Obsessive Compulsive Disorder
Conditions
Keywords
OCD, Functional Magnetic Resonance Imaging (fMRI), Magnetic Resonance Imaging (MRI)
Brief summary
The purpose of this study is to examine the brain functioning of children and adolescent with OCD before and after treatment with Exposure and Response Prevention (EXRP) therapy.
Detailed description
The capacity to coordinate thoughts and actions to execute goal-directed behaviors (cognitive control) and the capacity to anticipate, respond to, and learn from reward (reward processing) are key processes for human behavior. Dysfunction in these processes has been hypothesized to contribute to repetitive thoughts and behaviors in many disorders, including obsessive-compulsive disorder (OCD), Tourette Syndrome (TS), and eating disorders. The investigators will use multimodal imaging to investigate neural circuits that support cognitive control and reward processing, using pediatric OCD as a model system. The short-term goal is to clarify how circuit-based abnormalities contribute to repetitive thoughts/behaviors; these data will inform future trans-diagnostic studies. The long-term goal is to identify control and reward circuit-abnormalities as targets for new trans-diagnostic treatments.
Interventions
BEHAVIORALCBT treatment for OCD based on Exposure & Response Prevention (EX/RP) and when indicated medication treatment
CBT treatment consisted of 12-16 hour-long sessions. For exceptional cases not showing clinical improvement after six CBT treatment sessions, complementary pharmacological treatment (SSRI) was offered as part of our treatment protocol. CBT for OCD involves gradually exposing patients to anxiety provoking stimuli while having patients refrain from engaging in compulsive rituals and/or avoidance behaviors. There are three major components of CBT treatment for OCD, specifically: (1) exposure to anxiety provoking stimuli, (2) response prevention, and (3) cognitive techniques intended to decrease anxiety during the exposure and response prevention processes.
Sponsors
National Institute of Mental Health (NIMH)
New York State Psychiatric Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
5 Years to 17 Years
Healthy volunteers
Yes
Inclusion criteria
Patient Inclusion Criteria: * Participants must be 5-17 at the time of consent * Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) Diagnosis of OCD as the principal problem * Not on psychotropic medication and not receiving current psychotherapy for OCD * Written informed assent by the participants (8 and older) and consent by the parent * Participants and a parent/guardian must be able to read and understand English Patient
Exclusion criteria
* DSM-IV current diagnosis of major depressive disorder, attention-deficit hyperactivity disorder, Tourette's/Tic Disorder, or substance/alcohol abuse * DSM-IV lifetime diagnosis of psychotic disorder, bipolar disorder, eating disorder, pervasive developmental disorder, or substance/alcohol abuse * Active suicidal ideation * Females who are pregnant or nursing * Major medical or neurological problems * Presence of metallic device or dental braces * IQ\<80 * A current or past diagnosis of pediatric autoimmune neuropsychiatric disorders associated with streptococcus (PANDAS) * Individuals who are currently receiving CBT, other forms of psychotherapy, or psychotropic medications * Individuals who have received a full course of CBT in the past * A positive pregnancy test * Positive urine screen for illicit drugs * Inability of participant or parent/guardian to read or understand English Healthy Control Inclusion Criteria: * Participants must be 5-17 at the time of consent * Written informed assent by the participants (8 and older) and consent by the parent * Participants and a parent/guardian must be able to read and understand English Healthy Control
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Brain Activation Associated With the Resolution of Cognitive Conflict | single time point: baseline | Task-based functional magnetic resonance imaging (fMRI) will be acquired from children and adolescents diagnosed with OCD and healthy comparison subjects (HCs) during their performance of a Simon Spatial Compatibility Task. In each trial, participants are presented with a leftward or rightward pointing arrow that is either congruent or incongruent with their position (left or right) on the screen. Participants are instructed to respond as quickly and accurately as possible to the direction in which the arrow was pointing by pressing a button on a response box using the index finger for left and the middle finger for right. Brain activation during the resolution of cognitive conflict is computed by contrasting blood-oxygen-level-dependent (BOLD) signal during Incongruent versus Congruent trials. BOLD signal is expressed in arbitrary units (A.U.s). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Functional Connectivity | single time point: Baseline | Functional magnetic resonance imaging (fMRI) will be acquired from children and adolescents diagnosed with OCD and healthy comparison subjects (HCs) at baseline and after approximately 16-20 weeks (i.e., post-treatment for the participants with OCD). The whole brain is divided in 352 brain regions comprised of 333 cortical surface (Gordon et al. Cereb Cortex 2016;26:288-303) and 19 subcortical (Fischl et al. Neuron 2002;53:341-55) parcellated regions. FC-strength (average of Fisher-r-to-Z transformed Pearson correlation coefficients) between each region was computed. Values \>0 indicate regions are positively connected (synchronized), with larger values indicating stronger connection. Values \<0 indicate regions are negatively connected (inversely synchronized), with more negative values stronger negative connection. A value of 0 indicates that the regions are not connected. |
| Brain Gray Matter Thickness | Single time point: Baseline | Structural MRI will be acquired from children and adolescents diagnosed with OCD and healthy comparison subjects (HCs). Regional cortical thickness will be computed in the inferior frontal gyrus |
| Structural Connectivity (Streamline Counts) | Single time point (baseline) | Magnetic Resonance Imaging (MRI) with Diffusion Tensor Imaging (DTI) will be acquired from children and adolescents diagnosed with OCD and healthy comparison subjects (HCs). A structural connectivity matrix is estimated for each participant using the standard MRtrix3 preprocessing pipeline, yielding 164x164 symmetrical streamline count matrix for each participant using the FreeSurfer segmentations/parcellations noted above (148 cortical, 14 subcortical regions, and the left and right cerebellum). Using this approach, streamline count between brain regions is proportional to the cross-sectional area of white matter fibers connecting those regions. Thus, streamline count is a biologically plausible metric of structural connectivity proposed to represent the communication 'bandwidth' between regions. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Participants With Obsessive-compulsive Disorder (OCD) Children and adolescents who meet DSM-IV diagnostic criteria for OCD and had clinically significant obsessive-compulsive symptoms (CY-BOCS score \> 15). Comorbid anxiety disorders, but no other lifetime psychiatric diagnoses, were permitted in the OCD group as long as OCD was the primary diagnosis. Participants were unmedicated and had not received a full course of CBT with exposure and response prevention for OCD prior to their participation in the study. Following baseline assessment and scan, patients with OCD underwent a course of manualized treatment of CBT with E/RP adapted for pediatric OCD (March & Mulle, 1998) delivered by a licensed clinical psychologist or advanced supervised graduate student in clinical psychology at the NYSPI. CBT treatment consisted of 12-16 hour-long sessions. For exceptional cases not showing clinical improvement after six CBT treatment sessions, complementary pharmacological treatment (SSRI) was offered as part of our treatment protocol. CBT for OCD involves gradually exposing patients to anxiety provoking stimuli while having patients refrain from engaging in compulsive rituals and/or avoidance behaviors. There are three major components of CBT treatment for OCD, specifically: (1) exposure to anxiety provoking stimuli, (2) response prevention, and (3) cognitive techniques intended to decrease anxiety during the exposure and response prevention processes. | 28 |
| Healthy Control (HC) Participants Healthy control (HC) participants matched on age and sex with the OCD group. HC participants had no lifetime psychiatric disorders. HC participants were assessed and scanned at baseline. | 27 |
| Total | 55 |
Baseline characteristics
| Characteristic | Participants With Obsessive-compulsive Disorder (OCD) | Healthy Control (HC) Participants | Total |
|---|---|---|---|
| Age, Continuous | 12.14 years STANDARD_DEVIATION 3.34 | 11.26 years STANDARD_DEVIATION 3.23 | 11.69 years STANDARD_DEVIATION 3.23 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 9 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 16 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Full Scale Intelligence Quotient (FSIQ) | 106.96 T-Score STANDARD_DEVIATION 16.2 | 109.59 T-Score STANDARD_DEVIATION 12.14 | 108.25 T-Score STANDARD_DEVIATION 13.95 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 4 Participants | 9 Participants | 13 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 5 Participants | 6 Participants |
| Race (NIH/OMB) White | 21 Participants | 8 Participants | 29 Participants |
| Region of Enrollment United States | 28 participants | 27 participants | 55 participants |
| Sex: Female, Male Female | 14 Participants | 13 Participants | 27 Participants |
| Sex: Female, Male Male | 14 Participants | 14 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 27 |
| other Total, other adverse events | 0 / 28 | 0 / 27 |
| serious Total, serious adverse events | 0 / 28 | 0 / 27 |
Outcome results
Primary
Brain Activation Associated With the Resolution of Cognitive Conflict
Task-based functional magnetic resonance imaging (fMRI) will be acquired from children and adolescents diagnosed with OCD and healthy comparison subjects (HCs) during their performance of a Simon Spatial Compatibility Task. In each trial, participants are presented with a leftward or rightward pointing arrow that is either congruent or incongruent with their position (left or right) on the screen. Participants are instructed to respond as quickly and accurately as possible to the direction in which the arrow was pointing by pressing a button on a response box using the index finger for left and the middle finger for right. Brain activation during the resolution of cognitive conflict is computed by contrasting blood-oxygen-level-dependent (BOLD) signal during Incongruent versus Congruent trials. BOLD signal is expressed in arbitrary units (A.U.s).
Time frame: single time point: baseline
Population: Only participants with usable fMRI data were included in these analyses. One participant with OCD and 4 HC participants were excluded because of missing fMRI data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Obsessive-compulsive Disorder (OCD) | Brain Activation Associated With the Resolution of Cognitive Conflict | .7 Arbitrary units | Standard Deviation 0.2 |
| Healthy Control (HC) Participants | Brain Activation Associated With the Resolution of Cognitive Conflict | .59 Arbitrary units | Standard Deviation 0.2 |
Comparison: We hypothesized that compared to HC, children and adolescents with OCD would have increased activation in subcortical structures (insula, and putamen) comprising a right hemisphere dorsal frontostriatal circuit.p-value: 0.058595% CI: [-0.004, 0.224]t-test, 2 sided
Secondary
Brain Gray Matter Thickness
Structural MRI will be acquired from children and adolescents diagnosed with OCD and healthy comparison subjects (HCs). Regional cortical thickness will be computed in the inferior frontal gyrus
Time frame: Single time point: Baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Obsessive-compulsive Disorder (OCD) | Brain Gray Matter Thickness | 3 mm | Standard Deviation 0.2 |
| Healthy Control (HC) Participants | Brain Gray Matter Thickness | 2.89 mm | Standard Deviation 0.2 |
p-value: 0.046495% CI: [0.0018, 0.218]t-test, 2 sided
Secondary
Functional Connectivity
Functional magnetic resonance imaging (fMRI) will be acquired from children and adolescents diagnosed with OCD and healthy comparison subjects (HCs) at baseline and after approximately 16-20 weeks (i.e., post-treatment for the participants with OCD). The whole brain is divided in 352 brain regions comprised of 333 cortical surface (Gordon et al. Cereb Cortex 2016;26:288-303) and 19 subcortical (Fischl et al. Neuron 2002;53:341-55) parcellated regions. FC-strength (average of Fisher-r-to-Z transformed Pearson correlation coefficients) between each region was computed. Values \>0 indicate regions are positively connected (synchronized), with larger values indicating stronger connection. Values \<0 indicate regions are negatively connected (inversely synchronized), with more negative values stronger negative connection. A value of 0 indicates that the regions are not connected.
Time frame: single time point: Baseline
Population: Only participants with usable fMRI data were included in these analyses. Three participants with OCD and 4 HC participants were excluded because of missing fMRI data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Obsessive-compulsive Disorder (OCD) | Functional Connectivity | -0.312768356 arbitrary units | Standard Deviation 0.223710827 |
| Healthy Control (HC) Participants | Functional Connectivity | 0.182360856 arbitrary units | Standard Deviation 0.230155947 |
Comparison: Whole-Brain Connectome-Level Analyses were performed on the FC-strength indices between 352 regions. Edge-wise functional connectivity analyses was then be conducted across the resulting matrix comprised of 352 nodes and 123,904 edges, using the Network-Based Statistics (NBS) Toolbox. We hypothesized that youth with OCD would show altered FC between task-control circuit regions.p-value: 0.037t-test, 1 sided
Comparison: Separate cross-lagged panel models were computed in the OCD group for the three functional connections that differed significantly across groups at baseline (see Statistical Analysis 1). These models were constructed using IBM SPSS Amos (v.23) to test for directional relationships between OCD symptoms and FC pre- to post-treatment in the OCD patients. CY-BOCS total scores at each time point were used as the OCD symptoms measure.p-value: <0.05Regression, Linear
Secondary
Structural Connectivity (Streamline Counts)
Magnetic Resonance Imaging (MRI) with Diffusion Tensor Imaging (DTI) will be acquired from children and adolescents diagnosed with OCD and healthy comparison subjects (HCs). A structural connectivity matrix is estimated for each participant using the standard MRtrix3 preprocessing pipeline, yielding 164x164 symmetrical streamline count matrix for each participant using the FreeSurfer segmentations/parcellations noted above (148 cortical, 14 subcortical regions, and the left and right cerebellum). Using this approach, streamline count between brain regions is proportional to the cross-sectional area of white matter fibers connecting those regions. Thus, streamline count is a biologically plausible metric of structural connectivity proposed to represent the communication 'bandwidth' between regions.
Time frame: Single time point (baseline)
Population: Only participants with usable DTI data were included in these analyses. Three participants with OCD and 2 HC participants were excluded because of missing DTI data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Obsessive-compulsive Disorder (OCD) | Structural Connectivity (Streamline Counts) | 227.688 streamlines | Standard Deviation 86.169 |
| Healthy Control (HC) Participants | Structural Connectivity (Streamline Counts) | 328.224 streamlines | Standard Deviation 112.684 |
Comparison: Whole-Brain Connectome-Level Analyses were performed on the structural connectivity indices (streamline count) between 164 regions. Edge-wise structural connectivity analyses was then be conducted across the resulting matrix comprised of 164 nodes and 26,896 edges, using the Network-Based Statistics (NBS) Toolbox.p-value: <0.025Regression, Linear