Effects of Sertraline on Brain Connectivity in Adolescents With OCD (Obsessive-Compulsive Disorder)
Phase: PHASE1
Conditions: OCD
Sponsor: University of Minnesota

 
 
 
 
 
 
 
 
 
 
 
 
Effects of Sertraline on Brain Connectivity in Adolescents with OCD 
 
NCT02797808 
 
10/10/2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
PI: Gail A. Bernstein, M.D. 
Specific Aims: 
Obsessive-compulsive disorder (OCD) is a debilitating anxiety disorder that afflicts 1-3% of youth,1,2  often 
causing incapacitation by obsessions and compulsions. Although effective treatments are available, not all 
patients respond.3   This highlights the need for research to develop new treatments.  The groundwork for such 
developments will require neurobiological research that will (a) further elucidate the neural mechanisms of 
disease, (b) characterize the specific changes that underlie response to established treatments, and (c) 
demonstrate the specific neurobiology in patients who do not respond to established treatments. Previous 
research has suggested that dysregulation of the frontal-striatal-thalamic circuitry (FSTC) is associated with 
OCD.4 Functional magnetic resonance imaging (fMRI) studies in children and adults with OCD compared to 
controls have shown decreased activation in FSTC regions during tasks involving cognitive control.5-13 Also, 
emerging research in OCD using resting-state functional magnetic resonance imaging (R-fMRI)14-16 and 
diffusion imaging (DI) has begun to identify alterations in connectivity (i.e., connections within networks) within 
FSTC and points to alterations in connectivity between the frontal cortex and striatum (caudate and putamen). 
In our pilot study of 15 adolescents with OCD (mostly medicated) and 12 controls, we examined 22 specific 
connections within FSTC (11 per hemisphere) using R-fMRI. Findings demonstrated that in comparison with 
controls, adolescents with OCD show significantly lower connectivity and high effect sizes in 11 links. Lower 
functional connectivity in 10 of these segments  was associated with significantly higher  severity on the 
Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS).17 Furthermore, we examined how specific 
dimensions of OCD would map onto this circuitry. We found that bilaterally, for cortical-subcortical 
connections, the ordering/repeating dimension correlates with orbitofrontal cortex (OFC)-subcortical 
connections, the hoarding dimension correlates with rostral anterior cingulate cortex (ACC)-subcortical 
connections, and the forbidden thoughts dimension correlates with  caudal  ACC-subcortical  connections. 
These data were obtained using advances in brain imaging acquisition and analysis that were developed at the 
University of Minnesota (UMN) for the NIH-funded Human Connectome Project (HCP). We have also begun to 
show that our imaging tools can reliably and accurately measure structural connectivity within deep FSTC 
white matter connections of interest. Earlier imaging research had limitations (low spatial and temporal 
resolution, limited ability to resolve crossing white matter fibers, and OFC signal drop) that can be addressed 
with advances at our site. Since our pilot study included mostly medicated OCD adolescents, it is unclear to 
what extent the findings reflect effects of disease, treatment, or both. For example, it may be that prior to 
medication treatment, group differences are even larger than what we detected, and are then mitigated by 
treatment. Furthermore, treatment may alter some parts of FSTC more than others and key changes may 
underlie treatment response, which are not seen in non-responders. 
Selective serotonin reuptake inhibitors (SSRIs) are the pharmacological treatment of choice for pediatric 
OCD.18 Twelve weeks of sertraline, an SSRI, was found to be moderately effective in decreasing OCD 
symptoms in the NIMH-funded Pediatric OCD Treatment Study (POTS).3 There is some fMRI evidence that 
SSRIs reduce brain abnormalities in patients with OCD.19 We propose to comprehensively evaluate FSTC 
using a multi-modal neuroimaging approach [R-fMRI and high angular resolution diffusion imaging (HARDI)] in 
25 unmedicated adolescents with OCD and 25 matched healthy controls to confirm our pilot findings at 
baseline in unmedicated adolescents with OCD. We will examine how treatment with sertraline for 12 weeks 
impacts FSTC in this OCD sample. 
Specific Aim #1: To examine FSTC using advanced multi-modal imaging techniques (R-fMRI, HARDI) in 
25 medication-free youths with OCD (ages 8-17) in comparison with 25 matched healthy controls. 
Hypotheses: (A) Based on our pilot data, youths with OCD will show lower functional connectivity in FSTC 
at baseline when compared with controls, and , lower functional connectivity in FSTC will correlate with 
greater severity on CY-BOCS. (B) Youths with OCD will also show abnormalities in structural connectivity in 
FSTC at baseline when compared with controls, and structural and functional connectivity will be related. (C) 
We will explore relations between OCD dimensions and functional connectivity measures, and predict that the 
repeating/ordering dimension will correlate with OFC connections, hoarding will correlate with rostral ACC 
connections, and forbidden thoughts will correlate with caudal ACC connections. 
Specific Aim #2 (Exploratory): To investigate how sertraline impacts functional connectivity in FSTC in 
adolescents with OCD. Hypothesis: After 12 weeks of sertraline treatment, functional connectivity measures 
within FSTC for the OCD group will (on average) increase compared to baseline and will no longer be 

significantly different when compared with controls. Non-responders may show a different pattern (i.e. failure to 
show these changes). 

A. Background and Significance: OCD is a debilitating anxiety disorder with a prevalence rate of 1% to 
3% in youth.1,2 Children and adolescents with OCD are often incapacitated by obsessions and compulsions. 
Up to 80% of OCD cases may begin in childhood or adolescence.20 Studying youths with OCD (rather than 
adults) offers the advantage of identifying brain differences early in development when confounding factors of 
chronicity of symptoms and interventions (i.e., psychotropic medications and cognitive-behavioral therapy 
[CBT]) are less likely to be present. FSTC in OCD: Neuroimaging research has implicated FSTC in OCD. 
This network connects neurons in the frontal cortex, striatum (i.e., caudate, putamen), thalamus, and back to 
the frontal cortex.4,21 See basic diagram of FSTC in Figure 1. Task fMRI studies demonstrate that participants 
with OCD compared to matched healthy controls exhibit lower levels of activation of brain regions in FSTC 
regions.5-13 A review of neuroimaging studies concluded that results from a variety of imaging techniques 
converge to implicate abnormalities in FSTC in pediatric OCD.22 Theory suggests that abnormalities in the 
FSTC result in obsessional thoughts and compulsive behaviors.4 
Developmental 
Framework 
for 
Pediatric OCD: There are clinical and 
neuroimaging 
differences 
between 
childhood- 
and 
adult-onset 
OCD. 
Pediatric OCD has male predominance 
and is commonly comorbid with tic 
disorders (30%),23 whereas adult-onset 
is 
predominantly 
female 
and 
often 
comorbid with depression.22 Childhood 
OCD is viewed as a neurodevelopmental 
subtype of OCD based on similarity of its 
symptoms to developmentally normal 
childhood rituals,24,25 and comorbidity 
with 
Tourette’s 
disorder 
(a 
neurodevelopmental 
condition). 
It 
is 
thought to be related to prefrontal-striatal 
abnormalities 
that 
are 
neurodevelopmentally  
mediated.26 
Striatal structures mature earlier than 
prefrontal   regions   which   continue   to 
mature into early adulthood.27 During development, white matter changes are primarily due to increases in 
myelination which fine-tune the connectivity between prefrontal and subcortical regions.27 Meta-analysis of 
fMRI studies show involvement of OFC and caudate in adults with OCD,28 whereas pediatric OCD studies 
indicate involvement of other basal ganglia areas (e.g., putamen) and thalamus.29-31 Medication-naïve youth 
with OCD compared with controls demonstrate greater ACC gray matter.30 These differences highlight the 
importance of utilizing a developmental approach to studying FSTC in pediatric OCD. 
Advanced Neuroimaging Technologies for Connectivity: Recent advances in neuroimaging that 
assess brain “connectivity” allow for a sophisticated understanding of neural networks. Several studies have 
demonstrated significant differences in connectivity in the corticostriatal link of this circuit in adults14-16 and in 
youths with OCD.14 We have identified specific connections within this network that show significantly lower 
functional connectivity in adolescents with OCD compared with controls (see Pilot Data). We plan to evaluate 
brain connectivity in adolescents using two advanced, noninvasive technologies. First, R-fMRI measures the 
covariance of blood-oxygen-level-dependent (BOLD) signals between brain areas (“functional connectivity”).32 
Second, HARDI33 is a rapidly developing technology that includes a number of alternative approaches to 
inferring fiber orientations in white matter. Unlike traditional diffusion tensor imaging (DTI),34 HARDI 
techniques can resolve complex fiber architecture within a single voxel and permit assessment of 
microstructural integrity of white matter fiber tracts,33 indexing the anatomical strength of connections between 
brain areas (“structural connectivity”). Recently-developed acquisition schemes at UMN35 enable rapid 
collection of both types of connectivity data to reduce long acquisition times and minimize motion artifacts. 
Neuroimaging Studies Evaluating Connectivity in OCD: Functional Connectivity: Harrison and 
colleagues15 found reduced functional connectivity between the lateral prefrontal cortex and dorsal striatum 
and between the ventral striatum and the midbrain ventral tegmental area in 21 adults with OCD (mostly 
medicated) and 21 matched healthy controls.  Sakai and associates16 used R-fMRI to study 20 medication-free 

adults with OCD and 23 matched healthy controls. Significantly greater positive functional connectivity was 
found between regions of the frontal cortex and the ventral striatum in OCD participants. Fitzgerald et al. 
examined connectivity between OCD and controls in four developmental age groups [children 8-12 years (n = 
11), adolescents 13-17 (n = 18), young adults 18-25 (n = 18), and older adults 26-40 (n = 13)].14 Half of the 
OCD participants were on psychotropic medications. Across all age groups, OCD patients compared with 
controls showed increased connectivity between ventral medial frontal cortex and dorsal striatum. However, 
children with OCD showed reduced connectivity between rostral ACC and dorsal striatum (associated with 
greater OCD severity), and also between dorsal ACC and medial dorsal thalamus. No studies have reported 
R-fMRI results on medication-free youths with OCD. Structural Connectivity:  A handful of studies have used 
DI to examine white matter connectivity in OCD, with somewhat mixed findings. The first DI study in OCD 
found that adult patients had lower fractional anisotropy (FA) in the white matter of several cortical regions 
including ACC, parietal cortex, posterior cingulate gyrus, and occipital cortex. No areas of significantly higher 
FA were found in patients compared with healthy controls.36 Similarly, another study found significantly 
increased FA in the genu and body of corpus callosum and white matter of right superior frontal gyrus and 
corpus callosum in OCD compared with control subjects, and no areas  of significantly decreased FA.37 
However, one study found reduced fronto-callosal fiber integrity in unmedicated OCD adults versus controls.38 
No DI studies have focused on FSTC connections, and none have been conducted in pediatric OCD. 
SSRI Effects in OCD: Treatment-naïve adults with OCD (n = 13) exhibited smaller putamen volume which 
normalized following 12 weeks of SSRI treatment.39 Treatment-naïve children with OCD (N = 21) showed 
greater thalamic volume which normalized after 12 weeks of an SSRI.31 No studies were found of SSRI effects 
on connectivity in pediatric OCD. SSRIs have been demonstrated to be efficacious in reducing pediatric OCD 
symptoms in multiple randomized placebo-controlled trials.18,40  In POTS, 12 weeks of sertraline was effective 
in reducing OCD symptoms (ES = 0.67).3 Sertraline was selected because it was used in POTS, is FDA 
approved for pediatric OCD, and Dr. Bernstein has years of experience treating OCD youths with sertraline. 
B. Innovation: Given that OCD may have a neurodevelopmental etiology and that the networks of 
interest in OCD undergo considerable refinement throughout childhood and adolescence, examination of OCD 
circuitry in youth is critical. Furthermore, studying unmedicated youth allows for identifying brain differences 
without the confound of current pharmacological treatment. The proposed study is cutting edge because we 
will use innovative advanced data acquisition methods for fMRI and HARDI that have been developed at the 
UMN as part of the NIH-funded HCP. These tools allow us to collect data with much higher temporal and 
spatial resolution than has been standard. These advantages are important for OCD, a disease that involves a 
complex circuitry involving deep brain areas and orbitofrontal regions that have been difficult to study using 
standard techniques. We will look at change in functional connectivity measures in OCD  participants 
compared with controls after OCD participants receive 12 weeks of sertraline. This innovative approach will 
allow us to examine sertraline treatment effects on neural circuitry in OCD. To our knowledge, this has never 
been done and will represent an important advance. We hope to identify specific connections in the FSTC that 
normalize with response to SSRI treatment and identify links that do not change in treatment refractory 
participants. We will also explore OCD dimensions and their relations with functional connectivity links to 
identify possible differences in FSTC in OCD subtypes. 
C. 
Pilot Data: Functional and Structural Connectivity in Adolescents with OCD Seventeen 
adolescents with OCD and 13 controls were scanned using a 32 channel head coil on the 3T Human 
Connectome scanner (http://www.humanconnectome.org/about/project/MR-hardware.html). Three scans were 
eliminated (1 subject terminated the scan early and 2 were excluded during the “scrubbing”  process.41  
Anatomic Acquisition: Whole brain anatomical data with T1 contrast were acquired in 5 minutes using an MP- 
RAGE sequence with 1 mm isotropic resolution (TR=2530 ms, TE=3.52 ms, TI=1100 ms, flip  angle=7 
degrees). Processing and Analysis: The T1 images were processed using FreeSurfer. Regions of interest 
(ROIs) for each structure within FSTC were identified and later aligned to both functional and diffusion images. 
R-fMRI: Acquisitions: Resting state BOLD data were collected using a novel multi-band EPI pulse 
sequence that allows for the simultaneous acquisition of multiple slices.35,42 Resting scans lasting 12 minutes 
were acquired (TR=1.15 seconds, TE=30 ms, voxel size=2 mm isotropic, 60 slices, multiband=4, echo spacing 
0.57ms, 600 volumes) to assess functional connectivity. The subjects were instructed to close their eyes, 
remain awake, and not think about anything in particular. A field map scan with identical voxel parameters to 
the BOLD acquisition was also acquired to allow for correction of geometric distortion. Processing and 
Analysis:  FSL tools were used to conduct standard preprocessing steps, including skull removal, distortion 

correction, motion correction, and registration to MNI space. MELODIC was applied to each dataset to identify 
and remove noise components using fsl regfilt. To further remove confound due to transient head motion, we 
utilized the “scrubbing” procedure advocated by Power and colleagues,41 computing their frame-wise 
displacement (FD) and derivative variance (DVARS) metrics. Volumes with FD>0.5mm and/or DVARS>8 were 
excluded from analysis along with the previous volume and the two following volumes. Two subjects had more 
than 33% of volumes removed with “scrubbing” and were eliminated from analyses. There was no significant 
difference between the number of volumes excluded from remaining OCD subjects (n = 15, mean = 68.5, SD = 
70.2) and control subjects (n = 12, mean = 60.5, SD = 70.7) (F = .16, p = 0.76). Twelve FreeSurfer ROIs from 
the FSTC circuit, implicated in OCD, were selected for further investigation. Frontal regions included bilateral 
OFC, rostral ACC, and caudal ACC. Subcortical ROIs were bilateral caudate, putamen, and thalamus. The 
mean time series within each ROI was computed from the scrubbed data and cross-correlated. These r values 
were converted to z scores using the fisher transformation. The resulting z scores were used to investigate 
group differences in functional connectivity and in correlation analyses with measures of OCD severity (CY- 
BOCS) and impairment [Child Obsessive-Compulsive Impact Scale-Revised (COIS-R)].43 
Results: There were no significant differences between OCD and control groups on IQ, age, gender, SES, 
or ethnicity. Adolescents with OCD showed lower functional connectivity compared with controls on 19 of 22 
connectivity comparisons (11 per hemisphere) within FSTC. Eleven of 22 connectivity comparisons were 
significant at p < .05 (Table 1). Cohen’s d effect sizes for significant group differences were large (0.82 to 
1.10). Our results are consistent with findings of Fitzgerald et al.14 that show significantly lower functional 
connectivity between ACC and striatum and between ACC and thalamus in children with OCD compared with 
controls. Correlations between age and connectivity measures in the OCD sample were not significant. Using 
data from OCD participants, the CY-BOCS (OCD severity) demonstrated significant negative correlations with 
10 of 11 connectivity segments. Parent COIS-R and child COIS-R (OCD functional impairment) showed 
significant negative correlations with 5 of 11 and 3 of 11 of the connectivity measures, respectively. 
 
Table 1.  Functional Connectivity Measures 
 
Mean Scores (SD) 
Region 
OCD 
(n = 15) 
Control 
(n = 12) 
P 
Cohen’s 
D 
CY-BOCS 
r, p 
Parent 
COIS-R 
r, p 
Child 
COIS-R 
r, p 
R. OFC – R. Caudate 
0.31 (0.14) 
0.46 (0.23) 
.040 
0.82 
--- 
--- 
-.41, p=.04 
R. Caudal ACC – R. Caudate 
0.54 (0.16) 
0.71 (0.21) 
.023 
0.93 
-.44, p=.02 
--- 
-.41, p=.04 
R. Rostral ACC – R. Caudate 
0.44 (0.09) 
0.61 (0.23) 
.013 
0.99 
-.48, p=.01 
-.41, p=.05 
-.48, p=.02 
R. Caudal ACC – R. Putamen 
0.56 (0.18) 
0.77 (0.24) 
.017 
0.98 
-.46, p=.02 
-.43, p=.04 
--- 
L. Caudal ACC – L. Putamen 
0.57 (0.16) 
0.76 (0.25) 
.024 
0.91 
-.41, p=.04 
-.44, p=.03 
--- 
R. Caudal ACC – R. Thalamus 
0.60 (0.21) 
0.81 (0.18) 
.010 
1.10 
-.48, p=.01 
--- 
--- 
L. Caudal ACC – L. Thalamus 
0.59 (0.19) 
0.75 (0.16) 
.030 
0.90 
-.41, p=.04 
-.60, p<.01 
--- 
R. Rostral ACC – R. Thalamus 
0.49 (0.17) 
0.65 (0.20) 
.042 
0.82 
-.42, p=.03 
-.48, p=.02 
--- 
R. Caudate – R. Thalamus 
0.60 (0.16) 
0.81 (0.22) 
.010 
1.07 
-.51, p<.01 
--- 
--- 
R. Putamen – R. Thalamus 
0.57 (0.19) 
0.75 (0.20) 
.026 
0.92 
-.42, p=.03 
--- 
--- 
L. Putamen – L. Thalamus 
0.55 (0.17) 
0.72 (0.19) 
.020 
0.95 
-.44, p=.02 
--- 
--- 
 
HARDI: Acquisition: DI data were collected using a novel multi-band EPI pulse sequence that allows for 
the simultaneous acquisition of multiple slices.35,42 DI scans with left-right and right-left phase encoding were 
acquired on each subject (128 volumes with b=3000 and 9 volumes with b=0, TR=2300ms, TE=70ms, 2mm 
isotropic voxel, 60 slices, MB = 3, 5 minutes each). Preprocessing: Data were corrected for eddy currents and 
the skull was removed. FSL’s topup program was used to correct the DI for geometric distortions. The 
corrected data were then submitted to FSL’s bedpost and probabilistic tractography was then conducted 
between ROIs using FSL’s probtractx. 

Results:  We demonstrate rudimentary examples of tracking within FSTC in one subject in Figures 2-4. 
Refinements to the tracking procedure are currently underway prior to group analyses. 
 
 
 
 
 
Pediatric OCD Dimensions and Functional Connectivity: We completed an exploratory factor analysis 
(EFA) of CY-BOCS in 77 youths with OCD that revealed 4 OCD dimensions (58% of variance): 
ordering/repeating, contamination/cleaning, hoarding, and forbidden thoughts. Dimensional structure was 
similar to previous factor analyses of CY-BOCS.44-47  Based on the CY-BOCS Checklist, adolescents with OCD 
(n = 15) were given a score on each of 4 dimensions identified in EFA. Dimensional scores were the sum of 
the number of items currently endorsed in each of the CY-BOCS categories that loaded most strongly on the 
given dimension. Significant correlations were found between (1) ordering/repeating dimension scores and 3 
OFC-subcortical connections, (2) hoarding scores and 3 rostral ACC-subcortical connections, and (3) 
forbidden thoughts scores and 4 caudal ACC-subcortical connections. We plan to explore relations between 
OCD dimensions and functional connectivity in FSTC in this project. 
D. Approach: The aims of this protocol are to examine connectivity in FSTC using R-fMRI and HARDI in 
medication-free adolescents with OCD in comparison to controls and to investigate how sertraline impacts 
FSTC connectivity. Our pilot studies focus on functional connectivity. Participants: We will include 25 youths 
(males and females) with OCD ages 8-17 years and 25 age- and gender-matched healthy controls with 
no psychiatric disorders and without a family history of OCD. Inclusion Criteria for OCD participants: (1) OCD 
as the primary DSM-IV diagnosis based on the Anxiety Disorders Interview Schedule (ADIS) for DSM-IV, Child 
Version,48 and (2)  CY-BOCS49   score of greater than 15.  Exclusion  Criteria:  (1)  lifetime  diagnosis  of 
bipolar disorder, schizophrenia, or substance abuse/dependence on ADIS, (2) IQ < 80 on Wechsler 
Abbreviated Scales of Intelligence (WASI),50 (3) positive urine drug screen, (4) MRI-incompatible features (e.g., 
metal implants, claustrophobia), (5) current or recent trial of psychotropic medication (within the past 4 
weeks or past 6 weeks for fluoxetine), (6) non-response in > 2 SSRI trials of adequate dose/duration, (7) 
positive pregnancy test, (8) history of seizure disorder or serious head injury. 
Rationale for 
Inclusion/Exclusion Criteria: OCD participants will have CY-BOCS score above 15 because greater 
OCD severity correlated with lower functional connectivity in our pilot data. With CY-BOCS score above 
15, all participants will have moderate or severe OCD. While I originally suggested excluding MDD and 
ADHD due to connectivity differences in youth with MDD and ADHD that might confound the differences due 
to OCD, these comorbidities are so common that it is extremely difficult to find subjects with “pure” OCD. 
A more heterogeneous sample with respect to comorbidity will be more generalizable to all youth with OCD. 
Further, recently published neuroimaging studies of youth with OCD have not excluded participants with lifetime 
MDD, ADHD, or autism (e.g., Weber AM, Soreni N, & Noseworthy MD, 2014, Progress in Neuro-
Psychopharmacology & Biological Psychiatry, 53:129-136). I plan to include participants with lifetime 
diagnoses of ADHD, MDD, and autism/pervasive developmental disorder. 
Recruitment: For our pilot study, we scanned 30 teenagers (17 OCD and 13 controls) in 6 months. Of 30 
scans, one was excluded because the subject could not complete the scan and 2 were excluded due to 
excessive motion artifacts41 (10% excluded). In addition, we will factor in an attrition rate of 10% during 
sertraline treatment. Therefore, to have 40 sets of scans for full data analyses, we will plan to scan 50 
participants.  Participants will be recruited from Dr. Bernstein’s Child and Adolescent Anxiety Disorders Clinic 
Figure 2: Caudate-ACC tract 
Blue: Left caudate 
Red: Left ACC 
Pink: White matter tract 
Figure 3: Caudate- 
pallidum tract 
Blue: Left caudate 
Red: Left pallidum 
Pink: White matter 
tract 
Figure 4: Caudate- 
pallidum 
Blue: Left caudate 
Red: Left ACC 
Pink: White 
matter tract 

that has evaluated and treated over 800 youths with anxiety disorders over a 9-year period. Review of 24 
months of Anxiety Clinic records indicate approximately 9 new anxiety cases per month, of which 2 cases per 
month have OCD.  Approximately 50% of new cases with OCD are medication-free.  Therefore, approximately 
1 case per month or 12 new cases per year are diagnosed with OCD and are medication-free. To meet our 
necessary enrollment of 1-2 OCD cases per month, we will e-mail recruitment information to several hundred 
mental health providers and pediatricians in the Minneapolis/St. Paul metropolitan area. We will also use local 
newspapers, Craig’s List, and Facebook which were successful methods of recruitment in our pilot study. 
Additional participants will be recruited via posters in the community and in clinics. To facilitate enrollment of 
minorities, we will actively recruit from Northpoint Clinic and Children’s Hospitals and Clinics of Minnesota that 
serve underrepresented youths.  See letters of support. 
Procedure: After written informed consent and assent are obtained, a 2-3 hour diagnostic assessment 
Including Interviews and rating scales as described in the Assessment Instruments section will be administered 
by a trained interviewer with a master’s degree or above. Participants meeting inclusion/exclusion criteria 
based on diagnostic assessment will undergo neuroimaging at the CMRR within the following week. 
Assessment instruments and neuroimaging will be obtained at baseline and 12 weeks later in all participants 
(OCD and controls). Families will be offered $30 for completion of the diagnostic assessment and $45 for 
imaging studies at baseline and again at 12 weeks. Before the scans, participants will (1) provide a urine 
sample for drug screening and (for females who have begun their menstrual periods) pregnancy testing; and 
(2) complete a screening questionnaire to ensure MRI safety (e.g., to exclude subjects with metal implants). 
After baseline assessment and scans, OCD participants will receive 12 weeks of treatment with sertraline. See 
Medication Management section. 
Assessment Instruments: (1) ADIS, semistructured interview, will confirm OCD diagnosis and define 
comorbid diagnoses. Psychometric properties are good to excellent.51-53 (2) CY-BOCS and CY-BOCS 
Checklist, clinician-rated semistructured instrument to assess types and severity of obsessions and 
compulsions. Psychometric properties are satisfactory.17,54 (3) Tic Questionnaire, assesses the presence and 
severity of motor and vocal tics. (4) CDI-II, evaluates depressive symptoms in children and self-report 
scale to document severity of depression symptoms. (5)  Tanner Staging will be obtained for participants 
using drawings of Tanner pubertal stages.56,57 (6) COIS-R43 measures functional impairment due to OCD and 
has good psychometric properties.43 (7) WASI provides an abbreviated measure of cognitive functioning to 
ensure participants have IQs > 79. (8) Family Interview for Genetic Studies (FIGS)58 documents family 
history of OCD. (9) MASC-II, assesses the presence of symptoms related to anxiety disorders in youth aged 
8 to 19 years. (10) Side Effects Checklist will be completed at medication management appointments.  (11) 
Services Questionnaire will be completed at the final assessment in order to assess the presence of any 
therapy or medications sought by participants throughout the course of the study. 
Washout Period for Participants on Psychiatric Medications: For participants on psychiatric 
medications for OCD (SSRI or clomipramine) who have not had an adequate response to treatment (i.e., CY- 
BOCS score of greater than 15), Dr. Bernstein will recommend a safe schedule to gradually lower the 
medication dose and then stop it. The washout period (no medication) will be 4 weeks for most psychiatric 
medications and 6 weeks for fluoxetine. During the period of lowering and stopping the medication for OCD, 
there is a potential risk of discontinuation symptoms (for example, headaches or flu-like symptoms) which 
should be prevented by the gradual lowering of medication dose. There is also a risk of OCD symptoms 
worsening during the washout. If this occurs, Dr. Bernstein may recommend withdrawal from the study and re- 
starting the original psychiatric medication. 
Medication Management: After baseline assessment and scans, OCD participants will receive sertraline 
which will be titrated using a flexible dosing schedule and individualized based on maximizing efficacy and 
minimizing side effects. As in POTS, we will aim to achieve target dose by week 6 of the 12-week trial. Target 
dose will be 100-200 mg/day, based on age and weight of the participant, given as a single dose. Sessions 
will be 30 minutes every week for the first 4 weeks then every other week with Dr. Bernstein who may provide 
support and encouragement but no CBT. Sessions will include vital signs, monitoring of side effects with a 
checklist, and safety evaluation. Human Subjects section includes discussion of potential side effects and their 
management. Compliance will be monitored with pill counts. Sertraline level will be obtained at week 12 to 
further document compliance with taking sertraline. Independent evaluators (blind to study hypotheses) will 
obtain the CY-BOCS with parent and teenager together at baseline, week 6, and week 12. 

No concurrent therapies (e.g., CBT, family therapy) are permitted during medication trial. At the end of 12 
weeks, participants can choose to stay on sertraline with follow up in Dr. Bernstein’s Anxiety Clinic or see 
another physician (we will provide a referral letter), or taper off the medication. Non- or partial-responders can 
be referred to the Anxiety Clinic for CBT and/or crosstaper to another SSRI or clomipramine. 
Neuroimaging Data Acquisition and Procedures:  MRIs will be obtained at baseline and 12 weeks later 
in all participants (OCD and controls). The MRIs will take place at the CMRR using a standard Siemens 3T 
TIM Trio because the Human Connectome scanner (used for pilot data collection) has moved to Washington 
University. The HCP multi-band fMRI and DI sequences are available for the TIM; fMRI and HARDI data 
acquisition for this new study will use the multiband sequence,35,59 advances to which have recently been 
developed in CMRR for the HCP. The major advantage of the new sequences includes substantially 
accelerating whole brain image acquisition times.  For fMRI acquisitions, TRs for comparable acquisitions are 
1.24 seconds for the Trio, 1.15 seconds for the Human Connectome Scanner, and 4 seconds for the Trio 
without multi-band acquisition. We are currently running subjects using these modified sequences (i.e., Cullen 
1R21 MH094558) and obtaining excellent quality data of similar caliber to the HCP study and our pilot data. 
To ease anxiety, participants will have the option of practicing in the mock scanner, will be able to 
communicate with staff between acquisition periods, and will listen to music during parts of the scan. 
First, a high-resolution structural image will be collected (parameters as in Pilot Data). These data will be 
processed using FreeSurfer to yield ROIs within FSTC. A field map will be collected to correct for geometric 
distortions in the fMRI scans.  R-fMRI:  Subjects will be instructed to keep eyes open instead of closed, which 
is becoming more standard in the field. EPI images with whole brain coverage will be collected with TR=1.32 
seconds, multiband factor=4, voxel size=2 mm isotropic resolution, TE=30 ms, 64 contiguous AC-PC aligned 
axial slices (12 minutes). Such dramatic reduction of TR in comparison to standard TRs (4 sec) can 
substantially improve statistical significance of resting networks.35 HARDI: Diffusion encoding will  be 
performed along 128 non-collinear directions (single shell) with single shot EPI, multiband factor=3, 
TR=3800ms, TE=90ms, 2 mm isotropic resolution, 106 matrix, 212mm FOV, 66 contiguous slices, b 
value=3000, total acquisition time 9 min per scan (one PE left-to-right and one PE right-to-left). The number of 
directions and the high b value here are optimal for enhancing the capacity for resolution of crossing fibers. In 
addition, during part of the scan, the participant will be asked to complete a task.  The participant will be shown 
a set of three numbers on a projector, and be asked to press one of three buttons depending on the numbers 
he or she sees. This scan will provide information about areas of the brain that are activated in OCD versus 
control participants during the task. 
If the quality of the baseline or 12-week scan is poor due to motion artifacts from small head movements, 
the participant and his/her parents will be asked to consider returning for a repeat scan. This is optional. 
Imaging Data Analysis: Specific Aim #1:  Functional and Structural Connectivity Analysis:  The objective 
of the neuroimaging data analysis is to test the hypothesis that youth with OCD have abnormal functional and 
structural connectivity within FSTC. Functional Connectivity: First, pre-processing steps will be conducted as 
described in Pilot Data, to remove effects due to physiological noise and motion and to correct for geometric 
distortions. Freesurfer seed regions (medial OFC, rostral ACC, caudal ACC, caudate, putamen, and thalamus) 
will be aligned to the fMRI data. Mean time series for spontaneous fluctuations in BOLD signal of ROI will be 
calculated, correlations will be determined between these time series, and correlation values will be normalized 
using an r-z transformation. Normalized values are then used for group comparison using age as a covariate. 
Analysis of covariance (ANCOVA) will be applied to the data. Correlations will be calculated to examine the 
relations between functional connectivity in FSTC and severity on CY-BOCS.  Structural Connectivity: The 
structural connectivity analysis will be designed to supplement the functional connectivity analysis by 
investigating identical connections. The same Freesurfer ROIs as above will be aligned to the data. Following 
the methods of Lenglet and colleagues60 at UMN who have mapped human basal ganglia and thalamic 
connectome in healthy adults, we will delineate FSTC tracts in all participants with FSL software. We will first 
estimate fiber orientations with a maximum number of 3 crossing fibers using bedpostx and then probabilistic 
tractography (probtrackx) will be used to estimate the connectivity distribution of pathways within FSTC. We 
will then use connectivity measures (i.e., FA, mean diffusivity, and radial diffusivity within tracts, and number of 
samples passing from seed to target) to examine effects of group, accounting for the size of the seed region for 
each individual. ANCOVA will be applied to the baseline connectivity data to test the main effect of group 
using age as a covariate. Correlation coefficients will be calculated to examine the  relations  between 
functional and structural connectivity. Relations between OCD dimensions and functional connectivity will also 
be explored using correlations. Specific Aim #2: Effects of Sertraline on Connectivity: Change in connectivity 

data from baseline to 12 weeks will be compared between OCD and control groups using repeated-measures 
ANCOVA with group as between-subject main effect, time as within-subject main effect, group x time 
interaction effect and covariate effects of age. Group differences in connectivity at 12 weeks will be examined 
using t- tests. An OCD responder will be defined as a participant with a decrease of 35% in total CY-BOCS 
score from baseline to 12 weeks because the average decrease in OCD symptoms with SSRI treatment is 30- 
40%.40 Secondary repeated measures ANCOVA will be conducted including responder groups as a between- 
subject main effect to explore how change over time differs between these groups. Finally, baseline 
connectivity differences will be compared between OCD responders and non-responders using t-tests and chi- 
square tests to explore connectivity differences that are associated with response to sertraline in youth with 
OCD (i.e. response predictors). 
Power Analyses/Sample Size:  Specific Aim #1:  The study design is powered to accomplish Specific Aim 
#1. (a) Functional Connectivity: Pilot data from 15 OCD adolescents and 12 controls provided effect sizes for 
the functional connectivity power calculation. Effect sizes for significant group differences between OCD and 
controls ranged from 0.82 and 1.10 (Table 1). Thus, the effect size of 0.82 can be considered a conservative 
estimate or “upper bound” of sample size needed, while the effect size of 1.10 can be considered a “lower 
bound” estimate of sample size needed. For the upper bound estimate, a sample size of n = 25 per group is 
needed to detect significant group differences with power of 80% at alpha = .05. Using the lower bound 
estimate, we would require a sample size of n = 15 per group to detect significant group differences with power 
of 80% at alpha =.05. (b) Structural Connectivity: Feasibility of finding significant group differences in 
structural connectivity with the proposed sample size is based on a study with smaller sample size (14 
depressed adolescents and 14 healthy controls).61,62 Depressed adolescents had lower FA in the fiber tract of 
interest (tract connecting sgACC to amygdala) (p = 0.03, effect size d = 0.89), standard error of difference = 
0.01125. Based on this, minimum difference required to show a difference in FA for the OCD sample using a 
similar approach (tractography to delineate a desired tract and measuring FA) would be at least 0.2205 units of 
FA. Therefore, we will require a sample of 20 per group to have power of 80% to detect a group difference at 
alpha =0.05. Specific Aim #2 (Exploratory) will generate data (means, SDs and test statistics) that will inform 
effect sizes to calculate power and sample size for a R01 study. In the larger trial, impact of sertraline 
treatment on the abnormalities in functional and structural connectivity will be formally tested in youths with 
OCD. 

Risks to Human Subjects: 
 
Human Subjects Involvement and Characteristics: 
 
Twenty-five participants will meet criteria for OCD on the ADIS.  We will also enroll 25 healthy controls without 
a family history of OCD who are matched on age and gender to participants with OCD. All participants (OCD 
and controls) will have two scanning sessions, one at baseline and the second 12 weeks later. OCD 
participants will be treated with 12 weeks of sertraline, an SSRI medication. 
 
Inclusion Criteria: 
 
1. Ages 8-17 years. 
2. Female or male. 
3. Meets DSM-IV criteria for OCD as the primary diagnosis based on ADIS. 
4. CY-BOCS score greater than 15. 
 
Exclusion Criteria: 
 
1. Lifetime   diagnosis of bipolar disorder, schizophrenia, or substance abuse/dependence on ADIS. 
2. IQ < 80 on WASI. 
3. Positive urine drug screen. 
4. History of seizure disorder or significant head injury. 
5. MRI-incompatible features (e.g., metal implants other than dental fillings, claustrophobia). 
6. Fluoxetine treatment within the past 6 weeks or treatment with a different psychotropic drug within the 
past 4 weeks. 
7. Non-response to 2 previous SSRI trials of adequate dosage and duration. 
8. Positive pregnancy test. 
9. Presence of any psychiatric disorder on ADIS (for control subjects only). 
10. Family history of OCD (for control subjects only). 
11. Females with OCD who are unwilling to use an acceptable method of birth control if they are sexually 
active will be excluded. 
 
Sources of Research Materials: 
 
Research materials obtained from human participants include clinical interviews and rating scales. In addition, 
neuroimaging studies (HARDI and fMRI) will be obtained. These materials will be collected for the purposes of 
the research study. 
 
Potential Risks: 
 
Potential risks of participating in the study include: 
 
1. Issues related to confidentiality. 
2. Gathering of sensitive information during interviews and on rating scales. 
3. Anxiety about having MRI scans. 
4. Sertraline side effects. 
 
SSRIs are the pharmacological treatment of choice for pediatric OCD.18 They are the first-line standard 
medication treatment for OCD in children and adolescents. Sertraline, an SSRI, is generally well tolerated,; 
however, side effects can occur. Potential side effects of sertraline include stomachaches, insomnia, 
headaches, and sexual side effects. In addition, there are psychiatric side effects including motor activation, 
suicidal ideation/suicidal behaviors, and precipitation of manic symptoms. All antidepressant (including 
sertraline) have an FDA black box warning for children, adolescents, and young adults.  The black box warning 
is for the rare possibility of suicidal ideation or suicidal behavior while on an antidepressant. This is based on a 

meta-analysis of 24 short-term, placebo-controlled randomized trials of antidepressants for treatment of 
pediatric anxiety disorders (including OCD) or depressive disorders. The meta-analysis included >4,500 
children and adolescents and showed a 2% risk of suicidal ideation or behavior on placebo and 4% on 
antidepressants.63   There were no completed suicides in the 24 studies. 
 
Adequacy of Protection Against Risks: 
 
Recruitment Methods and Informed Consent: 
 
Recruitment of participants with OCD will be through the Principal Investigator’s Child and Adolescent Anxiety 
Disorders Clinic at the University of Minnesota Medical School. Dr. Bernstein and her colleagues have 
evaluated and treated over 800 youths with anxiety disorders over a 9-year period. Referrals to the Clinic are 
from school personnel, pediatricians, child psychiatrists, and psychologists. We have strong connections to 
school personnel, community primary care physicians, and mental health practitioners. Thus, recruitment for 
the proposed study will be through well-established referral sources. OCD is one of the most common anxiety 
diagnoses in our Clinic. Approximately 2 new OCD patients are evaluated in the Clinic each month including 
approximately one who is unmedicated. 
 
In addition, we have e-mail and address lists for several hundred pediatricians and mental health providers in 
the Minneapolis/St. Paul metropolitan area that will be used for recruiting children with OCD. Families with a 
child with OCD and healthy controls will also be recruited through flyers on bulletin boards in the community 
and in clinics, radio advertisements, and advertisements in newspapers. In our pilot study, we used 
advertising in Facebook which was an effective method of recruiting. A description of the study will be posted 
on the OCD Twin Cities Chapter and International OCD websites. 
 
If the potential participant is being seen in the Child and Adolescent Anxiety Disorders Clinic, the parents and 
child will be asked if they would be interested in being included in the study at the conclusion of their Clinic 
visit. Documentation will be presented at that time, and parents will have time to ask any questions about the 
proposed study. Parents will be encouraged to take documentation materials with them to consider their 
child's participation, and will be allowed to bring back or mail back the signed documentation. If the potential 
participant is a healthy adolescent, interested parents will be asked to contact research personnel through ads 
in local newspapers or Facebook, or via flyers posted on bulletin boards. 
 
Written informed consent from parents and written informed assent from adolescents will be obtained. Gail 
Bernstein, MD, PI, Kathryn Cullen, MD, Co-I, and Alexandra Zagoloff, Ph.D., Co-PI will be obtaining 
informed consent from participants and their parents. The project coordinator will also be obtaining informed 
consent after undergoing training from the PI in obtaining informed consent. 
 
Protections Against Risk: 
 
1. Issues Related to Confidentiality: All study staff will complete the U of MN HIPAA training. All data will 
be identified with subject number and will be stored in locked file cabinets with access only to designated 
study personnel. Other than research staff directly interfacing with participants (e.g., independent 
evaluators), only PI and Co-I will have access to subject data and subject identities. This approach is 
very likely to be effective in achieving protection of confidentiality. 
2. Gathering of Sensitive Information: The study personnel will be trained to be sensitive to the early signs 
of distress, to provide support, and to allow the participant the opportunity to stop at any time should 
he/she become uncomfortable or have questions.  The PI or Co-I will always be available for consultation 
if necessary and the subject will be allowed to withdraw from the study at any time. 
3. Anxiety about Scanning: The MRIs will take place at the CMRR, where a mock scanner is available. The 
mock scanner is a practice scanner that can be used to prepare the participants for the MRI. Participants 
who are anxious about the MRI will have the option of practicing in the mock scanner. They will be able 
to communicate with the scanners throughout the scanning session. The participants will have the 
opportunity to listen to music for relaxation during most parts of the scan. In the event that they are too 
uncomfortable with the procedure, the subjects will not be scanned. 

4. Sertraline Side Effects: All participants and their parents will receive psychoeducation about sertraline 
and the potential risks and benefits. They will be encouraged to ask questions and will be engaged in a 
dialogue about sertraline and potential risks and benefits. Participants will be seen for 30 minutes every 
week for the first 4 weeks then every other week by Dr. Bernstein for medication management. Weight 
and vital signs will be obtained at each visit. There is no need for EKGs, laboratory studies, and blood 
levels when treating with sertraline on a short-term basis. Side Effects Checklist will be administered by 
Dr. Bernstein at each appointment. Dr. Bernstein will assess for suicidal ideation at each appointment. 
To minimize the potential for side effects, treatment will be initiated with a low dose of sertraline followed 
by systematic increases based on side effects and clinical response. We will use a flexible dosing 
schedule which is individualized based on minimizing side effects and maximizing efficacy. We aim to 
reach target dose by week 6. Minor side effects may be managed by dose adjustments. If any any 
adverse medication reactions occur, the sertraline will be withdrawn and Dr. Bernstein will follow the 
patient closely until the adverse reaction remits. At the end of the 12 weeks, participants can choose to 
stay on sertraline and follow up in Dr. Bernstein’s Anxiety Clinic for medication management or with 
another physician (we will provide a referral letter), or taper off the medication. Non- or  partial- 
responders can be referred to Dr. Bernstein’s Clinic for CBT and/or crosstaper to another SSRI or 
clomipramine. If the family would like to taper off the medication, Dr. Bernstein will supervise a gradual 
taper down in order to avoid withdrawal effects and will monitor for potential recurrence of OCD 
symptoms. Dr. Bernstein has years of experience treating children and adolescents with sertraline. She 
teaches and supervises residents and fellows who are prescribing this medication in the Child and 
Adolescent Anxiety Clinic at the UMN. 
 
In order to protect against risk of harm to youths, several steps will be taken. Consent will be obtained 
from parent(s) and assent from adolescents. Youths and parents will be allowed to discontinue 
participation at any time. We believe that adequate protections against risks are in place as documented 
earlier in this section. 
 
Potential Benefits of the Proposed Research to Human Subjects and Others: 
 
The results of the psychiatric interviews and rating scales can be shared with families. This information could 
be beneficial in the care of children and adolescents with OCD. The findings will advance knowledge in the 
area of neuroimaging for pediatric OCD. In addition, the study will contribute to the knowledge about 
underlying mechanisms of obsessions and compulsions and site of action of SSRIs. 
 
Participants with OCD will receive 12 weeks of treatment with sertraline. They will attend medication 
management appointments with a child and adolescent psychiatrist. Potential benefits include relief of OCD 
symptoms from the sertraline. 
 
 
Importance of Knowledge to be Gained: 
 
If our proposed model of dysfunction in FSTC is supported by the neuroimaging findings, this will represent an 
important step in the effort to understand the neurobiology of pediatric OCD. We hope to delineate specific 
neural changes that underline response to sertraline. The findings of this study will inform future studies about 
the neurobiology of OCD and treatment response to SSRI medications. This study will yield information 
regarding the connectivity in the FSTC related to OCD and will move the field closer to understanding the 
etiology of pediatric OCD. 
 
 
 
 
 
Data and Safety Monitoring Plan: 

Data and safety monitoring will take place continuously throughout the course of the study. The PI will be 
responsible for coordinating and overseeing all data and safety monitoring efforts which include (but are not 
limited to) supervising all recruitment efforts; evaluating risks versus benefits for participants; and monitoring 
the quality, validity, and reliability of data gathered. Some data monitoring efforts will be delegated to research 
staff; however, the PI will oversee all monitoring activities through regularly scheduled meetings and review of 
data summaries. The PI has selected two University of Minnesota faculty members (Andrew Barnes, M.D., 
Department of Pediatrics, and Suma Jacob, M.D., Ph.D., Department of Psychiatry) uninvolved with the 
present study to serve on a Data and Safety Monitoring Board. The Board will review the data and safety of 
the study approximately once per year. 
 
All data collected will remain confidential and will be in file folders which will be stored in locked file cabinets in 
a locked room. File folders will contain only subject identification numbers. Only the PI, Dr. Cullen, Co-I, and 
Project Coordinator will have access to the master file containing names, identification numbers, and 
addresses. The master file will be kept separate from the data collection instruments and from the data file on 
the computer system protected by password. Information given to persons other than project personnel will 
occur only with written parental consent and for the specific purpose documented on the release of information 
form. The imaging data will be completely de-identified. All imaging data will be stored in the CMRR which is 
highly secure.  All processing will be conducted using the Minnesota Supercomputing Institute resources. 
 
Potential Adverse Events: 
 
The possibility of the following adverse events is low. We will monitor for: 
 
1. Suicidal or homicidal ideation or behavior. 
2. Worsening of clinical condition of children with OCD (i.e., symptoms become severe so that assessment 
for possible psychiatric hospitalization is needed). 
3. Suspected child abuse. 
 
 
Protocols for Managing Adverse Events: 
 
Project staff (including project coordinator and independent evaluators) will be trained by Drs. Bernstein and 
Cullen about how to assess for suicidal and homicidal ideation, how to identify deterioration of an adolescent’s 
clinical condition, and what clinical situations raise concern about suspected child abuse or neglect: 
 
1. If a child is identified as suicidal or homicidal, this will be reported to Dr. Bernstein, PI, or Dr. Cullen, 
Co-I, who will evaluate the patient and provide psychiatric care as needed. If suicidal ideation or 
suicidal behavior is determined to be secondary to sertraline, the sertraline will be discontinued and 
psychiatric care will be provided by the PI or Co-I. If necessary, the adolescent will be referred to the 
Emergency Room, or Behavioral Evaluation Center at the University of Minnesota Medical Center – 
Fairview, as deemed appropriate, based on clinical information. 
If evaluation results in 
recommendation for inpatient hospitalization, this can be arranged at the Child and Adolescent 
Psychiatry Inpatient Unit at the University of Minnesota Medical Center – Fairview. 
 
2. If worsening of clinical condition is  noted by a research staff member, it will be reported to Dr. 
Bernstein, PI or Dr. Cullen, Co-I. They will provide psychiatric care as needed and/or facilitate the child 
being evaluated in a local mental health clinic, the Emergency Room, or Behavioral Evaluation Center 
at the University of Minnesota Medical Center – Fairview, as deemed appropriate, based on clinical 
information. If the evaluator recommends inpatient hospitalization, admission to the Child and 
Adolescent Psychiatric Unit at the University of Minnesota Medical Center – Fairview can be arranged. 
 
3. If child abuse is suspected, the research staff member will immediately report to Dr. Bernstein or Dr. 
Cullen who will then assist the staff member in reporting to Child Protection and/or police immediately. 

Parents will be given office phone numbers for the Project Coordinator, Dr. Bernstein and Dr. Cullen to call 
during office hours in case any of the clinical situations described above occur and they will be given Dr. 
Bernstein’s cell phone number for after hours and weekends. 
 
Reporting Adverse Events: 
 
All serious adverse events (e.g., psychiatric hospitalization) that occur during the study will be reported within 
24 hours by the PI to the Institutional Review Board (IRB) at the University of Minnesota. Yearly written reports 
regarding data and safety monitoring will be provided to the University of Minnesota IRB and the NIMH Project 
Officer. 

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