Gamma ventral capsulotomy for treatment of resistant obsessive-compulsive disorder: A structural MRI pilot prospective study

Neuroscience Letters 447 (2008) 138–142

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Gamma ventral capsulotomy for treatment of resistant obsessive-compulsive disorder: A structural MRI pilot prospective study Janaína Philippi Cecconi a,∗ , Antônio Carlos Lopes a , Fábio Luis de Souza Duran a , Luciana Cristina Santos a , Marcelo Queiroz Hoexter a,b , André Felix Gentil a , Miguel Montes Canteras c , Claudio Campi de Castro a , George Norén d , Benjamin D. Greenberg d , Scott L. Rauch e , Geraldo F. Busatto a , Eurípedes Constantino Miguel a a

Department of Psychiatry, University of São Paulo Medical School (FMUSP), São Paulo, SP, Brazil Department of Psychiatry, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil c Institute of Neurological Radiosurgery, Hospital Santa Paula, São Paulo, SP, Brazil d Department of Psychiatry and Human Behavior and Department of Clinical Neurosciences-Neurosurgery, Brown University, Providence, RI, USA e Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA,USA b

a r t i c l e

i n f o

Article history: Received 13 May 2008 Received in revised form 13 August 2008 Accepted 22 September 2008 Keywords: Obsessive-compulsive disorder (OCD) Magnetic resonance imaging (MRI) Voxel-based morphometry Radiosurgery Neurosurgery

a b s t r a c t Objective: The purpose of this study was to investigate regional structural abnormalities in the brains of five patients with refractory obsessive-compulsive disorder (OCD) submitted to gamma ventral capsulotomy. Methods: We acquired morphometric magnetic resonance imaging (MRI) data before and after 1 year of radiosurgery using a 1.5-T MRI scanner. Images were spatially normalized and segmented using optimized voxel-based morphometry (VBM) methods. Voxelwise statistical comparisons between preand post-surgery MRI scans were performed using a general linear model. Findings in regions predicted a priori to show volumetric changes (orbitofrontal cortex, anterior cingulate gyrus, basal ganglia and thalamus) were reported as significant if surpassing a statistical threshold of p < 0.001 (uncorrected for multiple comparisons). Results: We detected a significant regional postoperative increase in gray matter volume in the right inferior frontal gyri (Brodmann area 47, BA47) when comparing all patients pre and postoperatively. Conclusions: Our results support the current theory of frontal-striatal-thalamiccortical (FSTC) circuitry involvement in OCD pathogenesis. Gamma ventral capsulotomy is associated with neurobiological changes in the inferior orbitofrontal cortex in refractory OCD patients. © 2008 Elsevier Ireland Ltd. All rights reserved.

Neurobiological models have postulated that abnormalities in the frontal-striatal-thalamic-cortical (FSTC) circuitry underlie the pathophysiology of obsessive-compulsive disorder (OCD) [32]. Functional and structural neuroimaging findings corroborate these theoretical models. Some studies have shown that clinical interventions such as drug or psychotherapeutic approaches are associated with changes in that circuitry [11,29,30]. Therefore, using neuroimaging techniques to study the outcome of therapeutic interventions on the brain of OCD patients can contribute to a better understanding of the FSTC circuitry and the therapeutic mechanisms of such treatments.

∗ Corresponding author at: Obsessive-Compulsive Spectrum Disorders Program (PROTOC), Department of Psychiatry, University of São Paulo School of Medicine, R. Dr. Ovídio Pires de Campos, 785, 3◦ andar, sala 9, 01060-970 São Paulo, SP, Brazil. Tel.: +55 11 3069 6972. E-mail addresses: [email protected], [email protected] (J.P. Cecconi). 0304-3940/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2008.09.061

Despite the existing evidence showing alterations in FSTC circuitry resulting from clinical treatment, there are few studies describing the consequences of neurosurgical interventions on these pathways. Stereotactic lesions within the anterior limb of the internal capsule have been shown to provide symptomatic relief in refractory cases of OCD. A select group of refractory patients that do not respond to any type of clinical treatment may benefit from this treatment [21]. Thus, it can be hypothesized that neurosurgical procedures for the treatment of OCD produce therapeutic effects through modulation of FSTC circuitry activity [26]. To date, no study has assessed whole brain morphometric changes after anterior capsulotomy radiosurgery for the treatment of refractory OCD. Although Lippitz et al. [19] has studied lesions caused by gamma knife radiosurgery, there are no studies showing the consequences of this technique on structures relative to the FSTC circuitry. This study describes the results obtained in the first five patients in our research center, who were submitted to a modified surgical technique, the gamma ventral capsulotomy, also known as

J.P. Cecconi et al. / Neuroscience Letters 447 (2008) 138–142 Table 1 Clinical and demographic characteristics of the sample. OCD patients N Male Female

2 3

Laterality Right-handed Left-handed

5 0

Age Age 1st OC symptoms (discomfort)

 35 (S.D. 11.07)  8.8 (S.D. 2.28)

Y-BOCS scores Pre-surgery Post-surgery

 32.2 (S.D. 1.48)  20.20 (S.D. 11.54)

Treatment Previous medications Previous SRI trials Previous CBT trials Previous other psychotherapies

 14.6 (S.D. 3.71)  5.4 (S.D. 1.34)  1 (S.D. 0)  0.6 (S.D. 0.89)

Hospitalizations

 3 (S.D. 3.67)

N, number of patients; , mean values; S.D., standard deviation; OC, obsessivecompulsive; OCD, obsessive-compulsive disorder; Y-BOCS, Yale-Brown ObsessiveCompulsive Scale.

ventral capsular/ventral striatal (VC/VS) gamma capsulotomy. It aims to analyze cerebral volumetric changes using magnetic resonance imaging (MRI) data from patients submitted to this procedure before and after the procedure, using the voxel-based morphometry (VBM) approach. Our a priori hypothesis is that gamma ventral capsulotomy will induce structural changes in regions that are part of the FSTC circuitry, namely the orbitofrontal cortex (OFC), anterior cingulate gyrus, caudate/putamen and mediodorsal thalamus. A detailed description of this project methodology can be found elsewhere [20,21]. Briefly, written informed consent was obtained in the presence of a member of the Brazilian OCD Association (ASTOC). Interviews were videotaped and analyzed by an independent review board, which verified patients’ actual knowledge of benefits and risks involved in the procedures. This study was approved by the Medical Ethics Committees of the School of Medicine, University of São Paulo (FMUSP) (where patients were clinically assessed), and by Santa Paula Hospital (where radiosurgeries were conducted), as well as by the National Commission on Research Ethics (CONEP). Patients had to fulfill refractoriness and inclusion criteria [20,21]. Five patients were selected between 2003 and 2004, fulfilling OCD diagnostic criteria as defined by DSM-IV [1], assessed by Structured Clinical Interview for DSM-IV (SCID) [9]. They consisted of two men and three women; mean age 35 ± 11.07 years, three of them single, one divorced, and one married. All have had disabling symptoms and psychosocial impairments for more than 5 years. Three patients had not completed college due to obsessivecompulsive symptoms (OCS). Only one patient was working at the time of surgery. Four patients had lifetime comorbid axis I diagnoses, as assessed by the SCID [9]: alcohol abuse; cyclothymic disorder, major depressive disorder, recurrent; social phobia; skin picking; major depressive disorder, single episode; panic disorder with agoraphobia; panic disorder without agoraphobia. Three of them had comorbid axis II diagnoses: one with borderline personality disorder and two with dependent personality disorder/avoidant personality disorder. For more detailed information about the sample see Table 1 and Lopes [20]. The severity of obsessive-compulsive symptoms was assessed by the Yale-Brown Obsessive-Compulsive Scale (YBOCS) at baseline and 2 weeks, and 1, 2, 3, 6, 9 and 12 months after surgery

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[13,14]. Clinical changes were prospectively evaluated by the Clinical Global Impression (CGI) scale and assessed in the same time intervals as the YBOCS. Response criteria was established as a minimum reduction of 35% in the Y-BOCS scores and “improved” or “much improved” scores on the CGI scale [16]. The gamma-knife procedure has been recently refined and a smaller, bilateral, double-shot technique is now employed, with fewer associated side effects and good efficacy profile, known as gamma ventral capsulotomy [23,25,15]. Lesions were targeted at the most ventral portions of the anterior limb of the internal capsule and some of the dorsal portion of the Ventral Striatum adjacent to the ventral capsule, by means of converging collimated beams of gamma radiation from 201 60 Co sources using 4 mm collimators. The target at the anterior internal capsule was covered by 50% isodoses; maximum doses (100%) were 180 Gy [21]. Pre- and 1-year postoperative magnetic resonance imaging (MRI) data were available for all patients. Images were acquired using the same 1.5 Tesla, Signa LX CVi equipment (General Electric, Milwaukee, WI, USA). Structural MRI data were acquired for all five OCD subjects pre- and postoperatively (range: 9–24 months later). For VBM analyses, we used contiguous 1.56-mm images acquired across the entire brain in all subjects with T1-weighted fast field echo protocols. Across subjects, parameters for image acquisition varied as follows: echo time of 1.5 or 5.2 ms; repetition time of 6.4, 12.1 or 21.7 ms; flip angle of 15◦ or 20◦ , matrix size of 256 × 192 or 256 × 256. Evaluation of brain volume changes after surgery was conducted by VBM using the SPM2 package (Wellcome Department of Imaging Neuroscience, London, United Kingdom) and executed in Matlab (Mathworks, Sherborn, Massachusetts). A standard template set was created specifically for the study, consisting of a mean T1-weighted image and a priori gray matter, white matter, and cerebrospinal fluid (CSF) templates [10], based on T1-SPGR images of 52 healthy volunteers of both genders, aged between 18 and 50 years, who were investigated using the same MRI equipment as the OCD patients included in the current study, using the following imaging parameters: contiguous 1.56-mm coronal slices, echo time = 5.2 ms, repetition time = 21.7 ms, flip angle = 20◦ , 256 × 192 matrix. For the construction of our customized, study-specific template, the MRI data of those volunteers were, initially, spatially normalized to the standard SPM T1-MRI template, which is based on 152 healthy subjects from the Montreal Neurological Institute (MNI) [22]. This spatial normalization step was restricted to linear 12-parameter affine transformations to minimize deformations of the images to be averaged for the study-specific template. Spatially normalized images were then segmented into gray matter, white matter, and CSF compartments using a modified mixture model cluster analysis technique [12]. This used the MNI prior probability maps provided in the SPM2 package, overlaid onto the images to classify voxels in terms of their probability of belonging to a particular tissue class. The segmentation method also included an automated brain extraction procedure to remove non-brain tissue and an algorithm to correct for image intensity nonuniformity. Finally, images of the 52 normal volunteers were smoothed with an isotropic Gaussian kernel (8 mm full width at half maximum) and averaged to provide the gray matter, white matter, and CSF templates in stereotactic space. This filtering size is compatible with the degree of smoothing of the normal MNI MRI datasets averaged for the standard SPM T1-MRI template. Subsequently, processing of the pre- and postoperative original images from all OCD patients was carried out. This begun by image segmentation using the study-specific, a priori gray matter, white matter, and CSF templates that were created as described above. Extracted gray and white matter images were then spatially normalized to the customized gray and white matter templates

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Table 2 Differences in regional gray matter volumes between patients with obsessive-compulsive disorder (OCD) and 52 normal controls pre-surgery. Brain regiona

Coordinatesb

Direction of difference

Findings in regions predicted a priori Left Caudate Decreased Right Caudate Decreased

Peak Zc score

x

y

−8 8

10 18

Numberd of voxels

z 16 8

3.81 3.69

100 47

a

Numbers refer to approximate Brodmann areas (BA). Talairach and Tornoux coordinates of maximal statistical significance vortex in each region [36]. c Z scores for maximal statistical significance vortex in each region; maximal scores for all regions reported in the table were significant at the two-tailed p < 0.001 level, uncorrected for multiple comparisons. d Total number of contiguous voxels in each region that surpassed the initial cutoff of Z ≥ 3.09. b

with 12-parameter linear and nonlinear (7 × 9 × 7 basis functions) transformations. The parameters resulting from this spatial normalization step were then reapplied to the original structural images. These fully normalized images were then resliced with trilinear interpolation to a final voxel size of 2 mm × 2 mm × 2 mm and segmented into gray matter, white matter, and CSF partitions. Voxel values were modulated by the Jacobian determinants derived from spatial normalization, thus allowing brain structures that had their volumes reduced after spatial normalization to have their total counts decreased by an amount proportional to the degree of volume shrinkage [12]. Statistical analyses were performed on modulated images to test for between-group regional differences in the absolute volume of gray matter [12], rather than differences in gray matter concentration as in previous, non-optimized VBM investigations of OCD [18]. Finally, all the pre- and postoperative images of OCD patients, as well as the images of the 52 normal controls, were smoothed with a 12-mm Gaussian kernel. This filtering size has been commonly used in previous VBM studies evaluating the cortical regions and subcortical nuclei focused in the present study. Two sets of statistical analyses were performed. First, comparisons of gray matter volume were performed between OCD patients (preoperatively) and the 52 normal controls, using unpaired t-tests. Subsequently, direct comparisons of gray matter volume in OCD patients between the two time points (before and after the surgery) were conducted, using paired t-tests. Presence of significant clusters in a priori predicted regions was evaluated (OFC, anterior cingulate gyrus, caudate/putamen and thalamus). Clusters in these regions were considered statistically significant if surpassing the threshold of a voxelwise Z value ≥ 3.09 (corresponding to p < 0.001, uncorrected for multiple comparisons), and an extent threshold of five voxels. MNI gray matter voxel coordinates were transformed into the Talairach and Tournoux system [6]. Postoperative MRI scans showed that all radiosurgical targets were in accordance with the preoperative gamma planning. There was no evidence of cerebral edema, except for the typical perilesional edema which involves treatment targets when we individually compared pre and postoperative MRI images.

The between-group comparisons (OCD patients before surgery versus normal controls) showed clusters of significance in one of the regions predicted a priori to show abnormalities in the OCD group, namely the caudate nucleus (Table 2), but not in the OFC, anterior cingulate gyrus or thalamus. Comparing all the patients as a group, preoperatively versus postoperatively, regional postoperative increases in gray matter volumes were found in one of our predicted territories, specifically the right inferior frontal gyrus (BA47) within the OFC (Table 3). To our knowledge, this is the first structural magnetic resonance neuroimaging study that has investigated volumetric brain alterations following a radiosurgical procedure in OCD patients. In accordance with our a priori predictions, we found increased volume in the right inferior OFC area (BA47), a brain region implicated in OCD physiopathology. These results provide further support that gamma ventral capsulotomy is able to modulate the FSTC circuitry, thus promoting its therapeutic effects. Current theoretical models suggest that OCD is associated with functional and structural abnormalities in orbitofronto-striatal circuits. This circuitry has two pathways. One direct striatal-GPi/SNr pathway that inhibits the GPi/SNr output nuclei, and thus causes a disinhibition of the thalamus. The second is an indirect pathway from the striatum to the GPi and SNr that has a net inhibitory effect at the level of the thalamus. OCD symptomatology may be due to an imbalance between direct and indirect pathway tone, leading to excessive thalamo-cortical activation [32]. The radiosurgical procedure we employed targeted the anterior limb of the internal capsule bilaterally based on the hypothesis that interruption of interconnecting neurons between the OFC and the medial nuclei of the thalamus could produce favorable results in OCD patients. Evidence from neuroimaging studies of OCD indicate that abnormalities in the FSTC circuit may derive from differences within the white matter tracts. Cannistraro et. al [7] conducted a diffusion tensor magnetic resonance imaging study with OCD patients, which found differences in white matter architecture within the anterior limb of the internal capsule, as well as the cingulum. Of greatest relevance to the current study, they found that OCD patients exhibited increased fractional anisotropy in the left

Table 3 Differences in regional gray matter volumes between patients with obsessive-compulsive disorder (OCD) before and after surgery. Brain regiona

Findings in regions predicted a priori Right inferior/orbital frontal cortex (BA47) a

Direction of difference

Increased

Coordinatesb x

y

z

16

10

−26

Peak Zc score

Numberd of voxels

3.86

12

Numbers refer to approximate Brodmann areas (BA). b Talairach and Tornoux [36] coordinates of maximal statistical significance vortex in each region. c Z scores for maximal statistical significance vortex in each region; maximal scores for all regions reported in the table were significant at the two-tailed p < 0.001 level, uncorrected for multiple comparisons. d Total number of contiguous voxels in each region that surpassed the initial cutoff of Z ≥ 3.09.

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anterior limb of the internal capsule when compared to controls. Thus, gamma capsulotomy may have its therapeutic effects by virtue of disrupting abnormal white matter tracts, which in turn may lead to normalization of activity within the FSTC. Several previous studies of OCD have found structural abnormalities in the orbitofrontal region. There are VBM-based MRI studies that found increased OFC volumes in OCD subjects relative to asymptomatic controls [35,18,37,34]. A number of other investigations using region-of-interest (ROI) based methods showed reduced OFC volume bilaterally in OCD patients [8,17,2,3], and in one of the largest VBM studies to date, Pujol et al. [24] found that patients with OCD compared with controls showed significant absolute decrease in gray matter volume in the left medial OFC. Another recent VBM study, including drug naïve children with OCD, found increase right OFC volume [34]. Discrepancies in the direction of morphometric OFC abnormalities in association with OCD may reflect differences in the involvement of separate functional subdivisions of the OFC in the pathophysiology of distinct OCD symptom dimensions [37]. Nevertheless, the repeated findings of abnormal OFC volumes in MRI studies, together with the results of numerous functional imaging investigations, indicate that anatomical abnormalities of the OFC are the most replicable feature in the neuroimaging literature of OCD [35,17,8,2,3,34]. Although it is possible to speculate that an increasing in the inferior frontal gyrus volume observed in this study could be related to edema, it does not seem quite probable because this region is located far away from the radiosurgical target. The comparison of OCD patients before radiosurgery versus healthy individuals did not reveal decreased OFC volume in OCD patients at baseline. We cannot therefore argue that the increase in BA47 volume following radiosurgical treatment would represent reversal of an abnormal volumetric decrement before surgery. However, we did detect reduced preoperative volumes in the OCD group in the caudate nuclei. These nuclei are part of the FSTC involved in OCD. As mentioned above, fibers of the FSTC interconnecting the orbitofrontal cortex and the medial nuclei of the thalamus are interrupted by our surgical procedure in the internal capsule. Therefore, it is appealing to consider that the increased volume of the right inferior/orbital frontal cortex (BA47) observed in the current study following therapeutic capsulotomy, may represent a direct effect of the procedure in the circuitry related to the pathophysiology of OCD. The laterality of findings in prior volumetric studies of OCD have been relatively inconsistent [35,2,3,8,18,37]. There are multiple studies that show changes after effective treatment on functional imaging that are preferentially on the right side of the brain [4,31,33]. Of greatest relevance to the current study, Lippitz et al. [19] used MRI to investigate the relationship between lesion placement and patient outcome after thermal anterior capsulotomy and found more favorable results with right-sided lesions. Although that single study supports the hypothesis that the right hemisphere may play a more important role in therapeutic effects of capsulotomy, the participation of the left hemisphere has been also implicated [5]. Whereas the current study examined structural indices, it remains unclear how the observed volumetric changes in OFC relate to regional brain function. A few neuroimaging studies have investigated brain function after surgery for OCD. Rauch et al. [27] used positron emission tomography (PET) to evaluate refractory OCD patients treated with bilateral ventral capsular/ventral striatal deep brain stimulation (DBS) and found significant activation in the right medial OFC during acute stimulation. Also, this same group evaluated morphometric changes in subcortical structures following anterior cingulotomy in a group of OCD patients [28]. Significant

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volume reductions were predicted and found bilaterally within the caudate nucleus, but not in the amygdala, thalamus, lenticular nuclei, or hippocampus. This study has some noteworthy limitations. Our sample was small, comprising only five patients from a pilot study. However, a restrictive statistical analysis was used aiming to compensate for our small cohort. All patients had received various pharmacological treatment regimens previous to surgery and medication was maintained during follow-up whenever possible. A larger study currently underway based on the same methodology will include for the first time in psychiatric neurosurgery history a sham control group in a double blind fashion [21]. Finally, there were variations in the acquisition parameters for the T1-weighted SPGR images obtained in the OCD group. However, such differences did not affect the quality of images for morphometric analyses using VBM, and they were not systematic between pre- and postoperative scans. Nevertheless, it is arguable that such variability would have decreased the sensitivity of the current investigation to detect preoperative versus postoperative differences in the OCD group, and it is possible that greater postoperative gray matter volume changes would be detectable with stable MRI parameters and a larger OCD sample, making our findings more conservative. In conclusion, contemporary neuroimaging techniques coupled with modern neurosurgical procedures are powerful investigational tools that provide the potential to elucidate the pathophysiology of psychiatric disorders, and in turn the development of efficacious and safe treatment alternatives for otherwise treatment-refractory patients. This endeavor has been particularly fruitful in OCD. Gamma ventral capsulotomy is a promising intervention for severe, otherwise treatment-refractory OCD. In the current study we demonstrate increases in right inferior/OFC volume following this therapeutic intervention. Although our findings require replication using a larger patient sample, they are convergent with a growing body of evidence from the literature implicating involvement of the OFC and internal capsule in the pathophysiology of OCD as well as in its successful surgical treatment. Acknowledgements This study received financial support in the form of grants to Dr. Miguel from Fundac¸ão de Amparo à Pesquisa do Estado de São Paulo (FAPESP, Foundation for the Support of Research in the State of São Paulo; grant #1999/08560-6 and #2005/55628-08), and from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, National Counsel of Scientific and Technological Development; grant no. 305548/2005-0). Scott Rauch’ financial disclosures are as follows: he received funded research through MGH for Brain Stimulation Therapy from Medtronics, Inc.; funded research through MGH for VNS from Cyberonics.; and funded research through MGH on anxiolytic action from Cephalon. He also received honorariums from Novartis for consultation on emerging treatments; Neurogen for his participation as a consultant on emerging trends in anxiety associated with insomnia; Sepracor for his consultation on fear/conditioning/extinction and from Primedia for his participation in developing a CE activity. Scott Rauch is also a trustee at McLean Hospital and also serves on the Board at Massachusetts Society for Medical Research (MSMR) as well as on the National Foundation of Mental Health (NFMH) Board. We thank Dr. Steve Rasmussen, Navid Tahamtani, Dr. George Schahin, Prof Raul Marino Jr, Prof Valentim Gentil Filho, Prof José Alberto Del Porto, Dr. Rui Castello Branco, Dr. Carlos Longo, Cláudia Midori Yamao, Patrícia Yamashita, whose help was fundamental to the execution of this project.

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