artikel gamma ventral capsulotomy

Embed Size (px)

Citation preview

  • 8/7/2019 artikel gamma ventral capsulotomy

    1/5

  • 8/7/2019 artikel gamma ventral capsulotomy

    2/5

    J.P. Cecconi et al. / Neuroscience Letters 447 (2008) 138142 139

    Table 1

    Clinical and demographic characteristics of the sample.

    OCD patients

    N

    Male 2

    Female 3

    Laterality

    Right-handed 5Left-handed 0

    Age 35 (S.D. 11.07)

    Age 1st OC symptoms (discomfort) 8.8 (S.D. 2.28)

    Y-BOCS scores

    Pre-surgery 32.2 (S.D. 1.48)

    Post-surgery 20.20 (S.D. 11.54)

    Treatment

    Previous medications 14.6 (S.D. 3.71)

    Previous SRI trials 5.4 (S.D. 1.34)

    Previous CBT trials 1 (S.D. 0)

    Previous other psychotherapies 0.6 (S.D. 0.89)

    Hospitalizations 3 (S.D. 3.67)

    N, number of patients; , mean values; S.D., standard deviation; OC, obsessive-

    compulsive; OCD, obsessive-compulsive disorder; Y-BOCS, Yale-Brown Obsessive-

    Compulsive 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 willinduce structural changes in regions that are part of the FSTC cir-

    cuitry, namely the orbitofrontal cortex (OFC), anterior cingulate

    gyrus, caudate/putamen and mediodorsal thalamus.

    A detailed descriptionof 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 inde-pendent 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 So Paulo (FMUSP) (where patients were

    clinically assessed), and by Santa Paula Hospital (where radiosurg-

    eries 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, ful-

    filling OCD diagnostic criteria as defined by DSM-IV [1], assessed

    by Structured Clinical Interview for DSM-IV (SCID) [9]. They con-

    sisted 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 than5 years. Three patients hadnot completedcollege dueto obsessive-

    compulsive symptoms (OCS). Only one patient was working at the

    time of surgery. Four patients had lifetime comorbid axis I diag-

    noses, 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

    themhad comorbidaxis II diagnoses: onewith borderline personal-

    ity disorder and two withdependent personality disorder/avoidant

    personality disorder. For more detailed information about the sam-

    ple see Table 1 and Lopes [20].

    The severity of obsessive-compulsive symptoms was assessed

    by the Yale-Brown Obsessive-Compulsive Scale (YBOCS) at base-

    line and 2 weeks, and 1, 2, 3, 6, 9 and 12 months after surgery

    [13,14]. Clinical changes were prospectively evaluated by the Clin-

    ical Global Impression (CGI) scale and assessed in the same time

    intervals as the YBOCS. Response criteria was established as a min-

    imum 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 asgamma ventral capsulotomy [23,25,15]. Lesions were targeted at

    the most ventral portions of the anterior limb of the internal cap-

    sule andsomeof thedorsal portion of the Ventral Striatumadjacent

    to the ventral capsule, by means of converging collimated beams

    of gamma radiation from 201 60Co sources using 4 mm collima-

    tors. 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: 924 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 256192 or

    256256.

    Evaluation of brain volume changes after surgery was con-

    ducted by VBM using the SPM2 package (Wellcome Department

    of Imaging Neuroscience, London, United Kingdom) and executed

    in Matlab (Mathworks, Sherborn, Massachusetts). A standard tem-

    plate setwas created specifically forthe study, consisting of a mean

    T1-weighted image anda priorigray matter, white matter, andcere-brospinal fluid (CSF)templates [10], based on T1-SPGR imagesof 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, echotime = 5.2ms,repetition time= 21.7 ms, flip angle = 20, 256192 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 compartmentsusing 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 brainextraction 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 (8mm full width at half maximum) andaveraged to provide

    the gray matter, white matter, and CSF templates in stereotactic

    space. This filtering size is compatible with the degree of smooth-

    ing of the normal MNI MRI datasets averaged for the standard SPM

    T1-MRI template.

    Subsequently, processing of the pre- and postoperative origi-

    nal 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

  • 8/7/2019 artikel gamma ventral capsulotomy

    3/5

    140 J.P. Cecconi et al. / Neuroscience Letters 447 (2008) 138142

    Table 2

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

    Brain regiona Direction of diffe re nce Coordin atesb Peak Zc score Numberd of voxels

    x y z

    Findings in regions predicted a priori

    Left Caudate Decreased 8 10 16 3.81 100

    Right Caudate Decreased 8 18 8 3.69 47

    a Numbers refer to approximate Brodmann areas (BA).b Talairach and Tornoux coordinates of maximal statistical significance vortex in each region [36].c Zscores 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 Z3.09.

    with 12-parameter linear and nonlinear (797 basis functions)

    transformations. The parameters resulting from this spatial nor-

    malization step were then reapplied to the original structural

    images. These fully normalized images were then resliced with tri-

    linear interpolation to a final voxel size of 2 mm2 mm2 mm

    and segmented into gray matter, white matter, and CSF partitions.

    Voxel values were modulated by the Jacobiandeterminants derived

    from spatial normalization, thus allowing brain structures that had

    their volumes reduced after spatial normalization to have theirtotal 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, aswell as the images of the 52normalcon-

    trols, 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, compar-

    isons of gray matter volume were performedbetweenOCD patients

    (preoperatively) and the 52 normal controls, usingunpaired t-tests.Subsequently, direct comparisons of gray matter volume in OCD

    patients between the twotime points (before and afterthe surgery)

    were conducted, using paired t-tests. Presence of significant clus-ters in a priori predicted regions was evaluated (OFC, anteriorcingulate gyrus, caudate/putamen and thalamus). Clusters in these

    regions were considered statistically significant if surpassing the

    threshold of a voxelwise Zvalue3.09 (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 tar-

    gets were in accordance with the preoperative gamma planning.

    There was no evidence of cerebral edema, except for the typical

    perilesional edemawhichinvolvestreatment targetswhen weindi-vidually 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 OCDgroup, 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 reso-

    nance 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 vol-

    ume in the right inferior OFC area (BA47),a brainregion 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 cir-

    cuits. 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 theGPi andSNr that has a netinhibitory effectat 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 bilaterallybasedon thehypothesisthat

    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 cin-

    gulum. Of greatest relevance to the current study, they found thatOCD 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 Direction of difference Coordinatesb Peak Zc score Numberd of voxels

    x y z

    Findings in regions predicted a priori

    Right inferior/orbital frontal cortex (BA47) Increased 16 10 26 3.86 12

    a Numbers refer to approximate Brodmann areas (BA).b Talairach and Tornoux [36] coordinates of maximal statistical significance vortex in each region.c Zscores 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 Z3.09.

  • 8/7/2019 artikel gamma ventral capsulotomy

    4/5

    J.P. Cecconi et al. / Neuroscience Letters 447 (2008) 138142 141

    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 abnor-

    malities 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 inves-tigations 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.

    Anotherrecent VBM study,including drugnave childrenwith OCD,

    found increase right OFC volume [34]. Discrepancies in the direc-

    tion 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 thatanatom-

    ical 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 observedin thisstudy 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 repre-

    sent 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 inter-

    connecting the orbitofrontal cortex and the medial nuclei of the

    thalamus are interrupted by our surgical procedure in the internalcapsule. 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 rep-

    resent a direct effect of the procedure in the circuitry related to the

    pathophysiology of OCD.

    Thelateralityof 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 capsulotomyand found

    more favorable results with right-sided lesions. Although that sin-gle 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

    remainsunclearhow theobservedvolumetricchanges in OFCrelate

    to regional brain function. A few neuroimaging studies have inves-

    tigated brain function after surgery for OCD. Rauch et al. [27] used

    positron emission tomography (PET) to evaluate refractory OCD

    patientstreatedwith bilateralventral capsular/ventralstriatal deep

    brain stimulation (DBS) and found significant activation in the right

    medial OFC during acute stimulation. Also, this same group eval-

    uated morphometric changes in subcortical structures following

    anterior cingulotomy in a group of OCD patients [28]. Significant

    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 pharmacolog-

    ical treatment regimens previous to surgery and medication wasmaintained during follow-up whenever possible. A larger study

    currently underway based on the same methodology will include

    forthe first time in psychiatricneurosurgeryhistorya 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 pre-

    operative versus postoperative differences in the OCDgroup, 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 inves-

    tigational tools that provide the potential to elucidate the

    pathophysiology of psychiatric disorders, and in turn the develop-

    ment of efficacious and safe treatment alternatives for otherwise

    treatment-refractory patients. This endeavor has been particu-

    larly 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 find-

    ings 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 treat-

    ment.

    Acknowledgements

    This study received financial support in the form of grants to

    Dr. Miguel from Fundaco de Amparo Pesquisa do Estado de SoPaulo (FAPESP, Foundation for theSupport of Research in theState of

    So Paulo; grant #1999/08560-6 and #2005/55628-08), and from

    the Conselho Nacional de Desenvolvimento Cientfico e Tecnolgico(CNPq, National Counsel of Scientific and Technological Develop-

    ment; 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 anxi-olytic 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 anxi-

    ety associated with insomnia; Sepracor for his consultation on

    fear/conditioning/extinction and from Primedia for his participa-

    tion 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 Jos

    Alberto Del Porto, Dr. Rui Castello Branco, Dr. Carlos Longo, Cludia

    Midori Yamao, Patrcia Yamashita, whose help was fundamental to

    the execution of this project.

  • 8/7/2019 artikel gamma ventral capsulotomy

    5/5

    142 J.P. Cecconi et al. / Neuroscience Letters 447 (2008) 138142

    We also acknowledge the contribution of Maristela S. Schaufel-

    berger, Paulo R. Menezes, Marcia Scazufca and other researchers of

    the BrazilianFirst Contact Psychosisteam (funded by the Wellcome

    Trust, UK) in the selection and evaluation of the healthy volun-

    teers whose imaging data was used to create the MRI templates

    employed in the current study.

    References

    [1] Association(AP),Diagnostic andStatisticalManual of Mental Disorders, 4thed.,American Psychiatric Press, 1994, 886 p.

    [2] M. Atmaca, B.H. Yildirim, B.H. Ozdemir, B.A. Aydin, A.E. Tezcan, A.S. Ozler,Volumetric MRI assessment of brain regions in patients with refractoryobsessive-compulsive disorder, Prog. Neuropsychopharmacol. Biol. Psychiatry30 (2006) 10511057.

    [3] M. Atmaca, H. Yildirim, H. Ozdemir, E. Tezcan, A.K. Poyraz, Volumetric MRIstudy of key brain regions implicated in obsessive-compulsive disorder, Prog.Neuropsychopharmacol. Biol. Psychiatry 31 (2007) 4652.

    [4] L.R. Baxter Jr., J.M. Schwartz, K.S. Bergman, M.P. Szuba, B.H. Guze, J.C. Mazz-iotta, A. Alazraki,C.E. Selin, H.K.Ferng,P. Munford,M.E. Phelps,Caudate glucosemetabolic rate changes with both drug and behavior therapy for obsessive-compulsive disorder, Arch. Gen. Psychiatry 49 (1992) 6816 89.

    [5] C. Benkelfat, T.E. Nordahl, W.E. Semple, A.C. King, D.L. Murphy, R.M. Cohen,Local cerebral glucose metabolic rates in obsessive-compulsive disorder.Patients treated with clomipramine, Arch. Gen. Psychiatry 47 (1990) 840848.

    [6] M. Brett, I.S. Johnsrude, A.M. Owen, The problem of functional localization inthe human brain, Nat. Rev. Neurosci. 3 (2002) 243249.

    [7] P.A. Cannistraro, N. Makris, J.D. Howard, M.M. Wedig, S.M. Hodge, S. Wilhelm,D.N. Kennedy, S.L. Rauch, A diffusion tensor imaging study of white matter inobsessive-compulsive disorder, Depress Anxiety (200 6).

    [8] J.S. Choi, D.H. Kang,J.J. Kim, T.H.Ha, J.M. Lee, T.Youn,I.Y. Kim, S.I. Kim, J.S. Kwon,Left anterior subregion of orbitofrontal cortex volume reduction and impairedorganizational strategies in obsessive-compulsive disorder, J. Psychiatr. Res.38(2004) 193199.

    [9] M. First, R. Spitzer, M. Gibbon, J. Williams, Users Guide for the StructuredClinical Interview for DSM-IV Axis I Disorders, Clinician Version (SCID-CV),American Psychiatric Press, 1997.

    [10] K.J. Friston, A.P. Holmes, K. Worsley, J.B. Poline, C.D. Frith, R.S.J. Frackowiak,Statistic parametric maps in functional imaging: a general linear approach,Hum. Brain Mapp. (1995) 189210.

    [11] A.R. Gilbert, G.J. Moore, M.S. Keshavan, L.A. Paulson, V. Narula, F.P. Mac Mas-ter, C.M. Stewart, D.R. Rosenberg, Decrease in thalamic volumes of pediatricpatients with obsessive-compulsive disorder who are taking paroxetine, Arch.

    Gen. Psychiatry 57 (2000) 449456.[12] C.D. Good, I.S.Johnsrude,J. Ashburner, R.N.Henson,K.J. Friston,R.S. Frackowiak,A voxel-basedmorphometric studyof ageing in465 normal adulthumanbrains,Neuroimage 14 (2001) 2136.

    [13] W.K. Goodman,L.H. Price, S.A.Rasmussen, C. Mazure, P. Delgado, G.R.Heninger,D.S. Charney, The Yale-Brown Obsessive Compulsive Scale. II. Validity, Arch.Gen. Psychiatry 46 (1989) 10121016.

    [14] W.K. Goodman, L.H. Price, S.A. R asmussen, C. Mazure, R.L. Fleischmann, C.L.Hill, G.R. Heninger, D.S. Charney, The Yale-Brown Obsessive Compulsive Scale.I. Development, use,and reliability,Arch. Gen.Psychiatry 46 (1989) 10061011.

    [15] B.D. Greenberg, L.H. Price, S.L. Rauch, G. Friehs, G. Noren, D. Malone, L.L.Carpenter, A.R. Rezai, S.A. Rasmussen, Neurosurgery for intractable obsessive-compulsive disorder and depression: critical issues, Neurosurg. Clin. N. Am. 14(2003) 199212.

    [16] W.Guy,Clinical Global Impression.ECDEU Assessment Manual forPsychophar-macology, Revised National Institute of Mental Health, 1976.

    [17] D.H. Kang, J.J. Kim, J.S. Choi, Y.I. Kim, C.W. Kim, T. Youn, M.H. Han, K.H.Chang, J.S.Kwon,Volumetricinvestigationof thefrontal-subcortical circuitryinpatients with obsessive-compulsive disorder, J. Neuropsychiatry Clin. Neurosci.

    16 (2004) 342349.[18] J.J. Kim, M.C. Lee, J. Kim, I.Y. Kim, S.I. Kim, M.H. Han, K.H. Chang,J.S. Kwon,Grey

    matter abnormalities in obsessive-compulsive disorder: statistical parametricmapping of segmentedmagneticresonance images, Br. J. Psychiatry 179 (2001)330334.

    [19] B.E. Lippitz, P. Mindus, B.A. Meyerson, L. Kihlstrom, C. Lindquist, Lesion topog-raphy and outcome after thermocapsulotomy or gamma knife capsulotomyfor obsessive-compulsive disorder: relevance of the right hemisphere, Neuro-surgery 44 (1999) 452458, 458460; discussion.

    [20] A. Lopes, Ventral Capsular and Ventral Striatal Gamma Capsulotomy in Obses-sive Compulsive Disorder: Initial Assessment of Efficacy and Profile of AdverseEvents,Department and Instituteof Psychiatry,Universityof SoPaulo MedicalSchool, So Paulo, 20 07, p. 277.

    [21] LopesAC, Greenberg BD,Norn G,CanterasMM,BusattoGF,MathisME, Taub A,DAlcante CC, Hoexter MQ, Gouvea FS, Cecconi JP, Gentil AF, Ferro YA, Fuentes

    D, Castro CC, Leite CC, Salvajoli JV, Duran FLS, Rasmussen S, Miguel EC. Treat-mentof resistant obsessive-compulsive disorderwith VentralCapsular/VentralStriatal Gammacapsulotomy: A pilotprospective study. J Neuropsychiatry ClinNeurosci. (2008), in press.

    [22] J.C. Mazziotta, A.W. Toga, A. Evans, P. Fox, J. Lancaster, A probabilistic atlas ofthe human brain: theory and rationale for its development. The InternationalConsortium for Brain Mapping (ICBM), Neuroimage 2 (1995) 89101.

    [23] P. Mindus, S.A. Rasmussen, C. Lindquist,Neurosurgical treatmentfor refractoryobsessive-compulsive disorder: implications for understanding frontal lobefunction, J. Neuropsychiatry Clin. Neurosci. 6 (1994) 467477.

    [24] J. Pujol,C. Soriano-Mas,P. Alonso, N. Cardoner, J.M. Menchon, J. Deus, J. Vallejo,Mapping structural brain alterations in obsessive-compulsive disorder, Arch.Gen. Psychiatry 61 (2004) 720730.

    [25] S. Rasmussen, B. Greenberg, P. Mindus, G. Friehs, G. Noren, Neurosurgicalapproaches to intractable obsessive-compulsive disorder, CNS Spectrosc. 5(2000) 2334.

    [26] S.L. Rauch, Neuroimaging and neurocircuitry models pertaining to the neuro-surgical treatment of psychiatric disorders, Neurosurg. Clin. N. Am. 14 (2003)

    213223, viiviii.[27] S.L. Rauch, D.D. Dougherty, D. Malone, A. Rezai, G. Friehs, A.J. Fischman, N.M.Alpert, S.N.Haber,P.H. Stypulkowski,M.T.Rise, S.A. Rasmussen, B.D.Greenberg,A functional neuroimaging investigation of deep brain stimulation in patientswith obsessive-compulsive disorder, J. Neurosurg. 104 (2006) 558565.

    [28] S.L. Rauch,H. Kim, N. Makris, G.R. Cosgrove,E.H.Cassem,C.R.Savage,B.H.Price,A.A. Nierenberg, D. Shera, L. Baer, B. Buchbinder, V.S. Caviness Jr., M.A. Jenike,D.N. Kennedy, Volume reduction in the caudate nucleus following stereotacticplacement of lesions in the anterior cingulate cortex in humans: a morpho-metric magnetic resonance imaging study, J. Neurosurg. 93 (2000) 10191025.

    [29] D.R. Rosenberg, N.R. Benazon, A. Gilbert, A. Sullivan, G.J. Moore, Thalamicvolume in pediatric obsessive-compulsive disorder patients before and aftercognitive behavioral therapy, Biol. Psychiatry 48 (2000) 294300.

    [30] D.R. Rosenberg, F.P. MacMaster, M.S. Keshavan, K.D. Fitzgerald, C.M. Stew-art, G.J. Moore, Decrease in caudate glutamatergic concentrations in pediatricobsessive-compulsive disorder patients taking paroxetine, J. Am. Acad. ChildAdolesc. Psychiatry 39 (2000) 10961103.

    [31] S. Saxena, A.L. Brody, K.M. Maidment, J.J. Dunkin, M. Colgan, S. Alborzian, M.E.

    Phelps,L.R. Baxter Jr., Localizedorbitofrontaland subcorticalmetabolicchangesand predictors of response to paroxetine treatment in obsessive-compulsivedisorder, Neuropsychopharmacology 21 (1999) 683693.

    [32] S. Saxena, A.L. Brody, J.M. Schwartz, L.R. Baxter, Neuroimaging and frontal-subcortical circuitry in obsessive-compulsive disorder, Br. J. Psychiatry Suppl.(1998) 2637.

    [33] J.M.Schwartz, P.W. Stoessel, L.R. Baxter Jr., K.M. Martin, M.E. Phelps, Systematicchanges in cerebral glucose metabolic rate after successful behavior modifi-cation treatment of obsessive-compulsive disorder, Arch. Gen. Psychiatry 53(1996) 109113.

    [34] P.R.Szeszko, C. Christian,F.Macmaster,T.Lencz, Y.Mirza,S.P. Taormina, P. Easter,M. Rose, G.A.Michalopoulou,D.R. Rosenberg, Gray matter structural alterationsin psychotropic drug-naive pediatric obsessive-compulsive disorder: an opti-mized voxel-based morphometry study, Am. J. Psychiatry (20 08).

    [35] P.R. Szeszko, D. Robinson, J.M. Alvir, R.M. Bilder, T. Lencz, M. Ashtari, H. Wu,B. Bogerts, Orbital frontal and amygdala volume reductions in obsessive-compulsive disorder, Arch. Gen. Psychiatry 56 (1999) 913919.

    [36] J. Talairach, P. Tornoux,Co-Planar StereotaxicAtlas of the HumanBrain,ThiemeMedical Publishers, 1988.

    [37] A.A.ValenteJr.,E.C.Miguel, C.C. Castro, E.AmaroJr., F.L. Duran,C.A. Buchpiguel,X. Chitnis, P.K. McGuire, G.F. Busatto, Regional gray matter abnormalities inobsessive-compulsive disorder: a voxel-based morphometry study, Biol. Psy-chiatry 58 (2005) 479487.