Abstract
Obsessive–compulsive disorder (OCD) is 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. The success of deep brain stimulation surgery for a variety of movement disorders over the past 2 decades has led to the exploration of this treatment modality for medically refractory OCD.
Keywords
Cortico–striato–thalamo–cortical loops, Deep brain stimulation, Neuromodulation, Obsessive–compulsive disorder, Psychosurgery
Outline
List of Abbreviations [CR]
Introduction 1033
Pathophysiology of Obsessive–Compulsive Disorder 1034
Deep Brain Stimulation for Obsessive–Compulsive Disorder 1036
Anterior Limb of Internal Capsule 1036
Ventral Capsule and Ventral Striatum 1037
Nucleus Accumbens 1038
Subthalamic Nucleus 1039
Inferior Thalamic Peduncle 1039
Other Targets 1039
Patient Selection, Team Approach, and Ethical Considerations 1040
Surgical Techniques of Deep Brain Stimulation Implantation 1040
Conclusion 1041
References 1041
List of Abbreviations
ACC
Anterior cingulate cortex
ALIC
Anterior limb of internal capsule
BDI
Beck depression inventory
CSTC
Cortico-striato-thalamic-cortical
DBS
Deep brain stimulation
fMRI
Functional magnetic resonance imaging
Gpi
Globus pallidus internus
ITP
Inferior thalamic peduncle
NAcc
Nucleus accumbens
OCD
Obsessive–compulsive disorder
OFC
Orbitofrontal cortex
PET
Positron emission tomography
slMFB
Superolateral branch of the medial forebrain bundle
SMA
Supplementary motor area
STN
Subthalamic nucleus
TRD
Treatment refractory disease
Vc/Vs
Ventral capsule and ventral striatum
Y-BOCS
Yale-brown obsessive compulsive scale
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.
Anterior Limb of Internal Capsule
The OFC and the subgenual anterior cingulate cortex are connected to the medial, dorsomedial, and anterior thalamic nuclei via the fibers in the ALIC. To mirror the beneficial effects of stereotactic capsulotomy in patients with medical-refractory OCD, this target was the first to be explored as a potential DBS target ( ). published the first series reporting the beneficial effects of DBS therapy in patients with medical-refractory OCD in 1999. They stimulated the ALIC bilaterally in four patients employing a target similar to that used for capsulotomy. Three of these four patients experienced some beneficial effect. One of these patients reported 90% improvement in her compulsive behavior and rituals following 2 weeks of stimulation. The major drawback of this study was lack of assessment scores to quantify improvements in mood or obsessive and compulsive behaviors following stimulation. Four years later the same investigators reported significant improvement in the Y-BOCS and global assessment of function (GAF) scales following bilateral ALIC DBS in six patients with medically refractory OCD ( ). In this double blind controlled study, Y-BOCS and clinical global severity scores improved from a mean of 32.3 to 19.8 and from 5 to 3.3 with the stimulator “off” versus “on,” respectively. Three of the six patients responded to stimulation (>35% reduction in Y-BOCS score), while global improvement functions were unchanged in one patient and two patients did not enter the assessment phase ( ). The four patients who entered assessment demonstrated significant worsening of OCD and mood symptoms in the DBS “off” state, but returned to the baseline and showed improvement in the “on” state. This stimulation-induced beneficial effect was maintained for at least 21 months following DBS implantation. The coordinates of the tip of the DBS electrode in the patient with the most favorable response in this study were 13 mm lateral to the midline on the right, 14 mm lateral to midline on the left, and 3.5 mm anterior to the anterior commissure at the level of the intercommissural plane ( ). In this study, the DBS electrode contact “0” was located near to or in the NAcc, contacts 1 and 2 were located in the internal capsule, and contact 3 was dorsal to the internal capsule. This group also noted increased pontine metabolism and decreased frontal lobe metabolism on fMRI and PET studies following 10 days and 3 months of continuous bilateral stimulation, respectively ( ). None of the patients had complications related to the DBS implantation, but cognitive and behavioral disinhibition was noted in two patients at 10.5 V, which was immediately controlled after decreasing the amplitude ( ). Follow-up of these patients was published in 2008 and showed that capsular DBS reduces Y-BOCS score (mean; stimulator on 19.8 ± 8.0 versus stimulator off 32.3 ± 3.9) with improvement in core symptoms at 21 months after implantation ( ). Another double-blind controlled study reported significant improvement in the mean Y-BOCS score (26.5 in DBS “on” state and 29.3 in DBS “off” state) following bilateral ALIC DBS in four patients with medical-refractory OCD ( ). During the blinded phase of the study one patient experienced >35% improvement in Y-BOCS score, another had a 17% reduction in Y-BOCS score, and the other two patients had no impact on their OCD symptoms. In contrast, 50% of patients were responders (>35% improvement in Y-BOCS score above baseline) during the open phase of the study. In this study, patients were randomized in on–off sequence of four 3-week blocks with a mean follow-up of 4–23 months ( ). Another study reported a 27 point decrease in Y-BOCS score following bilateral ALIC DBS stimulation at 10 months in an isolated patient with medical-refractory OCD ( ).
Ventral Capsule and Ventral Striatum
The Vs consists of the ventral portion of the caudate nucleus and the NAcc, which are believed to be the reward centers of the brain ( ). The combined Vc/Vs was explored as a potential DBS target for refractory OCD. The promising results of ventral capsulotomy and ALIC DBS for medically refractory OCD led investigators to explore structures adjacent to the internal capsule as potential DBS targets ( ). In Greenberg et al. performed bilateral Vc/Vs DBS in 10 patients with refractory OCD, noting a response rate of 40%. The Y-BOCS score decreased from a mean of 34.6 at baseline to 22.3 after 36 months of stimulation. Four of eight patients were classified as responders (>35% reduction in Y-BOCS score) and another two as partial responders (25%–35% reduction in Y-BOCS scores) ( ). Aspects such as depression, anxiety, independent living, and self-care were also improved. Adverse effects included asymptomatic hemorrhage, seizure, and superficial infection, and psychiatric symptoms such as hypomania and worsening of depression were reported ( ). Similarly, an open-label multinational study of ALIC–Vc/Vs DBS in 26 patients with refractory OCD reported a responder rate of 62% ( ). The authors observed an average 13.1 point decrease in the Y-BOCS score 3–36 months following DBS surgery ( ). This group also noted that stimulation closer to the junction of the anterior capsule, posterior Vs, and anterior commissure resulted in therapeutic benefits at lower charge densities in the last two cohorts of patients with refractory OCD. Twenty-three adverse events were reported in 11 patients (42.3%), including asymptomatic intracerebral hemorrhage in 2 patients (7.7%), seizure in 1 patient (3.8%), 1 superficial wound infection (3.8%), and 1 case each of stimulating lead and extension wire breakage (7.7%) ( ). In addition, nine stimulation-related adverse events (four cases of increased depression, three events of increased OCD severity, one case of hypomania, and one report of domestic problems/irritability) were noted. A randomized controlled study in six patients with refractory OCD reported a responder rate of 67% at 12 months following bilateral Vc/Vs DBS ( ). Depressive symptoms were improved in all six patients; global functions were improved in four (67%) ( ). Another study reported a significant correlation between stimulation-induced smile/laughter intraoperatively and the reduction in the Y-BOCS score at 15 months in four patients treated with bilateral Vc/Vs DBS for medical-refractory OCD ( ). An interesting report described successful removal of bilateral NAcc DBS followed by reimplantation at Vc/Vs (bilateral) for medical-refractory OCD, following failure to respond (10% improvement in Y-BOCS) at 1½ years following implantation ( ). This patient was reimplanted within a month of explantation, with good clinical response (33% reduction in Y-BOCS). Another report mentioned improvement in treatment-refractory OCD following bilateral Vc/Vs DBS in a patient with Parkinson’s disease (PD) who had bilateral STN DBS ( ). Vc/Vs DBS has also been shown to be effective in relieving OCD and Tourette’s syndrome symptoms in a patient with Kleefstra syndrome ( ). A recent long-term study showed that patients with Vc/Vs DBS had persistent long-term reduction in OCD symptoms (>35% reduction in Y-BOCS) at 6–9 years follow-up ( ). However, there was no sustained response in terms of comorbid depressive symptoms in these patients following DBS for OCD ( ). Based on a 15 O-PET study ( ), monopolar stimulation of the most ventral DBS in the Vc/Vs region has been shown to increase perfusion in the dACC, which correlated with improvement in depressive symptoms in six patients with OCD. In contrast, stimulation of the most dorsal contact has been shown to increase perfusion in the thalamus, striatum, and globus pallidus implicated in the pathophysiology of OCD ( ).
Nucleus Accumbens
The NAcc is located at the junction of the end of the ALIC, the head of the caudate nucleus, and the anterior portion of the putamen. This surgical node is one of the components of the Vs and is considered the “reward center” of the brain ( ). In a pilot study, investigated the efficacy of the shell region of the right NAcc as a potential DBS target in four patients with severe refractory OCD and anxiety disorders. They reported significant alleviation of symptoms in three patients (75%) at a follow-up of 24–30 months. Clinical improvement and physiological changes (inhibition of the ipsilateral dorso-lateral rostral putamen and activation of the right dorso-lateral PFC and cingulate cortex) was documented in one patient using 15-O H 2 O PET scan in this study ( ). Unfortunately, a validated clinical assessment tool such as the Y-BOCS was not used to quantify the results. In Aouizerate et al. reported remission of OCD symptoms (Y-BOCS <16) at 12–15 months following DBS of the ventral caudate nucleus in a patient with intractable OCD and associated depression. reported sustained improvement of OCD symptoms in a patient with concomitant residual schizophrenia following right ALIC–NAcc DBS at 24 months. However, this patient did not meet the criteria for responders on the Y-BOCS scale (preoperative and postoperative Y-BOCS scores were 32/40 and 24/40 respectively) ( ). In another open-label study, reported a 13 point decrease in the Y-BOCS score in one of two patients with medical-refractory OCD 24–27 months following bilateral NAcc DBS. In a double-blinded sham controlled study investigating the efficacy of right NAcc-DBS in 10 patients with medical-refractory OCD ( ), the mean Y-BOCS score decreased significantly from 32.2 at baseline to 25.4 at 12 months follow-up ( P < .05). Fifty percent of patients showed a >25% reduction in their Y-BOCS score following DBS; but only 10% of patients met the responder criterion of a >35% reduction in Y-BOCS score at 12 months follow-up ( ). In addition, there was alleviation in depression, global functioning, and quality of life with no significant changes in anxiety, global symptom severity, and cognitive function during the stimulation period. Adverse events included agitation/anxiety (four patients), hypomania (two patients), concentration difficulties with failing memory (one patient), suicidal thoughts (one patient), headache (one patient), weight gain (two patients), reduction in sleep duration (one patient), and dysesthesia in the subclavicular region (one patient) ( ). Another double-blinded sham controlled study reported a response rate of 56% following bilateral NAcc DBS in 16 patients with refractory OCD at 21 months follow-up ( ). There was a 72% decrease in Y-BOCS scores during the 8-month open-label treatment phase and a 25% decrease in Y-BOCS scores during the double-blind sham controlled phase of the study ( ). Associated symptoms such as depression and anxiety were significantly reduced. Reported adverse events included mild forgetfulness, word-finding problems, hypomania, numbness at the incision site, superficial wound infection, and feeling the extension leads ( ). There was reduced performance in visual organization and verbal fluency, with a trend toward reduced performance in visual memory and abstract reasoning, 3 weeks following NAcc DBS in 14 patients with refractory OCD ( ). However, 8 months later there was significant improvement in verbal fluency and the other cognitive measures were stabilized at the reduced level. There was no correlation between improvement in OCD symptoms and cognitive effects following DBS for OCD in these patients ( ).
A recent study has shown the effects of NAcc DBS on the hypothalamic–pituitary adrenal axis in patients who underwent stimulation for more than 1 year ( ). In the DBS “off” condition there was 41% and 39% decrease in plasma prolactin and TSH levels, which increased within 30 min of the DBS “on” condition and corresponded to hypomania observed following stimulation ( ).
Subthalamic Nucleus
The STN neurons in patients with OCD have been shown to have a lower mean firing rate, an asymmetrical (left-sided) distribution, less frequent prolonged bursts and increased activity in the anterior ventromedial area (nonmotor area), and primarily oscillatory activity in the δ-band ( ). In addition, a low-frequency nonregular pattern of STN stimulation has been shown to have a more desynchronizing effect compared to continuous standard stimulation in patients with refractory OCD, using a computational model ( ). These mechanisms point toward neuromodulation of STN as a potential tool in normalizing the neural circuits involved in the pathophysiology of OCD and thus its clinical symptoms. The STN is one of the nodal points in the dorsolateral prefrontal, orbitofrontal, and limbic loops, and STN DBS for PD has been shown to have neuropsychological affects with improvements in mood, anxiety, and OCD symptoms ( ).
There are reports of mirthful laughter/hilarity, transient acute depression, and episodes of hypomania/mania following supratherapeutic stimulation of the STN ( ). Ventromedial portions of the STN and surrounding structures such as the lateral hypothalamus, ventral tegmental area, substantia nigra, and zona incerta have been implicated in the neuropsychological effects of STN stimulation. In Mallet et al. reported 58% and 64% improvements in the Y-BOCS scores of two patients with PD and severe OCD following bilateral STN DBS at 6 months follow-up. One case report noted significant improvement in the Y-BOCS score (32 preoperatively versus 1 postoperatively) in a single patient with refractory OCD 12 months following bilateral STN DBS ( ). Based on these initial reports, investigated the efficacy of bilateral STN DBS in 16 patients with severe refractory OCD in a randomized double-blind cross-over multicenter study. Twelve of the 16 patients (75%) exhibited a >25% reduction in their Y-BOCS score following bilateral STN DBS as compared to baseline, and were categorized as “responders” ( ). The investigators reported significant improvement in the postoperative GAF scale, but depression, anxiety, and other neuropsychological measures were not affected. A total of 15 serious adverse events occurred in 11 patients, including 1 intracerebral hemorrhage and 2 infections leading to hardware explantation. In addition, 23 nonserious adverse events were identified in 10 patients ( ).
Inferior Thalamic Peduncle
There is only one open study investigating the efficacy of the inferior thalamic peduncle (ITP) as a potential DBS target to alleviate symptoms in patients with medical-refractory OCD. The ITP provides a route to the white fibers connecting the thalamus to the OFC, and thus it can be explored as a potential nodal point for neuromodulation ( ). In Jimenez-Ponce et al. reported a significant response (>35% reduction in Y-BOCS score) in all five patients (100% responders) who underwent bilateral ITP DBS for medically refractory OCD. In this open study there was a 17.2 point decrease in Y-BOCS score following stimulation at 12 months follow-up compared to baseline. The mean GAF improved from 20% to 70% following stimulation ( ). Neither significant adverse effects related to implantation surgery/chronic stimulation nor changes in neuropsychological functions following stimulation were found in this study ( ). Although the results of this study are promising, randomized controlled studies are needed to substantiate the efficacy of the ITP as a potential DBS target in patients with medical-refractory OCD.
Other Targets
Recently, bilateral DBS of the superolateral branch of the medial forebrain bundle has been shown to be effective in alleviating the symptoms of OCD in two patients with medical-refractory OCD ( ). One patient showed complete response (>35% reduction in Y-BOCS) and the other patient reached remission (Y-BOCS <14) at 3 months following continuous bilateral DBS stimulation ( ).
reported partial response on Y-BOCS (25%–35% reduction) in one out of four patients (two de novo, with the thalamus chosen as the primary target for DBS; and two rescue DBS after failed primary NAcc DBS) following continuous high-frequency stimulation of the medial dorsal and ventral anterior nucleus of the thalamus. Beck Depression Inventory scores improved by 46% in the de novo group and worsened in the rescue DBS group. Also, DBS had no effect on anxiety and mood symptoms in the de novo group. Based on these findings, the medial dorsal and ventral anterior nucleus of the thalamus are not optimal targets in relieving OCD symptoms, but the ventromedial nucleus of thalamus could be a potential target in treatment of depressive and anxiety disorders ( ).
investigated the efficacy of bilateral anteromedial (limbic) globus pallidus internus (GPi) DBS in four patients with Tourette’s syndrome and severe OCD who underwent surgery to alleviate the motor symptoms associated with their Tourette’s syndrome. Two patients reported 100% improvement while the other two achieved >85% improvement in their OCD symptoms based on the Obsessive–Compulsive Inventory (OCI) scale at 3–26 months follow-up ( ). Similarly, reported an average improvement of 39% in Y-BOCS compared to baseline following bilateral GPi DBS (2 patients unilateral Gpi DBS) in 18 patients with Tourette’s syndrome and OCD (total n = 24) at 1 year follow-up.
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