activation of the dorsolateral PFC following DBS of the ALIC–NAcc in patients with refractory OCD ( ). Nonresponders showed increased activation in the lateral OFC/anterior ventrolateral PFC in this study, thereby providing a road map to stimulate a specific group of fibers using a smaller amplitude compared to the whole pathways ( ).

Based on animal studies, increased prepulse inhibition following bilateral NAcc DBS has been seen in patients (n = 8) with refractory OCD, similar to that seen in healthy controls ( ), showing the NAcc to be a potential nodal point to modulate the networks involved in the pathophysiology of OCD. These neuroimaging, anatomic, and physiologic studies provide insights into the pathophysiology of OCD that may identify new nodes for surgical intervention ( ).

Deep Brain Stimulation for Obsessive–Compulsive Disorder

Neuromodulation offers an opportunity to manage these complex patients with treatment-refractory OCD. The advent of stereotaxy made it possible to target subcortical structures with submillimetric accuracy, thereby increasing surgical safety while maintaining the efficacy of earlier surgical procedures for OCD ( ). The success of DBS therapy in movement disorders led clinicians to explore this treatment option for patients with medically refractory OCD. In 1979 low-frequency (5 Hz) stimulation of the area near the parafascicular complex in the intralaminar thalamic nuclei was shown to ameliorate phobia and OCD symptoms at 1 year follow-up in a female patient ( ). Similarly, stimulation of the cerebellar vermis has been shown to improve OCD symptoms by targeting neural circuits instead of a specific target ( ). These preliminary studies paved the way for the exploration of newer DBS targets/circuits for medical-refractory OCD. In 2009 DBS surgery for OCD was granted an HDE by the FDA ( ). The advantages of reversibility, ability to adjust the stimulation parameters over time, and better surgical safety profile relative to ablation made DBS surgery an attractive and favorable treatment option for patients with refractory OCD. In addition, patients with DBS can be blinded to their stimulation status in research studies aimed at determining the efficacy of this therapy. To date, 116 patients (31 studies) have undergone DBS implantation surgery for OCD ( ). The paucity of data regarding the efficacy of DBS for OCD can be attributed to the heterogeneity of patients with medical-refractory OCD, nonuniformity in the assessment and enrollment criteria, prolonged titration periods, and operationalizing titration intervals in blinded randomized controlled studies, especially for patients traveling great distances for treatment.

The mechanism(s) underlying the therapeutic benefits of DBS remains elusive and is a matter of contentious debate. Initially it was proposed that high-frequency stimulation induces neuronal inhibition by depolarizing neurons in the vicinity of an electrode—a mechanism similar to ablation ( ). Hypotheses such as depolarization blockade, synaptic inhibition, synaptic depression, and stimulation-induced modulation of pathological network activity have suggested the probable mechanisms underlying the therapeutic efficacy of DBS ( ). Of these, stimulation-induced modulation of pathological network activity is the most likely mechanism providing the therapeutic benefits ( ). Furthermore DBS improves the functioning of thalamocortical neurons and potentially normalizes the imbalance in the cognitive–behavior–emotional circuit ( ). Structures such as the ALIC, Vc/Vs, NAcc, subthalamic nucleus (STN), inferior thalamic peduncle, and superolateral medial forebrain bundle have been explored as potential DBS targets in patients with refractory OCD, with varied results. The majority of reports regarding surgical outcomes represent uncontrolled or nonblinded studies that need to be cautiously interpreted. Nevertheless, surgical treatment can give hope to patients with severe and medically refractory OCD. All the procedures thus far employed tend to modulate activity within the orbitofrontal, dorsolateral frontal, and anterior cingulate cortices and their interactions with the basal ganglia and thalamus. Various surgical targets used for DBS and a review of pertinent literature are discussed below.