Andrew R. Gilbert

Brain structure and symptom dimension relationships in obsessive–compulsive disorder: A voxel-based morphometry study

BACKGROUND Obsessive-compulsive disorder (OCD) is a clinically heterogenous disorder characterized by temporally stable symptom dimensions. Past inconsistent results from structural neuroimaging studies of OCD may have resulted from the effects of these specific symptom dimensions as well as other socio-demographic and clinical variables upon gray matter (GM) volume. METHODS GM volume was measured in 25 adult OCD patients and 20 adult healthy controls using voxel-based morphometry (VBM), controlling for age and total brain GM volume. Univariate and multivariate regression analyses were carried out between regions of GM difference and age, age of onset, medication load, OCD severity, depression severity, and separate symptom dimension scores. RESULTS Significant GM volumetric differences in OCD patients relative to controls were found in dorsal cortical regions, including bilateral BA6, BA46, BA9 and right BA8 (controls>patients), and bilateral midbrain (patients>controls). Stepwise regression analyses revealed highly significant relationships between greater total OCD symptom severity and smaller GM volumes in dorsal cortical regions and larger GM volumes in bilateral midbrain. Greater age was independently associated with smaller GM volumes in right BA6, left BA9, left BA46 and larger GM volumes in right midbrain. Greater washing symptom severity was independently associated with smaller GM volume in right BA6, while there was a trend association between greater hoarding symptom severity and lower GM volume in left BA6. LIMITATIONS The sample was relatively small to examine the relationship between symptom scores and GM volumes. Multiple patients were taking medication and had comorbid disorders. CONCLUSIONS These analyses suggest dorsal prefrontal cortical and bilateral midbrain GM abnormalities in OCD that appear to be primarily driven by the effects of total OCD symptom severity. The results regarding the relationship between GM volumes and symptom dimension scores require examination in larger samples.

Thalamic volume in pediatric obsessive-compulsive disorder patients before and after cognitive behavioral therapy

BACKGROUND Neurobiologic abnormalities in the thalamus have been implicated in the pathophysiology of obsessive-compulsive disorder. We recently reported increased thalamic volume in treatment-naive pediatric obsessive-compulsive disorder patients versus case-matched healthy comparison subjects that decreased to levels comparable to control subjects after effective paroxetine therapy. To our knowledge, no prior study has measured neuroanatomic changes in the thalamus of obsessive-compulsive disorder patients near illness onset before and after cognitive behavioral therapy. METHODS Volumetric magnetic resonance imaging studies were conducted in 11 psychotropic drug-naive 8-17-year-old children with obsessive-compulsive disorder before and after 12 weeks of effective cognitive behavioral therapy monotherapy (> or =30% reduction in obsessive-compulsive disorder symptom severity). RESULTS No significant change in thalamic volume was observed in obsessive-compulsive disorder patients before and after cognitive behavioral therapy. CONCLUSIONS Our findings suggest that reduction in thalamic volume after paroxetine therapy may be specific to paroxetine treatment and not the result of a general treatment response or spontaneous improvement. These results are preliminary in view of the small sample studied.

Neural Correlates of Symptom Dimensions in Pediatric Obsessive-Compulsive Disorder: A Functional Magnetic Resonance Imaging Study

OBJECTIVE Neuroimaging studies have identified distinct neural correlates of obsessive-compulsive disorder (OCD) symptom dimensions in adult subjects and may be related to functional abnormalities in different cortico-striatal-thalamic neural systems underlying cognition and affective processing. Similar symptom dimensions are apparent in childhood and adolescence, but their functional neural correlates remain to be elucidated. METHOD Pediatric subjects with OCD (n = 18) and matched controls (n = 18), ages 10 to 17 years, were recruited for two functional magnetic resonance imaging experiments. They were scanned while viewing alternating blocks of symptom provocation (contamination-related or symmetry-related) and neutral pictures and imagining scenarios related to the content of each picture type. RESULTS The subjects with OCD demonstrated reduced activity in the right insula, putamen, thalamus, dorsolateral prefrontal cortex, and left orbitofrontal cortex (contamination experiment) and in the right thalamus and right insula (symmetry experiment). Higher scores on OCD symptom-related measures (contamination and total severity) were significantly predictive of reduced neural activity in the right dorsolateral prefrontal cortex during the contamination experiment. CONCLUSIONS Our findings indicate reduced activity in neural regions underlying emotional processing, cognitive processing, and motor performance in pediatric subjects with OCD compared with the controls. These between-group differences are present during both contamination and symmetry provocation experiments and during symptom provocation as well as viewing neutral pictures. The direction of activity is in contrast to adult findings in the insula and in components of cortico-striatal-thalamic neural systems. Our findings suggest developmental effects on neural systems underlying symptom dimensions in pediatric OCD.

Gray Matter Differences between Pediatric Obsessive-Compulsive Disorder Patients and High-Risk Siblings: A Preliminary Voxel-Based Morphometry Study

Neuroimaging studies have identified alterations in frontostriatal circuitry in obsessive-compulsive disorder (OCD). Voxel-based morphometry (VBM) allows for the assessment of differences in gray matter density across the whole brain. VBM has not previously been used to examine regional gray matter density in pediatric OCD patients and the siblings of pediatric OCD patients. Volumetric magnetic resonance imaging (MRI) studies were conducted in 10 psychotropic naïve pediatric patients with OCD, 10 unaffected siblings of pediatric patients with OCD, and 10 healthy controls. VBM analysis was conducted using SPM2. Statistical comparisons were performed with the general linear model, implementing small volume random field corrections for a priori regions of interest (anterior cingulate cortex or ACC, striatum and thalamus). VBM analysis revealed significantly lower gray matter density in OCD patients compared to healthy in the left ACC and bilateral medial superior frontal gyrus (SFG). Furthermore, a small volume correction was used to identify a significantly greater gray matter density in the right putamen in OCD patients as compared to unaffected siblings of OCD patients. These findings in patients, siblings, and healthy controls, although preliminary, suggest the presence of gray matter structural differences between affected subjects and healthy controls as well as between affected subjects and individuals at risk for OCD.

Obstetric Complications Correlate with Neurobehavioral and Brain Structural Alterations in Young Relatives at Risk for Schizophrenia

Abstract: As complications of pregnancy and birth may be important risk factors for the development of schizophrenia, studying the “roots” of schizophrenia in high‐risk offspring may better elucidate the interface between biology, environment, and susceptibility to illness. Using magnetic resonance imaging (MRI), neurobehavioral assessments and obstetric histories, we found several significant correlations between these multiple factors, suggesting that birth complications may be a nonspecific etiopathogenic risk factor for psychopathology in young relatives at risk for schizophrenia.

Evidence for successful implementation of exposure and response prevention in a naturalistic group format for pediatric OCD

Background: Although exposure and response prevention (ERP) is an effective treatment for youth with obsessive–compulsive disorder (OCD), the majority of studies, randomized clinical trials of individual therapy, find variability in treatment response. We evaluated the potential role of individual differences in OCD presentation, comorbid disorders, age, and gender on treatment effects. Moreover, we examined these potential effects in a group format in a naturalistic, clinic‐based sample of patients. Methods: Pediatric patients with a DSM‐IV diagnosis of OCD (n=41) were treated with ERP in an intensive outpatient community‐based program. OCD, mood, and anxiety symptom severity was measured at baseline, during treatment, and at discharge. Trajectories and predictors of treatment outcome were measured using linear growth models. Results: We found that group‐based ERP was effective in reducing pediatric OCD symptom severity in a naturalistic treatment setting irrespective of age or gender. Furthermore, ERP was found to be effective at reducing depressive symptoms but not other anxiety symptoms. We also found inter‐individual variability in the discharge levels of contamination, symmetry, and intrusive sexual thoughts and in the rate of severity reduction of intrusive sexual thoughts. Conclusion: Group‐based ERP is an effective treatment for children and adolescents with OCD. Several factors, including symptom dimensions and comorbid psychopathology, are associated with treatment response and outcome in this pediatric population. Depression and Anxiety, 2011.  © 2011 Wiley‐Liss, Inc.

Purification of Fibrinogen and Virus Removal Using Preparative Electrophoresis

Abstract: The Gradiflow is a novel, scalable preparative electrophoresis technique that uses the dual characteristics of size and charge to isolate target macro‐ and micromolecules from complex biological solutions. It does this with high resolution and in rapid time. The mild buffers are used to assist in retaining biological activity of the isolated protein. Gradiflow technology employs a sandwich of three polyacrylamide membranes configured to allow passage of macromolecules ranging in size from 10 kDa to 1,500 kDa. Fibrinogen was isolated from cryoprecipitate 1 using a single phase process. This separation was achieved within three hours with yields of 85%. Purified fibrinogen was then characterized using biophysical characterization of fibrin clot structure and compared with clots derived from a commercially available product and human plasma. Significantly, clots developed from Gradiflow fibrinogen had characteristics closer to human plasma. Viral removal characteristics of the Gradiflow were investigated by spiking the source material (cryoprecipitate 1) with canine parvovirus and testing for its presence in the isolated fibrinogen using PCR. Parvo removal was found to be greater than 4 logs and was achieved during the purification process. The Gradiflow offers the advantage of large‐scale separation of macromolecules and provides a new approach to fibrinogen separation that is quite distinct from other present‐day technologies. The technology is capable of isolating protein with high purity, recovery, and functionality in combination with the removal of viruses during the purification. Furthermore, it is capable of integrating into present production systems, significantly improving yield and functionality of target molecules.

MRI structural findings in schizophrenia

Introduction Described as “dementia praecox” by Emil Kraepelin in the early 1900’s, schizophrenia was considered a brain disease at that time. 1 It was predicted that the future would bring investigative techniques that would enable scientists to better understand the neuropathology of the illness. As we enter the 21 century, the predictions of Kraepelin and his contemporaries have become real, as MRI and more sophisticated neuroimaging techniques have emerged, unveiling many structural abnormalities that are best elucidated through in vivo neuroimaging. Neuroimaging allows for the in vivo measurement of brain regions without the potential confounds of fixation, and other sources of artifact that can influence postmortem examination of brain tissue. Furthermore, neuroimaging can be used to study first-episode patients, as well as the high-risk relatives of patients, thus understanding the biology of the illness without the potential confounding effects of age, prior treatment and illness chronicity. 2