Faculty Bibliography

CONTEXT: Because schizophrenia and related disorders have a chronic time course and subtle histopathology, it is difficult to identify which brain regions are differentially targeted. OBJECTIVE: To identify brain sites differentially targeted by schizophrenia, we applied a high-resolution variant of functional magnetic resonance imaging to clinically characterized patients and matched healthy controls and to a cohort of prodromal subjects who were prospectively followed up. Additionally, to explore the potential confound of medication use, the fMRI variant was applied to rodents receiving an antipsychotic agent. DESIGN: Cross-sectional and prospective cohort designs. SETTING: Hospital clinic and magnetic resonance imaging laboratory. PARTICIPANTS: Eighteen patients with schizophrenia, 18 controls comparable in age and sex, and 18 prodromal patients followed up prospectively for 2 years. Ten C57-B mice received an antipsychotic agent or vehicle control. MAIN OUTCOME MEASURES: Regional cerebral blood volume (CBV), as measured with magnetic resonance imaging, and symptom severity, as measured with clinical rating scales. RESULTS: In a first between-group analysis that compared patients with schizophrenia with controls, results revealed abnormal CBV increases in the CA1 subfield and the orbitofrontal cortex and abnormal CBV decreases in the dorsolateral prefrontal cortex. In a second longitudinal analysis, baseline CBV abnormalities in the CA1 subfield differentially predicted clinical progression to psychosis from a prodromal state. In a third correlational analysis, CBV levels in the CA1 subfield differentially correlated with clinical symptoms of psychosis. Finally, additional analyses of the human data set and imaging studies in mice suggested that antipsychotic agents were not confounding the primary findings. CONCLUSIONS: Taken as a whole, the results suggest that the CA1 subfield of the hippocampal subregion is differentially targeted by schizophrenia and related psychotic disorders. Interpreted in the context of previous studies, these findings inform underlying mechanisms of illness progression

The Autism Diagnostic Observation Schedule (ADOS; Lord et al., J Autism Dev Disord, 30(3):205-223, 2000) is widely accepted as a 'gold standard' diagnostic instrument, but it is of restricted utility with very young children. The purpose of the current project was to modify the ADOS for use in children under 30 months of age. A modified ADOS, the ADOS Toddler Module (or Module T), was used in 360 evaluations. Participants included 182 children with best estimate diagnoses of ASD, non-spectrum developmental delay or typical development. A final set of protocol and algorithm items was selected based on their ability to discriminate the diagnostic groups. The traditional algorithm 'cutoffs' approach yielded high sensitivity and specificity, and a new range of concern approach was proposed

Intolerance of uncertainty (IU) has contributed to our understanding of excessive worry and adult anxiety disorders, but there is a paucity of research on IU in child samples. This gap is due to the absence of a psychometrically sound measure of IU in youth. The present study adapted parallel child- and parent-report forms of the Intolerance of Uncertainty Scale (IUS) and examined the internal consistency, convergent validity, and classification properties of these forms in youth aged 7-17 (M = 11.6 years, SD = 2.6). Participating youth (N = 197; 100 girls, 97 boys) either met diagnostic criteria for an anxiety disorder (n = 73) or were nonreferred community participants (n = 124). The child-report form (i.e., IUS for Children, or IUSC), and to a lesser extent the parent-report form, demonstrated strong internal consistency and convergent validity, evidenced by significant associations with anxiety and worry (and reassurance-seeking in the case of the child-report form). Children diagnosed with anxiety disorders scored higher than nonreferred community youth on both forms. Receiver operating characteristic (ROC) analysis demonstrated acceptable overall utility in distinguishing the 2 groups of youth. Findings provide preliminary support for use of the IUSC for continuous measurement of children's ability to tolerate uncertainty

Epilepsy in women is influenced by endocrine status and antiepileptic drugs (AEDs), but without an animal model, the effects of endocrine variables and AEDs cannot be easily dissociated from the influence of epilepsy itself. Animal models have had limited utility because experimentally-induced seizures typically result in reproductive failure. This study was conducted to develop an improved animal model. The muscarinic convulsant pilocarpine was used to elicit status epilepticus (SE) in adult female Sprague-Dawley rats. The selective estrogen receptor modulator raloxifene was administered 30 min before pilocarpine. An anticonvulsant barbiturate, pentobarbital, was injected 5-10 min after the onset of SE, and at least once thereafter to minimize acute convulsions. Mortality, morbidity, estrous cyclicity, and the ultimate success of the procedure (i.e. induction of recurrent, spontaneous seizures) were monitored. The combination of raloxifene and pentobarbital led to significantly improved estrous cyclicity compared to previous methods. Animals treated with raloxifene and pentobarbital became epileptic, as defined by the recurrence of spontaneous convulsions in the weeks after SE. The results of this study provide an improved animal model to examine the interactions between seizures and ovarian hormone secretion. The results also suggest that treatment of SE with raloxifene may benefit women with SE

Olfaction represents an ideal model system for the study of mammalian habituation given that it is an anatomically relatively simple system with strong reciprocal connections to the limbic system, driving both reflexive and non-reflexive (motivated) behaviors that are easily quantifiable. Data are reviewed here demonstrating short-term habituation of the odor-evoked heart-rate orienting reflex described according to the criteria for habituation outlined by Thompson and Spencer [Thompson, R. F., & Spencer, W. A. (1966). Habituation: A model phenomenon for the study of neuronal substrates of behavior. Psychological Reviews, 73(1), 16-43]. A necessary and sufficient mechanism of short-term habituation is then described, which involves a metabotropic glutamate receptor mediated depression of afferent input to the piriform (primary olfactory) cortex. Finally, evidence for, and a mechanisms of, dishabituation of the orienting reflex and cortical adaptation are described

BACKGROUND: While immune system dysregulation has been postulated to play a role in Tourette's disorder (TD), most research has focused on the hypothesis of an autoimmune process similar to rheumatic fever. This study examined the potential role of cytokines, modulators of the immune system. We hypothesized that children with TD would have increased levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-12, IL-1 beta and IL-6, and decreased IL-2. We also explored whether comorbid obsessive compulsive disorder (OCD) had an effect on the cytokine profile of TD patients. METHOD: Thirty-two children and adolescents with TD (27 males, ages 7-18 years), 17 with comorbid OCD (14 males), and 16 healthy comparison subjects (7 males, ages 9-19), were enrolled. Plasma cytokines were examined using an enzyme-linked immunosorbent assay. The Mann-Whitney and binary logistic regression tests were used to compare the groups. RESULTS: Only patients with comorbid OCD (TD+OCD; n=17) had significantly elevated IL-12 plasma levels compared to controls (2.73+/-5.12 pg/ml vs. 0.55+/-0.88 pg/ml, rank statistic=222.5; p<0.04). IL-2 was significantly higher in the TD+OCD subgroup compared to the non-OCD TD subgroup (0.74+/-0.29 pg/ml vs. 0.49+/-0.24 pg/ml, rank statistics=108.5; p<0.03). There were no other significant cytokine differences between groups. CONCLUSIONS: Findings suggest a role for IL-12 and IL-2 in TD, and that the TD+OCD subgroup may involve different neuroimmunological functions than the TD-OCD subgroup. Larger studies with medication-free patients should follow

Emotion antecedents are defined as external or internal events that cause emotions in individuals. Their study brings us insight into individuals' emotion processing. Emotion antecedents have rarely been studied in schizophrenia. Thirty individuals with schizophrenia and 30 non-patient comparison subjects, matched by gender and age, related events when they felt extremely angry, disgusted, fearful, happy, sad and surprised. Each antecedent was summarized in a written sentence and 20 judges matched the antecedent with the correct emotion. The antecedents of individuals with schizophrenia were less frequently matched with their emotion than the antecedents of non-patient comparison subjects for all emotions. Moreover, error pattern analyses revealed distinct deficits for the emotion 'fear'. In the schizophrenia group, fear antecedents were more frequently judged as non-emotional, and non-fear antecedents were more often judged as fear antecedents when compared to the control group. A deficit in fear processing correlated with the Suspiciousness item on the Brief Psychiatric Rating Scale. Our results indicate differences in emotion processing in schizophrenia. Error pattern results are consistent with impairment in the appraisal of fear. Lower accuracy rates with schizophrenia subjects' antecedents may reflect lower emotion awareness for all emotions in schizophrenia. This study furthers the understanding of deficits in basic emotion processing in schizophrenia