STRUCTURAL ABNORMALITIES 1 A Look at Structural Abnormalities and Sy PDF
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Running head: STRUCTURAL ABNORMALITIES 1 A Look at Structural Abnormalities and Symptom Severity in Adolescents with Obsessive-‐ Compulsive Disorder Sarah Campbell University of Minnesota Mentor: Bonnie Klimes – Dougan Ph.D. Gail A. Bernstein M.D. Schmuel Lissek Ph.D. STRUCTURAL ABNORMALITIES 2 Abstract The objective of this research was to explore the volumetric differences between OCD and control participants in the cortico-‐striatal-‐thalamic-‐cortico (CSTC) circuit. Functional magnetic resonance imaging (fMRI) was obtained with the Human Connectome Project scanner using newly developed technologies. Seventeen OCD and 13 healthy control adolescents were scanned with the 3T scanner. Freesurfer technology was used to analyze the volumetric findings of the CSTC regions. The thalamic and striatal volume results were analyzed. Adolescents with OCD compared with controls showed no difference in the volumes of the thalamus, caudate and putamen. A significant difference was found between medication naïve and medicated OCD participants in the right putamen. No difference in volumetric regions of the CSTC between OCD and control participants suggests that connectivity may not be related to volumes of the involved regions. STRUCTURAL ABNORMALITIES 3 A Look at Structural Abnormalities and Symptom Severity in Adolescents with Obsessive-‐ Compulsive Disorder Obsessive-‐compulsive disorder (OCD) is an impairing anxiety disorder that affects all ages. Those affected suffer from persistent, unreasonable thoughts (obsessions), and repetitive behaviors (compulsions). Recent neuroimaging studies show an association between OCD and dysfunction in the cortico-‐striatal-‐thalamic-‐cortical circuit (CSTC) (Kalra & Swedo, 2009). Researchers hypothesize that there are brain structural abnormalities within this circuit that correspond to the severity of obsessive thoughts and compulsive behaviors. The cortico-‐striatal-‐thalamic-‐cortical circuit is a key neural network implicated in OCD. This circuit connects neurons in the frontal cortex, the striatum (putamen and caudate), the thalamus, and back to the frontal cortex. In OCD, it is believed that neurons in the frontal cortex send an excitatory signal to the striatum. This increases the signaling from the striatum to the next node, which is the globus pallidus internus and substantia nigra (GPi/SNr). Since the connection between the striatum and GPi/SNr is inhibitory, an increase in striatal stimulation leads to an increase in inhibition at the GPi/SNr. The next part of the circuit involves an inhibitory signal to the thalamus. This inhibitory signal decreases the amount of GABA, an inhibitory neurotransmitter. This leads to an excitatory signal from the thalamus to the frontal cortex, which is believed to be involved in obsessive thoughts and compulsive actions. This circuit in the brain can be measured using an fMRI and recording the connectivity between the varying regions in the circuit. In this research, hyperconnectivity refers to a greater strength of connections whereas hypoconnectivity refers to a lower STRUCTURAL ABNORMALITIES 4 strength of connections compared to the average. It is hypothesized that when this connectivity is measured using a resting state MRI (R-‐fMRI), the measured connections can reflect the structural architecture of the brain (volume, thickness) (van den Heuvel, Mandl & Hulshoff, 2009). Interpretation of what hyperactivation or hypoactivation in the brain means in terms of volume is scarce in the literature. A common view is that hypoactivation in the brain is thought to be a neuronal deficit, which can sometimes lead to hyperactivation as a compensatory mechanism and an enlargement of structures (Harrison et al., 2009). Others believe that hyperactivation could be stress-‐related excitotoxicity, thus decreasing the volume of certain structures (Suzuki et al., 2012). Emerging research supports the involvement of the CSTC circuit and volumetric abnormalities within the involved regions in adults with OCD. Specifically, recent research has focused on striatal and thalamic volume differences with OCD adults. Christian et al. (2008) presented data supporting the association between the circuit and adult OCD participants. OCD participants demonstrated more gray matter in the left thalamus. Christian speculated that the increase in grey matter could reflect a compensatory mechanism or a neuronal hypertrophy resulting from a neuronal deficit. Further evidence points to a connection between changing striatal volumes and OCD, though this has met with conflicting results. Robinson et al. (1995) looked at 26 adult OCD participants and 26 matched controls. This team found a reduced caudate volume in OCD participants versus control. This team focused on adult patients who had had prior treatment with psychotropic drugs such as selective serotonin reuptake inhibitors (SSRIs) or benzodiazepines. Szesko et al (2004) looked at 23 drug naïve OCD patients and 27 healthy STRUCTURAL ABNORMALITIES 5 volunteers. They found no difference in the volumes of the caudate nucleus or putamen, but found smaller globus pallidus volumes. Similar volumetric findings in children and adolescents with OCD have been found. Gilbert et al. (2000) measured neuroanatomical changes in the thalamus of 21 drug naïve children and adolescents with OCD and 21 age and gender matched controls. They found that thalamic volumes were significantly greater in OCD treatment naïve patients compared to controls, but after 12 weeks of paroxetine treatment, there was a significant decrease in thalamic volume. Rosenberg et al (1997) found similar striatal results to Robinson et al. (1995) but in adolescents and children. Robinson looked at 19 drug naïve children and adolescents and 19 gender and age matched healthy controls. The OCD participants had significantly smaller overall striatal volumes. Specifically, smaller putamen volumes were observed with no change in caudate volumes. The differing findings in striatal volumes in adolescents and children versus adults could be due to developmental factors or treatment effects (medication or cognitive-‐behavioral therapy). Furthermore, there is evidence that OCD symptom severity is correlated with volume changes in the brain in both adults and children. In Christian et al (2008), there was a positive correlation between gray matter in the left orbitofrontal cortex and symptom severity. Gilbert found that after the 12 weeks of paroxetine treatment, the OCD symptom severity had decreased with the thalamic volume. Both Christian and Gilbert used the Y-‐ BOCS/CY-‐BOCS assessment when interviewing their participants. The current research is sparse in connecting brain connectivity activation to volumetric findings; and little research exists that reports on connectivity and volumetric findings of the same participants. Central to this study are the findings from Bernstein et al. STRUCTURAL ABNORMALITIES 6 (2013, in progress). With the current sample they examined the CSTC circuit in OCD and adolescent control participants. Using fMRI they found that a lower level of connectivity, hypoactivation, was found in OCD participants. Because hypoactivtion was observed, one could expect to find lower volumes in the CSTC circuit regions resulting from some type of deficit. The current study aims to look at volumes of the thalamus and striatum in the CSTC and consider if these brain volumes are related to severity of OCD. Method Participants Seventeen OCD participants, ages 12-‐19, and 13 age-‐ and gender-‐ matched healthy controls were enrolled. All OCD participants (males=9, females=8) met DSM-‐IV criteria on the Anxiety Disorders Interview Schedule for DSM-‐IV (ADIS) (an interference rating of at least a 4) and CY-‐BOCS (overall severity rating > 15). Controls (males=8, females=7) had no psychiatric disorders and had no family history of OCD. Exclusion criteria included the following; autism, psychosis, bipolar disorder, major depression, and substance use disorders on the ADIS; mental retardation on the WASI (IQ<80), Positive urine drug screen done before the scan, MRI incompatible features (see Appendix B); currently pregnant, any anxiolytics outside of SSRI’s, anyone outside of the 12-‐19 age range. Recruitment Participants were recruited from the Child and Adolescent Anxiety Disorders Clinic at the University of Minnesota Fairview Medical Center. E-‐mails with recruitment information were sent to mental health providers and pediatricians in the Minneapolis/St. Paul metropolitan area (Appendix A). We also advertised in local newspapers, Craig’s List, and STRUCTURAL ABNORMALITIES 7 Facebook. Additional participants were recruited via posters in the community and in clinics. Procedure Parents of prospective participants were first interviewed using a phone screen, which included basic questions that would eliminate any participants from the study who met exclusionary criteria (see Appendix C). If participants met the inclusionary criteria, they were invited in for two in-‐person assessments: an interview and an MRI. During the in-‐person interview portion of the study, participants and their guardians were given a brief overview of the study and written informed consent and assent were obtained. A 2-‐3 hour interview followed where assessment instruments, such as interviews and rating scales as described in the Assessments section, were administered by trained researchers. Participants meeting inclusion criteria based on the interview portion underwent an MRI scan at the Center for Magnetic Resonance Imaging at the University of Minnesota. Families were offered $30 for completion of the diagnostic assessment and $35 for the imaging studies. During the second appointment, participants completed a one-‐hour MRI scan. At the start of the appointment, participants completed the safety screening form in the lobby of the CMRR to ensure that no metal was present on the participant (see appendix). Pre-‐scan procedures included a urine sample for drug screening and (if female) pregnancy testing at the CMRR. Participants’ height, weight, and head circumference were also taken for scanning purposes. Participants were offered the use of a ‘mock scanner’ before going into the actual scanner to ensure that they were comfortable and ready for the STRUCTURAL ABNORMALITIES 8 scan. To obtain the resting state MRI, participants were asked to rest and stay awake with eyes closed and to “not think about anything in particular.” Assessments Assessments were used to determine exclusionary comorbid disorders. The Children’s Yale-‐Brown Obsessive Compulsive Scale (CY-‐BOCS) (Scahill et al., 1997), was used to determine the severity of individual obsessions and compulsions. The CY-‐BOCS is a modified version of the Yale-‐Brown Obsessive Compulsive Scale (Y-‐BOCS), which is used for adults. The overall structure of the Y-‐BOCS assessment was retained but the wording was changed to fit children and adolescents understanding. The researchers used the composite score to determine overall severity. The CY-‐BOCS was administered with both the parent and the participant present. The Wechsler Abbreviated Scale of Intelligence (WASI), adopted from Wechsler (1999), was used to provide a measure of cognitive functioning. The WASI ensured that each participant’s IQ was greater than 79 to rule out any mental retardation. The Beck Depression Inventory (BDI), adopted from Beck (1996), was given tomeasure the severity of depression symptoms. Basic information obtained from participants included demographic information about place of residence, occupation (for Social Economic Status (SES) information), and contact information. The Family Interview for Genetic Studies (FIGS) was given to the participants’ guardians to obtain family history of mental disorders. Researchers were each trained in on how to appropriately administer the instruments. Any ambiguous findings were discussed during team meetings with psychiatrists present. Participants were compensated $30 for part one and were asked to sign a reimbursement form. At the end of the interview portion, STRUCTURAL ABNORMALITIES 9 participants were sent home with an “MRI experience form” that highlighted what it was like to be in an MRI scanner. MRI: Imaging was conducted on a 3T scanner using a 32-‐channel receive only head coil. This scanner is a new, state-‐of-‐the-‐art Siemens scanner named the SKYRA. The SKYRA uses updated technology to view white matter microstructure. This scanner is also being utilized on the Human Connectome project, a recent initiative to map the human brain. 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 = .52 ms, TI = 1100 ms, flip angle = 7 degrees). The T1 images were processed using FreeSurfer (http://surfer.nmr.mgh.harvard.edu/). Specific FreeSurfer ROIs for each structure within CSTC were identified and later aligned to functional images. Design In a between-‐subjects design, participants were recruited based on having OCD or being a healthy control. Measurements using a resting state MRI were made to see if brain structure differed between OCD/control participants. Results Participants: Demographic information and severity scores on the given assessments between the OCD and control groups can be seen in Table 1. There were no significant differences between STRUCTURAL ABNORMALITIES 10 the groups on socioeconomic status, age at assessment, gender, ethnicity or handedness. Twelve of the 15 total OCD participants were on an SSRI and/or clomipramine to manage their OCD. The mean score on the CY – BOCS for the OCD group was a 19.3, indicating that the average level of OCD severity was moderate. Volumetric Results: OCD versus control groups were compared on three bilateral brain regions. A multivariate analysis of variance (MANOVA) was run on the six brain regions between groups. There was a main group effect of 0.697. Intracranial brain volume was used as a covariate to remove its relationship from the volumetric findings. There were no significant differences between OCD participants and control participants (Table 2). Although not significant, larger volumes were found in the OCD group in the right and left thalamus, right and left caudate, and right putamen (figure 1). The volumes between medication naïve and medicated OCD participants (n=14 naïve, n=3 medicated) was ran with a significant difference (p = .005) in the volume of the right putamen. Association of Volumes with OCD Severity: Pearson correlation coefficients were run to evaluate if the volumetric data were significantly related to the severity on the CY–BOCS in the OCD group. The CY-‐BOCS total score, the total obsessions score, and the total compulsions score were ran versus the six brain regions. As seen in Table 3, no significant differences were found. Discussion
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