- Email: [email protected]
Deep brain stimulation in obsessive–compulsive disorder
Handbook of Clinical Neurology, Vol. 116 (3rd series) Brain Stimulation A.M. Lozano and M. Hallett, Editors © 2013 Elsevier B.V. All rights reserved
Chapter 19
Deep brain stimulation in obsessive–compulsive disorder: neurocircuitry and clinical experience 1 2
NIR LIPSMAN1, PETER GIACOBBE2, AND ANDRES M. LOZANO1* Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, Canada
Department of Psychiatry, Toronto General Hospital, University of Toronto, Toronto, Canada
BACKGROUND AND HISTORICAL CONTEXT Recognized in clinical psychiatry for over a century, obsessive–compulsive disorder (OCD) is a chronic psychiatric illness marked by persistent, unrelenting, and anxiety-generating thoughts or images (obsessions) alternating with troublesome and intrusive, repetitive behaviors (compulsions) typically performed with the goal of relieving the anxiety associated with the obsession. OCD is estimated to occur in the general population with a lifetime prevalence of 1–3%, affecting men and women equally (de Koning et al., 2011). Medical management is indicated when either or both of obsessions and compulsions significantly impede patient function. For nearly 25 years, the staple of OCD management has been pharmacological, with the use of selective serotonin reuptake inhibitor (SSRI) antidepressants, in an effort to maximize the amount of synaptic serotonin (see Figee and Denys (2009) for a review of current pharmacotherapeutic approaches for OCD). Estimates of treatment resistance in OCD, defined as a failure to show clinical benefit following an adequate trial of antidepressant medication and/or cognitive–behavioral therapy, range from 10% to as high as 40–60% (Figee and Denys, 2009; Abudy et al., 2011). Although such figures vary between centers, it is clear that a substantial proportion of patients remain resistant to conventional therapy, and may stand to benefit from novel neurotherapeutics. These patients are at risk not only for the deleterious effects of polypharmacy, but also to the ongoing, untreated natural history of the condition, which can include severe disability and even death, by suicide (Mian et al., 2010).
In the past, neurosurgical lesioning was used in patients with so-called “obsessional neuroses” who failed to respond to available therapies. The advent of stereotactic methodology, beginning in the 1940s and becoming widespread in the 1960s and 1970s, made accessing deep brain structures more accurate and safer. Cingulotomy and capsulotomy, the most commonly applied procedures, as well as limbic leucotomy, provided some benefit for patients deemed treatment-resistant. For example, an early report on limbic leucotomy by Kelly et al. (1973) in 40 patients saw clinical improvement in 13 of 17 patients with predominantly OCD symptoms. Limbic leucotomy combines subcaudate tractotomy and cingulotomy, and other groups explored the use of the latter alone in refractory psychiatric patients. A review by Ballantine and colleagues in 1987 described the authors’ experience with stereotactic cingulotomy in 198 psychiatric patients, of whom 32 (16%) were predominantly obsessive–compulsive. The authors commented, that compared with patients with affective disorders or those with nonobsessional anxiety, patients with OCD responded less favorably to surgical intervention, and were less likely to improve on functional outcome measures. More recently, cingulotomy was examined in 17 patients with refractory OCD, with researchers finding a mean improvement in the Yale–Brown Obsessive Compulsive Scale (YBOCS) of 48%, with 8 patients classified as responders (Jung et al., 2006). These results support work done at other centers with cingulotomy, where rates of response, defined by significant reductions in YBOCS scores, range from 25% to 50% (Jenike et al., 1991; Baer et al., 1995). Experience with capsulotomy, where the anterior limb of the internal capsule is targeted to interrupt frontosubcortical pathways, has shown it also
*Correspondence to: Dr Andres M. Lozano, M.D., Ph.D., Professor and Chair, Division of Neurosurgery, Toronto Western Hospital, 399 Bathurst Street, Toronto, M5T 2S8 Ontario, Canada. Tel: 416-603-6200, E-mail: [email protected]
246
N. LIPSMAN ET AL.
to be an effective, although perhaps not as effective as cingulotomy, approach to resistant OCD. Several groups have reported the use of both stereotactic and gammaknife capsulotomy for the management of refractory OCD, with promising results (Lopes et al., 2009; Kondziolka et al., 2011; Riestra et al., 2011).
CIRCUITRY OF OCD: TRANSLATION TO DEEP BRAIN STIMULATION Circuits subserving decision-making, affective and emotional processing, as well as voluntary movement, are all implicated in OCD. Importantly, this makes OCD unique among the anxiety disorders, as fear processing does not necessarily figure prominently in circuit-based OCD models. As such, OCD exists much more closely, and may have more in common, with motor and neuropsychiatric disorders, such as Tourette syndrome, rather than other anxiety disorders, such as panic and posttraumatic stress disorder. It is the prominence of predominantly frontal projections, via the anterior internal capsule, to what have traditionally been motor structures, including the striatum, subthalamic nucleus (STN), and thalamus, and back to frontal motor and premotor processing areas that has led to this important distinction (Cummings, 1993; Menzies et al., 2008). These structures have virtually all been considered for both ablative and stimulation-based therapies. Brain circuits implicated in OCD have been identified by both structural and functional neuroimaging studies (reviewed in Menzies et al., 2008). Structural magnetic resonance imaging (MRI) has shown differences between the brains of patients and healthy controls, including volumetric changes, such as reductions in orbitofrontal cortex (OFC) and medial frontal gray matter volumes in OCD (Choi et al., 2004; Pujol et al., 2004). The caudate, in particular, has been the focus of several region-based analyses, but results have been discrepant, with some studies showing increased, and others decreased, caudate volumes in patients with OCD (Scarone et al., 1992; Szeszko et al., 1999). As a whole, the strength of structural neuroimaging has been supportive of the role of frontosubcortical loops in patients with OCD, and hint at potential areas of interest, such as OFC and caudate, within those loops for further study. Functional imaging with positron emission tomography (PET) and fMRI has helped further to define the neurocircuitry of OCD. Resting-state fluorodeoxyglucose (FDG)-PET has shown increased basal metabolism in the OFC and caudate in patients with OCD versus healthy controls, and that this hypermetabolic state can reverse with successful treatment (Saxena et al., 2001; Menzies et al., 2008). Increased metabolism in the OFC, to the extent that this implies a functional role in
symptom generation, has been supported by multiple studies (McGuire et al., 1994), including ones that provoked anxiety using OCD-relevant cues (Rauch et al., 1994). Provocation studies have the added benefit of attempting to disentangle cause from effect, by showing positive correlations between structural activation (in caudate and OFC, specifically), and the presence of an anxiety-generating cue. A meta-analysis of fMRI studies by Menzies et al. (2008) further supports the theory of OFC–striatal dysfunction in OCD. Although the authors concede significant heterogeneity in methodology in the OCD imaging literature, they found abnormal activation in patients’ OFC, as well as in anterior cingulate, parietal lobe, and lateral frontal cortices. Such results suggest underlying OFC dysfunction in OCD, as well as dysfunction in its projections to subcortical and cortical structures that participate in action-monitoring and decision-making. In contrast to other anxiety disorders, basal ganglia structures are heavily implicated in the pathogenesis of OCD. Evidence for the involvement of basal ganglia circuitry in the generation and potential maintenance of OCD symptoms comes from primarily four sources: (1) the high rates of comorbidity between some movement disorders, such as Huntington’s disease and Tourette syndrome, with OCD (Cummings, 1993); (2) the existence of OCD-type behavior in patients with striatal pathology and lesions (Laplane et al., 1989); (3) the existence of decision-making deficits, such as impulsivity and compulsivity, in patients with movement disorders such as Parkinson’s disease (PD); and (4) the improvement of OCD symptoms following STN deep brain stimulation (DBS) in patients with comorbid PD and OCD. The latter in particular, ignited interest in the application of DBS for the exclusive treatment of OCD, using the STN as a target. Next, we review the results of DBS for OCD, by anatomical location, and evaluate how these results help further define OCD circuitry.
DBS IN OCD: EXPERIENCE WITH VARIOUS POTENTIAL TARGETS DBS is overtaking ablative techniques for the management of refractory OCD in several centers. The ability to adjust the activity in dysfunctional neural circuits, to titrate dosage to response, to control reversibly the side-effects of overstimulation, and to assign study patients to blinded stimulation and nonstimulation groups are some of the advantages of DBS therapy. Its limited long-term follow-up data and unknown durability in controlling OCD symptoms are reminders of the investigational status of DBS. As such, most applications of DBS in OCD are currently being examined in
DEEP BRAIN STIMULATION IN OBSESSIVE–COMPULSIVE DISORDER the context of clinical trials. Several potential DBS targets are being examined.
Anterior limb of the internal capsule Interest in the anterior limb of the internal capsule (ALIC) as the first to be used DBS target in OCD grew out of the experience with ablative capsulotomy for OCD on the presumption that stimulation could be used to produce a functional lesion. We identified four publications that specifically explored the ALIC as a DBS target in refractory OCD (Table 19.1). The first was published in 1999 by Nuttin et al, and examined ALIC DBS in 4 patients. Three of these patients had a significant clinical improvement, although the authors did not formally measure this. A follow-up study in 2003, utilizing validated YBOCS measurements, in 6 patients, found that in 3 of 4 patients who had preoperative and postoperative assessments there was a greater than 35% reduction in YBOCS score following surgery (Nuttin et al., 2003). Anderson and Ahmed (2003) published a single case report, finding a nearly 80% decrease in YBOCS score in a single patient with OCD following ALIC DBS, at 3-month follow-up. A study by Abelson et al. (2005) in 4 patients utilized an on–off design, whereby patients were assigned to randomized 3-week blocks of stimulation or nonstimulation, in a double-blind design. One of the 4 patients had a greater than 35% Table 19.1 Anterior limb of the internal capsule (ALIC) target in deep brain stimulation for obsessive–compulsive disorder
Reference Nuttin et al. (1999)
Nuttin et al. (2003)
No. of patients 4
6
Anderson and Ahmed (2003)
1
Abelson et al. (2005)
4
247
reduction in their YBOCS score after surgery, both in the double-blind phase and in long-term follow-up. The mechanism of action through which ALIC DBS may act is uncertain, but could include modulation of the thalamocortical and basal ganglia pathways that course in this structure.
Subthalamic nucleus The STN has long been considered a structure involved exclusively in voluntary motor control. The success of DBS in this structure in the management of PD has supported this. In 2002, Mallet and coworkers reported results in 2 patients with comorbid PD and OCD, and found serendipitous reductions in PD symptoms, and a 58% and 64% reduction in OCD symptoms in both patients as well (Table 19.2). An additional case report supporting the putative role of the STN in OCD, was published in 2004, with the authors reporting significant reductions in postoperative YBOCS scores in a patient with PD and OCD (Fontaine et al., 2004). Such findings led to the development of the only randomized doubleblind trial of DBS in OCD, which was undertaken in 2008, utilizing the STN as a target (Mallet et al., 2008). Sixteen patients received DBS, with 8 assigned to sham stimulation and 8 to active stimulation in this crossover design. Twelve of the 16 patients responded favorably to DBS therapy, with a greater than 25% reduction in YBOCS score. The STN target in OCD is commonly more medial than that used in PD DBS, reflecting the preferential placement of the electrodes within the limbic territory of the STN. Table 19.2
Outcome Three-quarters of patients had significant clinical benefit 4 patients had pre/post YBOCS assessments, and three-quarters showed > 35% reduction in YBOCS score 79% reduction in YBOCS score at 3-month follow-up Randomization to 3-week blocks of on- and offstimulation. 1 patient had reduction > 35% in YBOCS score during the double-blind period
YBOCS, Yale–Brown Obsessive Compulsive Scale.
Subthalamic nucleus target in deep brain stimulation for obsessive–compulsive disorder
Reference
No. of patients Outcome
Mallet et al. (2002)
2
Fontaine et al. (2004)
1
Mallet et al. (2008)
16
Comorbid PD and OCD; 58% and 64% reduction in OCD scores after surgery Comorbid PD and OCD; YBOCS score reduced from 32 to 1 at 1-year follow-up Randomized, double-blind design; 8 patients assigned to sham and 8 to active stimulation 12 of 16 had >25% reduction in YBOCS score
PD, Parkinson’s disease; OCD, obsessive–compulsive disorder; YBOCS, Yale–Brown Obsessive Compulsive Scale.
248
N. LIPSMAN ET AL.
Ventral caudate/ventral striatum and nucleus accumbens (NAcc) The terms ventral striatum (VS) and nucleus accumbens (NAcc) are often used interchangeably to refer to the confluence of putamen and caudate. VS (NAcc) participates heavily in reward processing and its dysfunction has been implicated in a broad range of psychiatric disorders, from depression to drug addiction. Importantly, it is in a position to affect both the affective and motor components of reward, making it a prime candidate for involvement in OCD. It has been proposed as a target for DBS therapy in OCD (Table 19.3). Sturm et al. (2003) reported their results of unilateral right NAcc DBS in 4 patients in 2003. They found “nearly total recovery” in 3 of the 4 patients, although no YBOCS scores were reported. Plewnia and colleagues (2008) provided further support for the NAcc as a target, reporting significant improvement in OCD symptoms in a 51-year-old patient with comorbid OCD and schizophrenia. There was a sustained decrease in YBOCS score, from 40 to 24, at both 6month and 1-year follow-up. The NAcc was also used as a target in 2 patients with refractory OCD by Franzini et al. (2010): both patients had decreased YBOCS scores (from 38 to 22, and from 30 to 20), although the latency
of response was 1 year for one patient and almost 22 months for the other. The most recent study utilizing the NAcc as a target involved an open treatment phase followed by a double-blind crossover design in 16 patients with treatment-resistant OCD (Denys et al., 2010). The authors reported a mean decrease in YBOCS score of 46% at 8 months during the open-label phase, and differences in YBOCS score of 25% between active and sham groups during the blinded phase. Consistent with previous reports, the authors reported improvements in both depression scores and quality-of-life measures. A case report of ventral caudate stimulation in a patient with comorbid major depressive disorder (MDD) and OCD showed remission of both conditions, although with variable latency of 6 and 12 months, respectively (Aouizerate et al., 2004). In one of the largest DBS OCD studies, Greenberg and colleagues (2006) examined ventral caudate (VC)/VS stimulation in 10 patients with resistant OCD. The VC/VS target was seen as a structural extension of the ALIC. Of 8 patients who were followed for 3 years, four had sustained and significant reductions in YBOCS score (>35%). The authors noted improvements in both global functioning and associated depressive symptoms. A further study in 2010 examined DBS of the VC/VS in 6 patients with
Table 19.3 Ventral caudate/ventral striatum and nucleus accumbens target in deep brain stimulation of obsessive–compulsive disorder Reference
No. of patients
Target
Outcome
Greenberg et al. (2006)
10
VC/VS
Goodman et al. (2010)
6
VC/VS
Sturm et al. (2003)
4
Unilateral NAcc
Aouizerate et al. (2004)
1
VC
Plewnia et al. (2008)
Unilateral NAcc
Franzini et al. (2010)
1 (OCD comorbid with schizophrenia) 2
Denys et al. (2010)
16
NAcc
8 patients followed for 3 years; 50% had >35% reduction in YBOCS score 4 of 6 patients had >35% reduction in YBOCS score at 36 months Three-quarters of patients had “near total recovery” at 24–30 months’ follow-up Comorbid OCD/MDD; remission of MDD at 6 months (HAM-D <7); remission of OCD after 12–15 months YBOCS score reduced from 40 to 22 at 6- month and 1-year follow-up Clinically beneficial response in 2 of 2 patients, with YBOCS score decreasing to 22 (from 38) and 20 (from 30) at 12 and 22 months, respectively Open-label phase followed by double-blind period; 48% reduction in YBOCS score at 8 months in open-label phase and 25% difference in YBOCS score between active and sham stimulated patients in blinded phase; 7 of 12 patients classified as clinical responders
NAcc
HAM-D, Hamilton Depression Rating Scale; MDD, major depressive disorder; NAcc, nucleus accumbens; OCD, obsessive–compulsive disorder; VC, ventral caudate; VS, ventral striatum; YBOCS, Yale–Brown Obsessive Compulsive Scale.
DEEP BRAIN STIMULATION IN OBSESSIVE–COMPULSIVE DISORDER OCD using a sham-controlled design and with the dorsal portion of the electrodes spanning the ALIC (Goodman et al., 2010). At 12 months of active stimulation, 4 of the 6 patients met response criteria (>35% reduction in YBOCS score), with the authors noting an absence of improvement in a sham stimulation period. The choice of the ventral striatal target has been in part as a consequence of its close proximity to the ALIC and the observation that some patients with electrodes placed in the region of the ALIC derived benefits from the most ventral electrode contacts, which were, in reality, within the immediately adjacent ventral striatum.
Inferior thalamic peduncle Jime´nez-Ponce et al. (2009) have suggested that stimulation of the inferior thalamic peduncle (ITP) may mimic the effects of subcaudate tractotomy, a procedure popularized by the neurosurgeon Professor Geoffrey Knight, whereby thalamocortical projections are interrupted to and from the OFC. DBS of the ITP was applied in 5 patients with resistant OCD, with the authors reporting a clinically meaningful response in all patients at 1 year, with mean reductions in YBOCS score from 35 to 17. The main rationale for the ITP target is the possibility to modulate thalamocortical projections, and also its proximity to the bed nucleus of the stria terminalis which in DBS animal models shows some interesting behavioral properties.
CONCLUSION: OCD AS A NEUROPSYCHIATRIC ILLNESS OCD remains a significant treatment challenge, even in the modern neurosurgical and DBS era. The above results show that, despite a growing understanding of the circuitry of the illness, and relatively safe and consistent surgical methodology, results are similar between centers and targets. Several important points can be made. First, all targets thus far selected for DBS in OCD appear to participate in the same corticostriatothalamocortical circuit. Although structurally and histologically different, ALIC, VC/VS, NAcc, and ITP are not only in close proximity, but are likely functionally connected, by afferent and efferent fibers. Interestingly, the OFC, which has been implicated most consistently in OCD imaging studies, has not been a direct target for stimulation, probably because of its size and the complexity of safely reaching it surgically. Indeed, no cortical target has been tried in OCD, unlike in major depression, where epidural stimulation has been tried (Kopell et al., 2011). It may be that subcortical, specifically striatal, targets offer the greatest impact, given the confluence and concentration of widely projecting fibers in these locations.
249
It appears that DBS in resistant OCD leads to a clinical improvement in approximately one-half to twothirds of patients, with comparable results reported from the stimulation of diverse neuroanatomical targets. Thus far, however, DBS remains an experimental treatment for the condition, and there are few data suggesting long-term durability of response and effect. The results, however, are promising, with future studies needing to define better which patients may benefit from DBS, and why, and whether there exist predictive features of the illness or the patient that portend a beneficial outcome.
REFERENCES Abelson JL, Curtis GC, Sagher O et al. (2005). Deep brain stimulation for refractory obsessive–compulsive disorder. Biol Psychiatry 57: 510–516. Abudy A, Juven-Wetzler A, Zohar J (2011). Pharmacological management of treatment-resistant obsessive-compulsive disorder. CNS Drugs 25: 585–596. Anderson D, Ahmed A (2003). Treatment of patients with intractable obsessive-compulsive disorder with anterior capsular stimulation. Case report. J Neurosurg 98: 1104–1108. Aouizerate B, Cuny E, Martin-Guehl C et al. (2004). Deep brain stimulation of the ventral caudate nucleus in the treatment of obsessive-compulsive disorder and major depression. Case report. J Neurosurg 101: 682–686. Baer L, Rauch SL, Ballantine HT Jr et al. (1995). Cingulotomy for intractable obsessive-compulsive disorder. Prospective long-term follow-up of 18 patients. Arch Gen Psychiatry 52: 384–392. Ballantine HT, Jr, Bouckoms AJ, Thomas EK et al. (1987). Treatment of psychiatric illness by stereotactic cingulotomy. Biol Psychiatry 22: 807–819. Choi JS, Kang DH, Kim JJ et al. (2004). Left anterior subregion of orbitofrontal cortex volume reduction and impaired organizational strategies in obsessive-compulsive disorder. J Psychiatr Res 38: 193–199. Cummings JL (1993). Frontal-subcortical circuits and human behavior. Arch Neurol 50: 873–880. de Koning PP, Figee M, van den Munckhof P et al. (2011). Current status of deep brain stimulation for obsessivecompulsive disorder: a clinical review of different targets. Curr Psychiatry Rep 13: 274–282. Denys D, Mantione M, Figee M et al. (2010). Deep brain stimulation of the nucleus accumbens for treatment-refractory obsessive-compulsive disorder. Arch Gen Psychiatry 67: 1061–1068. Figee M, Denys D (2009). New pharmacotherapeutic approaches to obsessive-compulsive disorder. CNS Spectr 14: 13–23. Fontaine D, Mattei V, Borg M et al. (2004). Effect of subthalamic nucleus stimulation on obsessive-compulsive disorder in a patient with Parkinson disease. Case report. J Neurosurg 100: 1084–1086. Franzini A, Messina G, Gambini O et al. (2010). Deep-brain stimulation of the nucleus accumbens in obsessive
250
N. LIPSMAN ET AL.
compulsive disorder: clinical, surgical and electrophysiological considerations in two consecutive patients. Neurol Sci 31: 353–359. Goodman WK, Foote KD, Greenberg BD et al. (2010). Deep brain stimulation for intractable obsessive compulsive disorder: pilot study using a blinded, staggered-onset design. Biol Psychiatry 67: 535–542. Greenberg BD, Malone DA, Friehs GM et al. (2006). Three-year outcomes in deep brain stimulation for highly resistant obsessive-compulsive disorder. Neuropsychopharmacology 31: 2384–2393. Jenike MA, Baer L, Ballantine T et al. (1991). Cingulotomy for refractory obsessive-compulsive disorder. A long-term follow-up of 33 patients. Arch Gen Psychiatry 48: 548–555. Jime´nez-Ponce F, Velasco-Campos F, Castro-Farfa´n G et al. (2009). Preliminary study in patients with obsessivecompulsive disorder treated with electrical stimulation in the inferior thalamic peduncle. Neurosurgery 65: 203–209. Jung HH, Kim CH, Chang JH et al. (2006). Bilateral anterior cingulotomy for refractory obsessive-compulsive disorder: long-term follow-up results. Stereotact Funct Neurosurg 84: 184–189. Kelly D, Richardson A, Mitchell-Heggs N et al. (1973). Stereotactic limbic leucotomy: a preliminary report on forty patients. Br J Psychiatry 123: 141–148. Kondziolka D, Flickinger JC, Hudak R (2011). Results following gamma knife radiosurgical anterior capsulotomies for obsessive compulsive disorder. Neurosurgery 68: 28–32. Kopell BH, Halverson J, Butson CR et al. (2011). Epidural cortical stimulation of the left dorsolateral prefrontal cortex for refractory major depressive disorder. Neurosurgery 69: 1015–1029. Laplane D, Levasseur M, Pillon B et al. (1989). Obsessivecompulsive and other behavioural changes with bilateral basal ganglia lesions. A neuropsychological, magnetic resonance imaging and positron tomography study. Brain 112: 699–725. Lopes AC, Greenberg BD, Nore´n G et al. (2009). Treatment of resistant obsessive-compulsive disorder with ventral capsular/ventral striatal gamma capsulotomy: a pilot prospective study. J Neuropsychiatry Clin Neurosci 21: 381–392. Mallet L, Mesnage V, Houeto JL et al. (2002). Compulsions, Parkinson’s disease, and stimulation. Lancet 360: 1302–1304. Mallet L, Polosan M, Jaafari N et al. (2008). Subthalamic nucleus stimulation in severe obsessive-compulsive disorder. STOC Study Group. N Engl J Med 359: 2121–2134.
McGuire PK, Bench CJ, Frith CD et al. (1994). Functional anatomy of obsessive-compulsive phenomena. Br J Psychiatry 164: 459–468. Menzies L, Chamberlain SR, Laird AR et al. (2008). Integrating evidence from neuroimaging and neuropsychological studies of obsessive-compulsive disorder: the orbitofrontostriatal model revisited. Neurosci Biobehav Rev 32: 525–549. Mian MK, Campos M, Sheth SA et al. (2010). Deep brain stimulation for obsessive-compulsive disorder: past, present, and future. Neurosurg Focus 29: E10. Nuttin B, Cosyns P, Demeulemeester H et al. (1999). Electrical stimulation in anterior limbs of internal capsules in patients with obsessive-compulsive disorder. Lancet 354: 1526. Nuttin BJ, Gabriels L, van Kuyck K et al. (2003). Electrical stimulation of the anterior limbs of the internal capsules in patients with severe obsessive-compulsive disorder: anecdotal reports. Neurosurg Clin N Am 14: 267–274. Plewnia C, Schober F, Rilk A et al. (2008). Sustained improvement of obsessive-compulsive disorder by deep brain stimulation in a woman with residual schizophrenia. Int J Neuropsychopharmacol 11: 1181–1183. Pujol J, Soriano-Mas C, Alonso P et al. (2004). Mapping structural brain alterations in obsessive-compulsive disorder. Arch Gen Psychiatry 61: 720–730. Rauch SL, Jenike MA, Alpert NM et al. (1994). Regional cerebral blood flow measured during symptom provocation in obsessive-compulsive disorder using oxygen 15-labeled carbon dioxide and positron emission tomography. Arch Gen Psychiatry 51: 62–70. Riestra AR, Aguilar J, Zambito G et al. (2011). Unilateral right anterior capsulotomy for refractory major depression with comorbid obsessive-compulsive disorder. Neurocase 17: 491–500. Saxena S, Bota RG, Brody AL (2001). Brain–behavior relationships in obsessive-compulsive disorder. Semin Clin Neuropsychiatry 6: 82–101. Scarone S, Colombo C, Livian S et al. (1992). Increased right caudate nucleus size in obsessive-compulsive disorder: detection with magnetic resonance imaging. Psychiatry Res 45: 115–121. Sturm V, Lenartz D, Koulousakis A et al. (2003). The nucleus accumbens: a target for deep brain stimulation in obsessivecompulsive- and anxiety-disorders. J Chem Neuroanat 26: 293–299. Szeszko PR, Robinson D, Alvir JM et al. (1999). Orbital frontal and amygdala volume reductions in obsessivecompulsive disorder. Arch Gen Psychiatry 56: 913–919.
Chapter 19
Deep brain stimulation in obsessive–compulsive disorder: neurocircuitry and clinical experience 1 2
NIR LIPSMAN1, PETER GIACOBBE2, AND ANDRES M. LOZANO1* Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, Canada
Department of Psychiatry, Toronto General Hospital, University of Toronto, Toronto, Canada
BACKGROUND AND HISTORICAL CONTEXT Recognized in clinical psychiatry for over a century, obsessive–compulsive disorder (OCD) is a chronic psychiatric illness marked by persistent, unrelenting, and anxiety-generating thoughts or images (obsessions) alternating with troublesome and intrusive, repetitive behaviors (compulsions) typically performed with the goal of relieving the anxiety associated with the obsession. OCD is estimated to occur in the general population with a lifetime prevalence of 1–3%, affecting men and women equally (de Koning et al., 2011). Medical management is indicated when either or both of obsessions and compulsions significantly impede patient function. For nearly 25 years, the staple of OCD management has been pharmacological, with the use of selective serotonin reuptake inhibitor (SSRI) antidepressants, in an effort to maximize the amount of synaptic serotonin (see Figee and Denys (2009) for a review of current pharmacotherapeutic approaches for OCD). Estimates of treatment resistance in OCD, defined as a failure to show clinical benefit following an adequate trial of antidepressant medication and/or cognitive–behavioral therapy, range from 10% to as high as 40–60% (Figee and Denys, 2009; Abudy et al., 2011). Although such figures vary between centers, it is clear that a substantial proportion of patients remain resistant to conventional therapy, and may stand to benefit from novel neurotherapeutics. These patients are at risk not only for the deleterious effects of polypharmacy, but also to the ongoing, untreated natural history of the condition, which can include severe disability and even death, by suicide (Mian et al., 2010).
In the past, neurosurgical lesioning was used in patients with so-called “obsessional neuroses” who failed to respond to available therapies. The advent of stereotactic methodology, beginning in the 1940s and becoming widespread in the 1960s and 1970s, made accessing deep brain structures more accurate and safer. Cingulotomy and capsulotomy, the most commonly applied procedures, as well as limbic leucotomy, provided some benefit for patients deemed treatment-resistant. For example, an early report on limbic leucotomy by Kelly et al. (1973) in 40 patients saw clinical improvement in 13 of 17 patients with predominantly OCD symptoms. Limbic leucotomy combines subcaudate tractotomy and cingulotomy, and other groups explored the use of the latter alone in refractory psychiatric patients. A review by Ballantine and colleagues in 1987 described the authors’ experience with stereotactic cingulotomy in 198 psychiatric patients, of whom 32 (16%) were predominantly obsessive–compulsive. The authors commented, that compared with patients with affective disorders or those with nonobsessional anxiety, patients with OCD responded less favorably to surgical intervention, and were less likely to improve on functional outcome measures. More recently, cingulotomy was examined in 17 patients with refractory OCD, with researchers finding a mean improvement in the Yale–Brown Obsessive Compulsive Scale (YBOCS) of 48%, with 8 patients classified as responders (Jung et al., 2006). These results support work done at other centers with cingulotomy, where rates of response, defined by significant reductions in YBOCS scores, range from 25% to 50% (Jenike et al., 1991; Baer et al., 1995). Experience with capsulotomy, where the anterior limb of the internal capsule is targeted to interrupt frontosubcortical pathways, has shown it also
*Correspondence to: Dr Andres M. Lozano, M.D., Ph.D., Professor and Chair, Division of Neurosurgery, Toronto Western Hospital, 399 Bathurst Street, Toronto, M5T 2S8 Ontario, Canada. Tel: 416-603-6200, E-mail: [email protected]
246
N. LIPSMAN ET AL.
to be an effective, although perhaps not as effective as cingulotomy, approach to resistant OCD. Several groups have reported the use of both stereotactic and gammaknife capsulotomy for the management of refractory OCD, with promising results (Lopes et al., 2009; Kondziolka et al., 2011; Riestra et al., 2011).
CIRCUITRY OF OCD: TRANSLATION TO DEEP BRAIN STIMULATION Circuits subserving decision-making, affective and emotional processing, as well as voluntary movement, are all implicated in OCD. Importantly, this makes OCD unique among the anxiety disorders, as fear processing does not necessarily figure prominently in circuit-based OCD models. As such, OCD exists much more closely, and may have more in common, with motor and neuropsychiatric disorders, such as Tourette syndrome, rather than other anxiety disorders, such as panic and posttraumatic stress disorder. It is the prominence of predominantly frontal projections, via the anterior internal capsule, to what have traditionally been motor structures, including the striatum, subthalamic nucleus (STN), and thalamus, and back to frontal motor and premotor processing areas that has led to this important distinction (Cummings, 1993; Menzies et al., 2008). These structures have virtually all been considered for both ablative and stimulation-based therapies. Brain circuits implicated in OCD have been identified by both structural and functional neuroimaging studies (reviewed in Menzies et al., 2008). Structural magnetic resonance imaging (MRI) has shown differences between the brains of patients and healthy controls, including volumetric changes, such as reductions in orbitofrontal cortex (OFC) and medial frontal gray matter volumes in OCD (Choi et al., 2004; Pujol et al., 2004). The caudate, in particular, has been the focus of several region-based analyses, but results have been discrepant, with some studies showing increased, and others decreased, caudate volumes in patients with OCD (Scarone et al., 1992; Szeszko et al., 1999). As a whole, the strength of structural neuroimaging has been supportive of the role of frontosubcortical loops in patients with OCD, and hint at potential areas of interest, such as OFC and caudate, within those loops for further study. Functional imaging with positron emission tomography (PET) and fMRI has helped further to define the neurocircuitry of OCD. Resting-state fluorodeoxyglucose (FDG)-PET has shown increased basal metabolism in the OFC and caudate in patients with OCD versus healthy controls, and that this hypermetabolic state can reverse with successful treatment (Saxena et al., 2001; Menzies et al., 2008). Increased metabolism in the OFC, to the extent that this implies a functional role in
symptom generation, has been supported by multiple studies (McGuire et al., 1994), including ones that provoked anxiety using OCD-relevant cues (Rauch et al., 1994). Provocation studies have the added benefit of attempting to disentangle cause from effect, by showing positive correlations between structural activation (in caudate and OFC, specifically), and the presence of an anxiety-generating cue. A meta-analysis of fMRI studies by Menzies et al. (2008) further supports the theory of OFC–striatal dysfunction in OCD. Although the authors concede significant heterogeneity in methodology in the OCD imaging literature, they found abnormal activation in patients’ OFC, as well as in anterior cingulate, parietal lobe, and lateral frontal cortices. Such results suggest underlying OFC dysfunction in OCD, as well as dysfunction in its projections to subcortical and cortical structures that participate in action-monitoring and decision-making. In contrast to other anxiety disorders, basal ganglia structures are heavily implicated in the pathogenesis of OCD. Evidence for the involvement of basal ganglia circuitry in the generation and potential maintenance of OCD symptoms comes from primarily four sources: (1) the high rates of comorbidity between some movement disorders, such as Huntington’s disease and Tourette syndrome, with OCD (Cummings, 1993); (2) the existence of OCD-type behavior in patients with striatal pathology and lesions (Laplane et al., 1989); (3) the existence of decision-making deficits, such as impulsivity and compulsivity, in patients with movement disorders such as Parkinson’s disease (PD); and (4) the improvement of OCD symptoms following STN deep brain stimulation (DBS) in patients with comorbid PD and OCD. The latter in particular, ignited interest in the application of DBS for the exclusive treatment of OCD, using the STN as a target. Next, we review the results of DBS for OCD, by anatomical location, and evaluate how these results help further define OCD circuitry.
DBS IN OCD: EXPERIENCE WITH VARIOUS POTENTIAL TARGETS DBS is overtaking ablative techniques for the management of refractory OCD in several centers. The ability to adjust the activity in dysfunctional neural circuits, to titrate dosage to response, to control reversibly the side-effects of overstimulation, and to assign study patients to blinded stimulation and nonstimulation groups are some of the advantages of DBS therapy. Its limited long-term follow-up data and unknown durability in controlling OCD symptoms are reminders of the investigational status of DBS. As such, most applications of DBS in OCD are currently being examined in
DEEP BRAIN STIMULATION IN OBSESSIVE–COMPULSIVE DISORDER the context of clinical trials. Several potential DBS targets are being examined.
Anterior limb of the internal capsule Interest in the anterior limb of the internal capsule (ALIC) as the first to be used DBS target in OCD grew out of the experience with ablative capsulotomy for OCD on the presumption that stimulation could be used to produce a functional lesion. We identified four publications that specifically explored the ALIC as a DBS target in refractory OCD (Table 19.1). The first was published in 1999 by Nuttin et al, and examined ALIC DBS in 4 patients. Three of these patients had a significant clinical improvement, although the authors did not formally measure this. A follow-up study in 2003, utilizing validated YBOCS measurements, in 6 patients, found that in 3 of 4 patients who had preoperative and postoperative assessments there was a greater than 35% reduction in YBOCS score following surgery (Nuttin et al., 2003). Anderson and Ahmed (2003) published a single case report, finding a nearly 80% decrease in YBOCS score in a single patient with OCD following ALIC DBS, at 3-month follow-up. A study by Abelson et al. (2005) in 4 patients utilized an on–off design, whereby patients were assigned to randomized 3-week blocks of stimulation or nonstimulation, in a double-blind design. One of the 4 patients had a greater than 35% Table 19.1 Anterior limb of the internal capsule (ALIC) target in deep brain stimulation for obsessive–compulsive disorder
Reference Nuttin et al. (1999)
Nuttin et al. (2003)
No. of patients 4
6
Anderson and Ahmed (2003)
1
Abelson et al. (2005)
4
247
reduction in their YBOCS score after surgery, both in the double-blind phase and in long-term follow-up. The mechanism of action through which ALIC DBS may act is uncertain, but could include modulation of the thalamocortical and basal ganglia pathways that course in this structure.
Subthalamic nucleus The STN has long been considered a structure involved exclusively in voluntary motor control. The success of DBS in this structure in the management of PD has supported this. In 2002, Mallet and coworkers reported results in 2 patients with comorbid PD and OCD, and found serendipitous reductions in PD symptoms, and a 58% and 64% reduction in OCD symptoms in both patients as well (Table 19.2). An additional case report supporting the putative role of the STN in OCD, was published in 2004, with the authors reporting significant reductions in postoperative YBOCS scores in a patient with PD and OCD (Fontaine et al., 2004). Such findings led to the development of the only randomized doubleblind trial of DBS in OCD, which was undertaken in 2008, utilizing the STN as a target (Mallet et al., 2008). Sixteen patients received DBS, with 8 assigned to sham stimulation and 8 to active stimulation in this crossover design. Twelve of the 16 patients responded favorably to DBS therapy, with a greater than 25% reduction in YBOCS score. The STN target in OCD is commonly more medial than that used in PD DBS, reflecting the preferential placement of the electrodes within the limbic territory of the STN. Table 19.2
Outcome Three-quarters of patients had significant clinical benefit 4 patients had pre/post YBOCS assessments, and three-quarters showed > 35% reduction in YBOCS score 79% reduction in YBOCS score at 3-month follow-up Randomization to 3-week blocks of on- and offstimulation. 1 patient had reduction > 35% in YBOCS score during the double-blind period
YBOCS, Yale–Brown Obsessive Compulsive Scale.
Subthalamic nucleus target in deep brain stimulation for obsessive–compulsive disorder
Reference
No. of patients Outcome
Mallet et al. (2002)
2
Fontaine et al. (2004)
1
Mallet et al. (2008)
16
Comorbid PD and OCD; 58% and 64% reduction in OCD scores after surgery Comorbid PD and OCD; YBOCS score reduced from 32 to 1 at 1-year follow-up Randomized, double-blind design; 8 patients assigned to sham and 8 to active stimulation 12 of 16 had >25% reduction in YBOCS score
PD, Parkinson’s disease; OCD, obsessive–compulsive disorder; YBOCS, Yale–Brown Obsessive Compulsive Scale.
248
N. LIPSMAN ET AL.
Ventral caudate/ventral striatum and nucleus accumbens (NAcc) The terms ventral striatum (VS) and nucleus accumbens (NAcc) are often used interchangeably to refer to the confluence of putamen and caudate. VS (NAcc) participates heavily in reward processing and its dysfunction has been implicated in a broad range of psychiatric disorders, from depression to drug addiction. Importantly, it is in a position to affect both the affective and motor components of reward, making it a prime candidate for involvement in OCD. It has been proposed as a target for DBS therapy in OCD (Table 19.3). Sturm et al. (2003) reported their results of unilateral right NAcc DBS in 4 patients in 2003. They found “nearly total recovery” in 3 of the 4 patients, although no YBOCS scores were reported. Plewnia and colleagues (2008) provided further support for the NAcc as a target, reporting significant improvement in OCD symptoms in a 51-year-old patient with comorbid OCD and schizophrenia. There was a sustained decrease in YBOCS score, from 40 to 24, at both 6month and 1-year follow-up. The NAcc was also used as a target in 2 patients with refractory OCD by Franzini et al. (2010): both patients had decreased YBOCS scores (from 38 to 22, and from 30 to 20), although the latency
of response was 1 year for one patient and almost 22 months for the other. The most recent study utilizing the NAcc as a target involved an open treatment phase followed by a double-blind crossover design in 16 patients with treatment-resistant OCD (Denys et al., 2010). The authors reported a mean decrease in YBOCS score of 46% at 8 months during the open-label phase, and differences in YBOCS score of 25% between active and sham groups during the blinded phase. Consistent with previous reports, the authors reported improvements in both depression scores and quality-of-life measures. A case report of ventral caudate stimulation in a patient with comorbid major depressive disorder (MDD) and OCD showed remission of both conditions, although with variable latency of 6 and 12 months, respectively (Aouizerate et al., 2004). In one of the largest DBS OCD studies, Greenberg and colleagues (2006) examined ventral caudate (VC)/VS stimulation in 10 patients with resistant OCD. The VC/VS target was seen as a structural extension of the ALIC. Of 8 patients who were followed for 3 years, four had sustained and significant reductions in YBOCS score (>35%). The authors noted improvements in both global functioning and associated depressive symptoms. A further study in 2010 examined DBS of the VC/VS in 6 patients with
Table 19.3 Ventral caudate/ventral striatum and nucleus accumbens target in deep brain stimulation of obsessive–compulsive disorder Reference
No. of patients
Target
Outcome
Greenberg et al. (2006)
10
VC/VS
Goodman et al. (2010)
6
VC/VS
Sturm et al. (2003)
4
Unilateral NAcc
Aouizerate et al. (2004)
1
VC
Plewnia et al. (2008)
Unilateral NAcc
Franzini et al. (2010)
1 (OCD comorbid with schizophrenia) 2
Denys et al. (2010)
16
NAcc
8 patients followed for 3 years; 50% had >35% reduction in YBOCS score 4 of 6 patients had >35% reduction in YBOCS score at 36 months Three-quarters of patients had “near total recovery” at 24–30 months’ follow-up Comorbid OCD/MDD; remission of MDD at 6 months (HAM-D <7); remission of OCD after 12–15 months YBOCS score reduced from 40 to 22 at 6- month and 1-year follow-up Clinically beneficial response in 2 of 2 patients, with YBOCS score decreasing to 22 (from 38) and 20 (from 30) at 12 and 22 months, respectively Open-label phase followed by double-blind period; 48% reduction in YBOCS score at 8 months in open-label phase and 25% difference in YBOCS score between active and sham stimulated patients in blinded phase; 7 of 12 patients classified as clinical responders
NAcc
HAM-D, Hamilton Depression Rating Scale; MDD, major depressive disorder; NAcc, nucleus accumbens; OCD, obsessive–compulsive disorder; VC, ventral caudate; VS, ventral striatum; YBOCS, Yale–Brown Obsessive Compulsive Scale.
DEEP BRAIN STIMULATION IN OBSESSIVE–COMPULSIVE DISORDER OCD using a sham-controlled design and with the dorsal portion of the electrodes spanning the ALIC (Goodman et al., 2010). At 12 months of active stimulation, 4 of the 6 patients met response criteria (>35% reduction in YBOCS score), with the authors noting an absence of improvement in a sham stimulation period. The choice of the ventral striatal target has been in part as a consequence of its close proximity to the ALIC and the observation that some patients with electrodes placed in the region of the ALIC derived benefits from the most ventral electrode contacts, which were, in reality, within the immediately adjacent ventral striatum.
Inferior thalamic peduncle Jime´nez-Ponce et al. (2009) have suggested that stimulation of the inferior thalamic peduncle (ITP) may mimic the effects of subcaudate tractotomy, a procedure popularized by the neurosurgeon Professor Geoffrey Knight, whereby thalamocortical projections are interrupted to and from the OFC. DBS of the ITP was applied in 5 patients with resistant OCD, with the authors reporting a clinically meaningful response in all patients at 1 year, with mean reductions in YBOCS score from 35 to 17. The main rationale for the ITP target is the possibility to modulate thalamocortical projections, and also its proximity to the bed nucleus of the stria terminalis which in DBS animal models shows some interesting behavioral properties.
CONCLUSION: OCD AS A NEUROPSYCHIATRIC ILLNESS OCD remains a significant treatment challenge, even in the modern neurosurgical and DBS era. The above results show that, despite a growing understanding of the circuitry of the illness, and relatively safe and consistent surgical methodology, results are similar between centers and targets. Several important points can be made. First, all targets thus far selected for DBS in OCD appear to participate in the same corticostriatothalamocortical circuit. Although structurally and histologically different, ALIC, VC/VS, NAcc, and ITP are not only in close proximity, but are likely functionally connected, by afferent and efferent fibers. Interestingly, the OFC, which has been implicated most consistently in OCD imaging studies, has not been a direct target for stimulation, probably because of its size and the complexity of safely reaching it surgically. Indeed, no cortical target has been tried in OCD, unlike in major depression, where epidural stimulation has been tried (Kopell et al., 2011). It may be that subcortical, specifically striatal, targets offer the greatest impact, given the confluence and concentration of widely projecting fibers in these locations.
249
It appears that DBS in resistant OCD leads to a clinical improvement in approximately one-half to twothirds of patients, with comparable results reported from the stimulation of diverse neuroanatomical targets. Thus far, however, DBS remains an experimental treatment for the condition, and there are few data suggesting long-term durability of response and effect. The results, however, are promising, with future studies needing to define better which patients may benefit from DBS, and why, and whether there exist predictive features of the illness or the patient that portend a beneficial outcome.
REFERENCES Abelson JL, Curtis GC, Sagher O et al. (2005). Deep brain stimulation for refractory obsessive–compulsive disorder. Biol Psychiatry 57: 510–516. Abudy A, Juven-Wetzler A, Zohar J (2011). Pharmacological management of treatment-resistant obsessive-compulsive disorder. CNS Drugs 25: 585–596. Anderson D, Ahmed A (2003). Treatment of patients with intractable obsessive-compulsive disorder with anterior capsular stimulation. Case report. J Neurosurg 98: 1104–1108. Aouizerate B, Cuny E, Martin-Guehl C et al. (2004). Deep brain stimulation of the ventral caudate nucleus in the treatment of obsessive-compulsive disorder and major depression. Case report. J Neurosurg 101: 682–686. Baer L, Rauch SL, Ballantine HT Jr et al. (1995). Cingulotomy for intractable obsessive-compulsive disorder. Prospective long-term follow-up of 18 patients. Arch Gen Psychiatry 52: 384–392. Ballantine HT, Jr, Bouckoms AJ, Thomas EK et al. (1987). Treatment of psychiatric illness by stereotactic cingulotomy. Biol Psychiatry 22: 807–819. Choi JS, Kang DH, Kim JJ et al. (2004). Left anterior subregion of orbitofrontal cortex volume reduction and impaired organizational strategies in obsessive-compulsive disorder. J Psychiatr Res 38: 193–199. Cummings JL (1993). Frontal-subcortical circuits and human behavior. Arch Neurol 50: 873–880. de Koning PP, Figee M, van den Munckhof P et al. (2011). Current status of deep brain stimulation for obsessivecompulsive disorder: a clinical review of different targets. Curr Psychiatry Rep 13: 274–282. Denys D, Mantione M, Figee M et al. (2010). Deep brain stimulation of the nucleus accumbens for treatment-refractory obsessive-compulsive disorder. Arch Gen Psychiatry 67: 1061–1068. Figee M, Denys D (2009). New pharmacotherapeutic approaches to obsessive-compulsive disorder. CNS Spectr 14: 13–23. Fontaine D, Mattei V, Borg M et al. (2004). Effect of subthalamic nucleus stimulation on obsessive-compulsive disorder in a patient with Parkinson disease. Case report. J Neurosurg 100: 1084–1086. Franzini A, Messina G, Gambini O et al. (2010). Deep-brain stimulation of the nucleus accumbens in obsessive
250
N. LIPSMAN ET AL.
compulsive disorder: clinical, surgical and electrophysiological considerations in two consecutive patients. Neurol Sci 31: 353–359. Goodman WK, Foote KD, Greenberg BD et al. (2010). Deep brain stimulation for intractable obsessive compulsive disorder: pilot study using a blinded, staggered-onset design. Biol Psychiatry 67: 535–542. Greenberg BD, Malone DA, Friehs GM et al. (2006). Three-year outcomes in deep brain stimulation for highly resistant obsessive-compulsive disorder. Neuropsychopharmacology 31: 2384–2393. Jenike MA, Baer L, Ballantine T et al. (1991). Cingulotomy for refractory obsessive-compulsive disorder. A long-term follow-up of 33 patients. Arch Gen Psychiatry 48: 548–555. Jime´nez-Ponce F, Velasco-Campos F, Castro-Farfa´n G et al. (2009). Preliminary study in patients with obsessivecompulsive disorder treated with electrical stimulation in the inferior thalamic peduncle. Neurosurgery 65: 203–209. Jung HH, Kim CH, Chang JH et al. (2006). Bilateral anterior cingulotomy for refractory obsessive-compulsive disorder: long-term follow-up results. Stereotact Funct Neurosurg 84: 184–189. Kelly D, Richardson A, Mitchell-Heggs N et al. (1973). Stereotactic limbic leucotomy: a preliminary report on forty patients. Br J Psychiatry 123: 141–148. Kondziolka D, Flickinger JC, Hudak R (2011). Results following gamma knife radiosurgical anterior capsulotomies for obsessive compulsive disorder. Neurosurgery 68: 28–32. Kopell BH, Halverson J, Butson CR et al. (2011). Epidural cortical stimulation of the left dorsolateral prefrontal cortex for refractory major depressive disorder. Neurosurgery 69: 1015–1029. Laplane D, Levasseur M, Pillon B et al. (1989). Obsessivecompulsive and other behavioural changes with bilateral basal ganglia lesions. A neuropsychological, magnetic resonance imaging and positron tomography study. Brain 112: 699–725. Lopes AC, Greenberg BD, Nore´n G et al. (2009). Treatment of resistant obsessive-compulsive disorder with ventral capsular/ventral striatal gamma capsulotomy: a pilot prospective study. J Neuropsychiatry Clin Neurosci 21: 381–392. Mallet L, Mesnage V, Houeto JL et al. (2002). Compulsions, Parkinson’s disease, and stimulation. Lancet 360: 1302–1304. Mallet L, Polosan M, Jaafari N et al. (2008). Subthalamic nucleus stimulation in severe obsessive-compulsive disorder. STOC Study Group. N Engl J Med 359: 2121–2134.
McGuire PK, Bench CJ, Frith CD et al. (1994). Functional anatomy of obsessive-compulsive phenomena. Br J Psychiatry 164: 459–468. Menzies L, Chamberlain SR, Laird AR et al. (2008). Integrating evidence from neuroimaging and neuropsychological studies of obsessive-compulsive disorder: the orbitofrontostriatal model revisited. Neurosci Biobehav Rev 32: 525–549. Mian MK, Campos M, Sheth SA et al. (2010). Deep brain stimulation for obsessive-compulsive disorder: past, present, and future. Neurosurg Focus 29: E10. Nuttin B, Cosyns P, Demeulemeester H et al. (1999). Electrical stimulation in anterior limbs of internal capsules in patients with obsessive-compulsive disorder. Lancet 354: 1526. Nuttin BJ, Gabriels L, van Kuyck K et al. (2003). Electrical stimulation of the anterior limbs of the internal capsules in patients with severe obsessive-compulsive disorder: anecdotal reports. Neurosurg Clin N Am 14: 267–274. Plewnia C, Schober F, Rilk A et al. (2008). Sustained improvement of obsessive-compulsive disorder by deep brain stimulation in a woman with residual schizophrenia. Int J Neuropsychopharmacol 11: 1181–1183. Pujol J, Soriano-Mas C, Alonso P et al. (2004). Mapping structural brain alterations in obsessive-compulsive disorder. Arch Gen Psychiatry 61: 720–730. Rauch SL, Jenike MA, Alpert NM et al. (1994). Regional cerebral blood flow measured during symptom provocation in obsessive-compulsive disorder using oxygen 15-labeled carbon dioxide and positron emission tomography. Arch Gen Psychiatry 51: 62–70. Riestra AR, Aguilar J, Zambito G et al. (2011). Unilateral right anterior capsulotomy for refractory major depression with comorbid obsessive-compulsive disorder. Neurocase 17: 491–500. Saxena S, Bota RG, Brody AL (2001). Brain–behavior relationships in obsessive-compulsive disorder. Semin Clin Neuropsychiatry 6: 82–101. Scarone S, Colombo C, Livian S et al. (1992). Increased right caudate nucleus size in obsessive-compulsive disorder: detection with magnetic resonance imaging. Psychiatry Res 45: 115–121. Sturm V, Lenartz D, Koulousakis A et al. (2003). The nucleus accumbens: a target for deep brain stimulation in obsessivecompulsive- and anxiety-disorders. J Chem Neuroanat 26: 293–299. Szeszko PR, Robinson D, Alvir JM et al. (1999). Orbital frontal and amygdala volume reductions in obsessivecompulsive disorder. Arch Gen Psychiatry 56: 913–919.