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8/7/2019 artikel gamma ventral capsulotomy
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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
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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.
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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
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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.
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