This article describes the basis for neuromodulation procedures for obsessive-compulsive disorder (OCD) and summarizes the literature on the efficacy of these interventions. Discussion includes neural circuitry underlying OCD pathology, the history and types of ablative procedures, the targets and modalities used for neuromodulation, and future therapeutic directions.
Key points
- •
Obsessive-compulsive disorder (OCD) is refractory to standard psychotherapy and pharmacology in 40% to 60% of patients.
- •
In patients with OCD, corticostriatothalamocortical circuits show hyperactivity during resting states, which becomes further accentuated during symptom provocation, but can diminish after successful treatment.
- •
Neuromodulation targets have included the ventral capsule/ventral striatum (nucleus accumbens), subthalamic nucleus, and inferior thalamic peduncle.
- •
Studies examining the efficacy of deep brain stimulation for OCD report responder rates of 40% to 75%; however, these are mainly case series of fewer than 30 patients.
- •
There is a paucity of randomized, placebo-controlled, prospective trials of neuromodulation in the population with OCD.
Introduction
Obsessive-compulsive disorder (OCD) is a chronic psychiatric disorder defined by recurrent obsessions or compulsions that cause significant impairments in daily functioning. Global prevalence of OCD is 1% to 2%, with slight female gender predominance among adults, but a 2:1 male/female ratio among pediatric patients. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision defines obsessions as recurrent and persistent thoughts or impulses that cause marked distress, with the person driven to perform repetitive, excessive compulsions to reduce or neutralize the distress or dreaded consequence. These obsessions and compulsions interfere with the person’s normal functioning and social relationships.
OCD has a profound impact on the lives of patients. The severity of symptoms varies considerably between patients and during the course of the disease. Although most patients experience continuous symptoms, many suffer a relapsing/remitting course, with periods of only subclinical symptoms. In a prospective study of 293 patients with a diagnosis of OCD seeking treatment, enrollment interviews revealed that 27% of patients were unable to work because of psychopathology and more than 70% were categorized as moderate to severe severity using the well-described Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Quality-of-life research in patients with OCD shows lower marriage rates and significant interference with ability to study and work. Patients with OCD lose on average 3 full years of wages. Thirteen percent of patients carried out a suicide attempt. The direct and indirect costs attributable to OCD are significant; however, despite increased awareness of the disorder and its treatments, on average, 17 years pass from onset of symptoms and the start of appropriate treatment.
Introduction
Obsessive-compulsive disorder (OCD) is a chronic psychiatric disorder defined by recurrent obsessions or compulsions that cause significant impairments in daily functioning. Global prevalence of OCD is 1% to 2%, with slight female gender predominance among adults, but a 2:1 male/female ratio among pediatric patients. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision defines obsessions as recurrent and persistent thoughts or impulses that cause marked distress, with the person driven to perform repetitive, excessive compulsions to reduce or neutralize the distress or dreaded consequence. These obsessions and compulsions interfere with the person’s normal functioning and social relationships.
OCD has a profound impact on the lives of patients. The severity of symptoms varies considerably between patients and during the course of the disease. Although most patients experience continuous symptoms, many suffer a relapsing/remitting course, with periods of only subclinical symptoms. In a prospective study of 293 patients with a diagnosis of OCD seeking treatment, enrollment interviews revealed that 27% of patients were unable to work because of psychopathology and more than 70% were categorized as moderate to severe severity using the well-described Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Quality-of-life research in patients with OCD shows lower marriage rates and significant interference with ability to study and work. Patients with OCD lose on average 3 full years of wages. Thirteen percent of patients carried out a suicide attempt. The direct and indirect costs attributable to OCD are significant; however, despite increased awareness of the disorder and its treatments, on average, 17 years pass from onset of symptoms and the start of appropriate treatment.
Cognitive models
Cognitive theories of OCD informed early pharmacologic and surgical interventions. Hobart Mowrer proposed a 2-factor avoidance learning theory in 1939. In the first stage, a neutral cue becomes associated with a negative event, which is recalled on reexposure to the neutral cue. In the second stage, the anxiety aroused by the neutral cue is reduced by engaging in stereotyped behaviors. Thus, these behaviors are rewarding in the perceived avoidance of the anxiety-provoking event. In OCD, the behaviors reduce distress, and thus lead to maintenance of avoidance rituals. This relationship between obsessions and compulsions became the definition of OCD.
In 1986, Foa and Kozak extended this cognitive model with their emotional processing theory. Patients with OCD assign an erroneously high danger level to safe situations (eg, failing to scrub hands repeatedly and extensively after touching a door handle leads to serious disease). In addition, an exaggerated and often illogical negative repercussion is assigned to failing to assuage the obsession (eg, failing to turn a light switch on and off 4 times leads to a spouse’s death). OCD sufferers presume that a situation is dangerous in the absence of evidence of safety. For example, this assumption may manifest in everyday life as refusal to eat at a restaurant without evidence of meticulous cleanliness, rather than a more typical assumption of cleanliness unless presented with evidence of unsanitary and dirty conditions. These cognitive models support focusing treatment interventions on modifying the erroneous assumptions, leading to intense fear and altering the reward pathway that maintains compulsive behaviors.
Circuits and mechanisms of OCD
Noninvasive techniques (eg, neuroimaging) used in modern neuroscience provided the capability of an in-depth examination of the brain basis of self-regulation and behavioral control. Converging evidence points to the involvement of corticostriatothalamocortical (CSTC) circuits as being fundamental to cognitive and motor functions. CSTC circuits are organized in a common looplike fashion, in which circuits project from specific territories in frontal cortex, to targets within the striatum, and then via direct and indirect pathways project through specific areas in the basal ganglia to the thalamus, and back to the original frontal territory ( Fig. 1 ). Functional neuroimaging has been used to elucidate the pathophysiology of OCD by comparing the function and dysfunction of CSTC circuits at the level of the individual fiber tract, nucleus, or cortical region. The delineation of these brain circuits at different levels is necessary, because disorders resulting from the dysfunction of these circuits are unlikely to be explained solely by neurotransmitters, genetics, or brain region abnormalities.
Within a broad framework, CSTC circuits convey information flow from cortical and limbic regions to modulate several processes, which include motivation, attention, and motor function. Corrupting this information flow can result in disordered behavioral and emotional processing, which are core pathophysiologic features of OCD. The key nodes within these circuits include: dorsal lateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), and striatum (specifically the caudate). Various imaging techniques have been used in mainly 4 different paradigm states in an attempt to focus on these key areas in order to understand the potential mechanisms that underlie OCD.
Comparing Patients with OCD with Healthy Controls in Neutral or Baseline States
Baxter and colleagues conducted one of the first studies to quantify the different neural signatures of OCD by using positron emission tomography (PET) to compare a group of patients suffering from the disease with a sample of healthy participants. These investigators reported compelling results, which showed drastic differences in the neural profiles of each group when at a resting state. Patients with OCD showed bilateral hyperactivity in the OFC, in addition to predominantly right-sided hyperactivity in the caudate nucleus. Outside these key areas, the investigators also found that the glucose-metabolic rates in parietal and occipitoparietal regions were lower in patients with OCD. Similar studies have replicated these findings, in addition to showing that patients with OCD also have increased metabolic rates in the DLPFC, ACC, and thalamus.
It has been discovered that along with showing different neural baseline states, patients with OCD also show differences in the neuroanatomic structures. For example, morphometric magnetic resonance imaging (MRI) and spectroscopy imaging, used to compare patients with OCD with healthy controls, have shown subtle differences in the caudate nucleus characterized by decreased tissue volume as well as decreased levels of N -acetyl aspartate, a marker of neuronal density.
Measuring Cerebral Activity Changes that Correspond to Treatment Response
Many studies have examined the changes in overall brain activity before and after patients with OCD have received a variety of different treatments, including serotonin (5-HT) reuptake inhibitors, cognitive behavioral therapy, or neurosurgery. The consensus of such studies shows that after treatment a significant reduction of glucose metabolism or regional cerebral blood flow (rCBF) can be found across the CSTC circuits. Specifically, PET results have revealed that responders commonly showed significant decreases in bilateral OFC, bilateral caudate, and cingulate gyri metabolism. Furthermore, the observed regional activity levels in patients with OCD has been shown to shift closer to healthy controls.
The Differences Between OCD Symptoms During Provocation Versus a Neutral State
Hyperactivity in CSTC circuits is observed in patients with OCD during a neutral state, but there remains a question of how that baseline activity changes during symptom provocation. Breiter and colleagues scanned patients with OCD with PET during both a resting state, in which patients were presented with a nonprovoking stimulus, and during a symptomatic state, in which patients were provoked by a specific stimulus that induced OCD symptoms. During the symptomatic state, PET scans showed a significant increase in rCBF in the OFC, ACC, and caudate nucleus. The same study repeated with functional MRI (fMRI) confirmed the finding in addition to revealing activation in lateral frontal, anterior temporal, insular cortex, amygdala, and lenticular nucleus. Another study also showed that the striatum, globus pallidus, thalamus, and left hippocampus have higher rCBF in a symptomatic state.
Patients with OCD During Performance of a Cognitive Task and Comparison Conditions
Experimental studies that have used neuroimaging in combination with specific cognitive tasks have shed a great deal of light on the pathophysiology of OCD by showing abnormalities in neural profiles associated with the performance of cognitive tasks. Brain activation patterns studied with both PET and fMRI have shown that patients with OCD, compared with healthy controls, activate different brain structures during the performance of an implicit procedural learning task. Rauch and colleagues reported that both patients and controls show learning of the task; however, patients with OCD showed bilateral mesial temporal activation, indicating that learning was occurring as a result of using brain systems implicated in explicit memory. In contrast, controls activated the bilateral inferior striatum, a brain region typically associated with implicit learning. These results suggest that patients with OCD have CSTC dysfunction that does not allow them to access brain systems that would process the task implicitly, as controls do without awareness. The brain activation of patients with OCD during a phonologically guided word-generation task has also been quantified with fMRI. The study found that patients with OCD showed significantly greater frontal cortical activation during word generation and a defective suppression of this activation during the following rest period. The abnormal activation patterns provide further evidence of latent brain dysfunction associated with OCD during the performance of cognitive tasks. Continuing with this premise, Lucey and colleagues used single-photon emission computed tomography (SPECT) during performance of the Wisconsin Card Sort Task to test the ability of patients with OCD to shift their cognitive set, compared with controls. The study found that patients with OCD not only made more errors but also had a high yield of null-sorts or responses that fail to match any of the possible cards. Furthermore, rCBF in left inferior frontal cortex and left caudate of patients with OCD was significantly correlated with the occurrence of null-sorts. No such activation patterns were observed in controls.
A plethora of imaging studies have focused on evaluating OCD to provide converging evidence that CSTC circuits show hyperactivity during resting or baseline states, which becomes further accentuated during symptom provocation, but can diminish after successful treatment. These crucial findings can now be interpreted to speculate on mechanisms that underlie abnormal cognitive and motor behavior seen in patients with OCD.
Striatum
At the cellular level, the striatum is composed of 2 main neural components: smaller patchy compartments called striosomes, which are surrounded by a larger compartment called the matrix. Ventral and anterior regions of the striatum are highly concentrated with striosomes and receive cortical afferents from the OFC and ACC. Studies that have evaluated the neuroanatomy of this frontal-subcortical circuit suggest that the striosomes are neurochemically specialized to exert a strong inhibitory influence on dopaminergic input, thus influencing negative-feedback inhibition on the main frontal-subcortical circuits. A supposed function of the frontal projections that pass through the striatum is the execution of complex and emotional response behaviors that typically are executed quickly in response to stimuli. Therefore, dysfunction involving striosomes, commonly quantified as hyperactivity in the caudate nucleus, might result in overactive inhibition of the negative-feedback processes that affect frontal cortices. Feedback of this nature allows for levels of cortical excitability that are higher than normal, leading to brain activation patterns in frontal-subcortical circuits that may underlie mechanisms for cognitive (eg, learning) and emotional deficits observed in patients with OCD.
Prefrontal Cortices
The OFC plays an important role in emotion and social behavior. This brain region is involved in the mediation of emotional responses as well as allowing for integration of emotional information. Hyperactivity in the OFC can corrupt the weighing of emotional information, thereby skewing the consequences of immediate action to generate uncontrolled thoughts and behavior. Different subregions of the OFC have also been evaluated in respect to OCD. Imaging studies have discovered that lateral orbital frontal cortex (LOFC) and medial orbital frontal cortex (MOFC) play distinct roles in processing behavioral control. Specifically, activation in the LOFC seems to correlate with ritualized behavioral responses, whereas the MOFC seems more involved in emotion regulation and reward processing. Discovery of such regional distinction in the OFC provides a new level of detail, which can help elucidate the complexities of the disorder.
The DLPFC is a higher-order brain region that is implicated in executive processes needed for voluntary, goal-directed behavior. The region is also associated with different aspects of cognitive control, including the ability to focus thoughts or actions and the ability to flexibly shift that focus according to the environment. Hyperactive brain patterns observed in the DLPFC of patients with OCD may corrupt these cognitive resources and impair executive function to cause compulsive behavior and obsessive thoughts.
The ACC is associated with cognitive processes such as attention, motivation, problem solving, detecting the presence of cognitive conflict, and error monitoring and detection. Behavioral paradigms that use conflicting conditions, congruent or reflexive responses versus incongruent or responses that require the inhibition of reflexive behavior cause a large degree of activation in the ACC. Patients with OCD who are tested on such tasks show hyperactivation of the ACC in response to the incongruent relative to the congruent conditions. A specific study that used fMRI to examine the effective connectivity of frontal cortices while patients with OCD performed an error control task found significantly enhanced connectivity between ACC and the DLPFC. The study concluded that such connectivity supports the idea of abnormal corticocortical interactions affecting error processing in patients with OCD, and adversely affecting decision making. Hyperactivation of the ACC may facilitate faulty error detection, which contributes to cognitive difficulties and obsessions.
Other Brain Regions
Although many studies are dedicated to examining frontal cortex activation patterns associated with OCD, the disease is not an entirely prefrontal condition. Other regions have been found to be involved and may help to elucidate the complexity of the syndrome. Functional neuroimaging has revealed hypometabolism in the insula and the dorsoparietal cortex. The insular cortex is believed to be involved in processing emotional aspects such as empathy and compassion as well as characteristics such as fairness and cooperation. Areas of parietal cortex have been implicated in aspects such as attention, spatial perception, and response inhibition. Accordingly, dysfunction in areas that process such information contributes to the OCD syndrome.
The cerebellum has also been implicated in OCD. The brain region is involved in a variety of cognitive functions, such as attention, verbal learning and memory, and cognitive planning. Scans of patients with OCD using SPECT have revealed higher rCBF in the cerebellum than in controls. Hyperactivity in such a critical cognitive processing center may underlie complex cognitive deficits observed in patients with OCD.
Current treatments for OCD
Psychotherapy
Psychotherapy via exposure and response cognitive behavioral therapy (CBT) is considered first-line treatment. In a randomized control study, 21 patients with OCD randomly assigned to the therapy arm completed 12 weeks of intensive CBT (daily visits for 4 weeks, followed by 8 weeks of weekly visits), resulting in a 55% decrease in Y-BOCS score. Response rates were 86% for the therapy arm. The intensive therapy regime in this study is atypical, with a usual outpatient treatment regime consisting of weekly therapy sessions. Outcomes after typical weekly sessions outside clinical trials show less effectiveness, with Y-BOCS reductions of 24% to 44% reported.
Pharmacology
Several trials have examined effects of serotonergic medications, primarily the tricyclic antidepressant clomipramine and selective serotonin reuptake inhibitors. Multiple placebo-controlled randomized trials confirm the efficacy of serotonergic medications, with mean Y-BOCS reductions of 31% to 40%. Most studies define partial responders as experiencing a decrease in Y-BOCS score greater than 25% and full responders at experiencing a decrease in Y-BOCS score greater than 35%; however, nonresponse to OCD treatment is common. The rate of nonresponders is 40% to 60%, with an additional fraction experiencing only partial response (Y-BOCS reduction of 25%–35%). Although there is debate about how to define nonresponders, there is a definitive, substantial population of patients for whom therapy and pharmacologic treatments are inadequate.
Targeted Therapy
Guided by neuroanatomic and neuroimaging studies, new treatments target distinct brain circuits associated with OCD in an attempt to modulate disease state activation patterns and improve symptoms in resistant patients. There are many neuromodulatory techniques, which range in their degree of invasiveness. Some of these neurosurgical approaches include stereotactic lesioning, deep brain stimulation (DBS), vagus nerve stimulation (VNS), and transcranial magnetic stimulation (TMS). In the following section, the current state of each therapeutic intervention, in association with treating OCD, is discussed.
Stereotactic Lesioning
Stereotactic lesions or localized ablation of the human brain is the oldest method for treating psychiatric illness. In 1888, the Swiss psychiatrist Gottlieb Burkhardt carried out what is likely the first series of psychiatric neurosurgical procedures in the modern era. He removed focal regions of cortex to alter behavior in 6 patients: 1 with mania, 1 with dementia, and 4 described as suffering from paranoia. His surgical results were modest, with 1 patient dying postoperatively after developing status epilepticus, 1 improved (although later committed suicide), 2 stable, and 2 subdued. The first broad use of neurosurgery for psychiatric conditions may be attributed to the Portuguese neurologist Egas Moniz. Inspired by the American neuroscientists Carlyle Jacobsen and John Fulton, who performed frontal lobectomies in primates, Moniz proposed frontal cortex ablation for psychiatric patients. With the assistance of the Portuguese neurosurgeon Pedro Almeida Lima, he popularized the frontal leukotomy, aiming to sever white matter connections within the frontal lobes. He introduced the leukotome, a rod with a retractable wire loop that could be inserted via a burr hole and rotated to carry out the procedure quickly and reproducibly. For his efforts, he was awarding the Nobel Prize in Medicine or Physiology in 1949. Walter Freeman and James Watts introduced the transorbital leukotomy in 1946, enabling the procedure to be performed in an office setting rather than an operating room. They devised the orbitoclast, an ice pick–like tool that was driven through the orbital roof bilaterally into the brain and swept across white matter tracts. Frontal leukotomy expanded as a treatment of various psychiatric illnesses, with an estimated 60,000 procedures performed between 1936 and 1956. However, with relative indiscriminate application of frontal leukotomy came increasing complications and public outcry around the world. The advent of effective neuroleptic medications and increasing popularity of psychoanalysis cemented the decline of the frontal leukotomy era.
In the late 1940s, a coordinate system devised by Jean Talairach combined with the development of stereotactic targeting systems by Ernest Spiegel and Henry Wycis in America and Lars Leksell in Sweden allowed for precise targeting of intracranial structures. This system allowed surgeons to create small, focal lesions and thereby reduce complications. Stereotactic ablation procedures, including anterior cingulotomy, capsulotomy, subcaudate tractotomy, and limbic leukotomy, were developed in the decades after the prefrontal leukotomy era.
Modern ablative psychiatric neurosurgical procedures are performed using stereotactic open surgical approaches or often by using radiofrequency or Gamma Knife methodologies. With converging evidence pointing to hyperactivity in CSTC as the cause of OCD, the logic of stereotactic intervention, pertaining to OCD, stems from reducing hyperactivity through targeted ablation.
Cingulotomies and capsulotomies are common neurosurgical lesioning procedures used to treat OCD ( Fig. 2 ). Small bilateral lesions in the cingulum bundle ( Fig. 3 A) or anterior limb of the internal capsule (ALIC) sever fibers from the white matter of the cingulate gyrus or internal capsule, respectively, in an attempt to disrupt hyperactive CSTC circuits. These interventions have shown moderate efficacy in severe, treatment-refractory OCD and have been reported to decrease the state of anxiety in patients. Other stereotactic procedures include subcaudate tractotomies and limbic leukotomies (see Fig. 3 B), which are also geared toward disrupting white matter fibers in CSTC circuits. A lesion is made in the substantia innominate, a small region located beneath the head of the caudate, during a subcaudate tractotomy, whereas a lesion in both the frontal lobe and cingulum is made during a leukotomy. Both procedures have been shown to relieve symptoms of anxiety and obsession in OCD, presumably through the interruption of frontothalamic circuits. Multiple studies have examined the efficacy of these various procedures, with reported responder rates of 27% to 86% ( Table 1 ).
| Study | Procedure | n | Responders (%) |
|---|---|---|---|
| Liu et al, 2008 | Anterior capsulotomy | 35 | 86 a |
| Rück et al, 2008 | Anterior capsulotomy | 25 | 48 b |
| Ballantine et al, 1987 | Cingulotomy | 32 | 25 c |
| Jenike et al, 1991 | Cingulotomy | 33 | 27 d |
| Dougherty et al, 2002 | Cingulotomy | 44 | 32 e |
| Sheth et al, 2013 | Cingulotomy | 34 | 38 e |
| Hodgkiss et al, 1995 | Subcaudate tractotomy | 15 | 33 f |
| Mitchell-Heggs et al, 1976 | Limbic leukotomy | 27 | 67 f |
| Kelly et al, 1973 | Limbic leukotomy | 17 | 41 f |
c Investigators’ determination of normal with or without pharmacologic or behavioral treatment.
d Y-BOCS reduction of ≥25% or investigators’ determination of at-least moderate improvement based on clinical record review.
f Investigators’ determination of completely recovered or only mild residual symptoms.
DBS
Because of the resulting success of DBS in movement disorders (eg, Parkinson disease [PD]) as well as the low-risk reversible nature of the intervention, DBS has become an attractive and prominent therapeutic intervention for therapy-refractory psychiatric disorders. The underlying mechanism of DBS was first believed to be similar to stereotactic lesioning, by which inhibitory DBS created a functional lesion through a depolarization blockage of neural circuits close to the electrodes. Nevertheless, through modeling and imaging studies, stimulation has been discovered to work in a more complicated fashion, which activates neural circuitry in the brain to modulate activation patterns. How this modulation works to alleviate motor and cognitive deficits it difficult to interpret, because several variables (eg, proximal cytoarchitecture and neuropil, stimulation parameters, electrode impedance) have been shown to affect the efficacy of DBS. However, in general, there exists an overarching interpretation that DBS alleviates deficits by increasing the fidelity of neural signaling to modulate disease state activation patterns and allow for better functionality.
From successful ablative procedures for treating OCD, early DBS cases focused on exploring similar brain regions in the hope of replicating the success without the severity. The first studies chose DBS implantation sites within the ALIC, based on the success of the capsulotomy (see Fig. 2 ). Nuttin and colleagues first published findings from patients with bilateral ALIC DBS. The initial study used only clinical observations, reporting a decrease of complaints and a progression away from being seriously disabled. Further studies from the group used the Y-BOCS questionnaire, to find an average 40% symptom decrease, and PET scans, to find a decrease in frontal cortex activity. Overall, the work was the first to robustly quantify the effects of ALIC DBS in patients with OCD. Subsequently, investigations using DBS expanded to explore the rostral-caudal extent of the ALIC, focusing on the ventral aspect of the anterior limb of the ventral capsule (VC) and the ventral striatum (VS). In 2006, Greenberg and colleagues reported a 3-year observation on 8 of 10 patients with OCD implanted with bilateral DBS systems targeting the VC/VS. The study found that, on average, complaints decreased 30% in the group and symptoms changed from severe to moderate. Furthermore, 4 patients were found to be responders and on average showed 35% reduction in symptoms. A more recent study reported by the same group found that by refining the implantation site toward the VS, more patients with OCD had positive responses as well as needing lower-parameter settings (ie, pulse width, voltage). The use of PET imaging in certain patients also showed that DBS increased perfusion in areas such as the OFC, ACC, and thalamus. Several other studies have also reported benefit in targeting the VC/VS to treat OCD ( Table 2 ).
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
