Special Supplement Peer-Review ReportDeep Brain Stimulation for Obsessive-Compulsive Disorder: Subthalamic Nucleus Target
Introduction
Obsessive-compulsive disorder (OCD) is a major cause of disability and can be responsible for severe impairment in quality of life. It is one of the most frequent and disabling psychiatric problems after phobia, mood disorders, and substance abuse (13). It affects 2%–3% of the population. OCD is characterized by recurrent unwanted ideas, images, or impulses (obsessions), and repetitive, stereotyped behaviors or mental acts (compulsions), often intended to neutralize the anxiety induced by the obsessions. The variability of symptoms mirrors their heterogeneity in response to conventional treatments. OCD usually tends to be chronic and might require long-term medication and cognitive-behavior therapy (CBT). First-line treatments for OCD are well established and consist in CBT, including exposure and ritual prevention, associated with medications, particularly selective serotonin reuptake inhibitors (12). Such conventional treatments can lead to satisfactory responses but improvement after medication and CBT is usually partial. After conventional treatments, 20%–40% of patients with OCD remain severely disabled. Surgery is an option for treatment-refractory patients who are usually those most severely affected.
For decades, surgery has consisted in thermolesion of different key structures supposedly involved in the control of OCD. OCD was one of the rare indications responding successfully to lobotomy (24), but at the price of a severe frontal syndrome. The patient is apathetic and disinhibited. This leaves the patient suffering from major changes in personality and behavior (35). Stereotactic surgery was first developed in 1947 by Spiegel et al. (31) with the aim of performing small selective thalamic lesions aiming at interrupting cortico-thalamo-cortical loops (30) to avoid or reduce the side effects of lobotomy. Since then different targets have been explored including thermolesion in the cingulate cortex, the anterior limb of the internal capsule, or the subcaudate region. Leukotomies combined cingulotomy and subcaudate tractotomy. Different centers worldwide have established the efficacy of such surgical treatments, which are still proposed in cases of intractable OCD (7, 8, 11, 20, 29). In the past decade, the use of deep brain stimulation (DBS) has progressively replaced lesions and Bart Nuttin and his team (25) were the first to apply the concept of high frequency stimulation of a deep target, the anterior limb of the internal capsule, to treat patients suffering from severe OCD. Since this original report in 1999, there has been a growing interest in the neurosurgical field to define new brain structures that could be targeted by DBS, which has the advantage (versus ablative surgery) of reversibility and adaptability. The surgical experience accumulated in the field of movement disorders surgery, the development of functional imaging leading to better comprehension of neuronal networks involved in OCD and depression, the observation of nonmotor (side) effects of DBS in Parkinson disease (PD), as well as the serendipitous observation of OCD symptoms being improved in some patients with PD on subthalamic stimulation, These experiences have helped to bring electrical stimulation as a therapeutic tool into psychiatric disorders.
Behavioral side effects induced by acute changes in stimulation parameters in patients with PD treated with subthalamic nucleus (STN)-DBS include mirthful laughter (19), acute depression (4), aggressiveness (5), and hypomania or full blown mania (19, 23, 33). These clinical observations have been carefully reported and have led to the concept that deep nuclei, such as the STN, a target commonly used to treat patients with PD, could induce limbic side effects systematically reproduced when the stimulator was switched ON. These observations paved the way for new exploratory applications of electrical stimulation targeting limbic/cognitive regions to treat nonmotor symptoms that are encountered in psychiatric disorders such as OCD, depression, Gilles de la Tourette syndrome, or addiction (18). This regain of interest in surgery for mood and cognitive disorders brought together anatomic and physiologic knowledge of the neuronal circuitry involved in these psychiatric disorders. This is an attempt to better understand the close relationships between limbic, cognitive, and motor neuronal networks in the basal ganglia.
If the dorsolateral motor portion of the STN is known to be a major entry of the motor cortical information into the basal ganglia circuitry, the anteroventral STN also receives information from the dorsolateral and orbitobasal frontal cortex, from the cingulate cortex, and from the lateral temporal neocortex (26, 27, 32). In monkeys, anatomic studies using retrograde tracers have demonstrated the somatotopic organization between associative, motor, and limbic cortex on one hand, and subterritories of the basal ganglia on the other hand. For example, nonmotor territories of the external globus pallidus send massive projections to the nonmotor STN (noM-STN) through the indirect pathway (15). The noM-STN appears to be a key node between the associative/limbic cortex, the nonmotor subterritories of basal ganglia, and the thalamus. Review of the surgical literature in the field of psychiatry (18) has highlighted that all targets shown to improve symptoms of OCD, depression, Gilles de la Tourette syndrome, or addiction involve the nonmotor (limbic and/or associative) corticobasal ganglia–thalamo-cortical loops described in the Alexander model of basal ganglia circuitry (1) (see Temel et al. [32] for review).
Recent experimental data have shed light on the role of the STN in compulsive behavior. It has been shown that in the quinpirole rat model of OCD and in a behavior model of OCD (attenuation rat model of OCD) (16, 38), high-frequency stimulation (HFS) as well as pharmacologic inactivation of the STN alleviated compulsive checking (39). These works are in line with the published literature that has already demonstrated the role of STN in decision process, reward (2), and control of impulsivity and choices. Usually lesions of STN lead to modulation of impulsive choice and action (34, 37). Increase of impulsivity has recently been proposed (18) as one of the mechanism of action of STN-DBS in OCD (discussed later).
In monkeys, stereotypies can be obtained after microinjection of bicuculline into the limbic part of STN (14). In this animal model, it has been reported that acute HFS of the anterior-medial part (limbic) of the STN could dramatically reverse these stereotypies (3). Even if OCD cannot be summarized by successive stereotypies, these data acquired in subhuman monkeys demonstrated the potential powerful effect of electrical inhibition of the noM-STN to treat “compulsive” behavior. Interestingly, the authors did not report any attention or task execution impairment during the experiments.
This maxim can be illustrated with the discovery of the potential effect of STN-DBS to treat OCD. Three patients who had a history of severe PD and also intractable OCD symptoms were treated with STN-DBS and had great improvement of PD symptoms and surprisingly also of OCD symptoms.
Mallet et al. (21) first reported the case of two patients who underwent presurgical evaluation for severe PD and who presented OCD as a comorbidity. The patients received bilateral STN implantation to treat PD symptoms. The first patient had a 5-year history of PD and presented with severe OCD (cleaning, arranging, “fear of being dead in a dirty house”) that lasted for 33 years. Two weeks after surgery, she spontaneously described a dramatic improvement of OCD symptoms and the Yale-Brown obsessive-compulsive scale (YBOCS) was reduced by 81% (preoperative, 26; postoperative, 5). The second patient had a 16-year history of PD with also a 40-year history of OCD (repeated checking of locks). Two weeks after, OCD were also dramatically improved by 83%. In these two patients, the anti-OCD effect of STN-DBS was still present 1 year after surgery. When looking at the precise location of the lead within the STN, it turned out that the electrodes were slightly anterior and medial and that the current could have potentially diffused to the nonmotor part of the STN.
In 2004, Fontaine et al. (9) confirmed previous findings with the report of the case of a man, aged 49 years, presenting with severe PD and who also suffered from refractory OCD (accumulating, rubbing, gathering) for 16 years. He was operated on for PD with bilateral STN implantation. At 1-year follow-up, PD was improved as expected but at the same time, OCD symptoms disappeared (preoperative YBOCS, 32; postoperative YBOCS, 1).
These three intriguing observations were the basis of a larger pilot study that involved several centers in France and that aimed at evaluating the presumed effect of STN-DBS on OCD.
In 2002, the French “comité national d'éthique” was asked by one of the senior author (ALB) to answer whether DBS, a surgical methodology developed for movement disorders, could potentially be applied in psychiatric disorders including OCD. This committee stated that OCD patients could be involved in therapeutic trials with the following restriction: 1) the first purpose of the trial must be to treat the patient and research must not be the primary goal, 2) the patient must be able to give inform consent, 3) the trial must be validated by an external adviser, and 4) the presumed reversibility of DBS technique must be continually assessed in its reality.
Section snippets
STOC Study
In 2005, the French Stimulation ≪dans le Trouble Obsessionnel Compulsif≫ (STOC) Study, headed by L. Mallet, started in France, and involved 10 academic centers. This protocol was approved by the local ethical committee of Pitié-Salpetrière. It consisted in a double-blind, crossover study, assessing the efficacy and safety of STN-DBS in 16 patients. The primary outcome measure was the severity of OCD, as assessed by the YBOCS, at the end of two 3-month periods. Inclusion criteria are described
Electrophysiologic Findings During Microrecordings
We have recently described how STN neurons behave in the noM-STN in patients with OCD (28). Briefly, compared to STN of patients with PD, STN neurons in patients with OCD have a lower frequency rate but, more important, they exhibit a bursting pattern, which we have interpreted as a signature of dysfunction of the nonmotor basal ganglia network. Interestingly, in patients with OCD, the proportion of neurons with burst activity (70%) is similar to that seen in patients with PD. However, these
Responder versus Nonresponder
In our cohort, one patient (case 4) responded partially (improvement of about 34%) to chronic stimulation despite optimal anatomic placement of the lead within the anterior part of STN, and despite multiple stimulation parameter settings (monopolar, bipolar, stimulation of multiple contacts). In this patient, neither the semiology of OCD symptoms, nor his past history and medication, differed from other patients who did respond to the stimulation. However, several issues were raised during
Conclusion
Surgical treatment of psychiatric disorders in general, and for OCD in particular, is entering a new area because options, such as DBS, can be proposed in addition to conventional lesions or gamma knife surgery. Among DBS targets that are currently investigated, the nonmotor subdivision of the STN is promising. Our preliminary results show a benefit of STN-DBS that can reach 50%–75% on the YBOCS. Side effects are voltage-dependant and comprise hypomania and anxiety, which require fine-tuning
Acknowledgments
The authors thank Brigitte Piallat, Manik Battacharjee, and Laurent Goetz for their help in the acquisition of data and conception of the figures.
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Conflict of interest statement: Dr. Chabardès has received reimbursement of travel costs to scientific meetings in the past by Medtronic. The remaining authors have no conflicts to report.