Faculty Bibliography

ABSTRACT: BACKGROUND: Molecular genetic studies suggest the dopamine D1 receptor (D1R) may be implicated in attention-deficit/hyperactivity disorder (ADHD). As little is known about the potential motor role of D1R in ADHD, animal models may provide important insights into this issue. Methods: We investigated the effects of a full and selective D1R agonist, SKF-81297 (0.3, 3 and 10 mg/kg), on motor behaviour and expression of the plasticity-associated gene, c-fos, in habituated young adult male Spontaneously Hypertensive Rats (SHR), the most commonly used animal model of ADHD, and Wistar-Kyoto (WKY; the strain from which SHR were derived). Results: SHR rats were more behaviourally active than WKY rats after injection with vehicle. The 0.3 mg/kg dose of SKF-81297 increased motor behaviour (locomotion, sifting, rearing, and sniffing) in both SHR and WKY rats. Total grooming was also stimulated, but only in WKY rats. The same dose increased c-fos mRNA expression in the piriform cortex of both strains. The 3 mg/kg dose increased sifting and sniffing in both strains. Locomotion was also stimulated towards the end of the testing period. The intermediate dose decreased total rearing in both strains, and produced a significant increase in c-fos mRNA in the striatum, nucleus accumbens, olfactory tuberculum, and in the cingulate, agranular insular and piriform cortices. The 10 mg/kg dose of SKF-81297 produced a biphasic effect on locomotion, which was characterized by an initial decrease followed by later stimulation. The latter stimulatory effect was more pronounced in SHR than in WKY rats when compared to their respective vehicle-injected groups. The 10 mg/kg dose also stimulated sifting and sniffing in both strains. Both the 3 and 10 mg/kg doses had no effect on total grooming. The 10 mg/kg dose induced significantly higher levels of c-fos mRNA expression in the nucleus accumbens and adjacent cortical regions (but not striatum) of SHR when compared to WKY rats. CONCLUSION: The present results suggest a potential alteration in D1R neurotransmission within the frontal-striatal circuitry of SHR involved in motor control. These findings extend our understanding of the molecular alterations in SHR, a heuristically useful model of ADHD

The spatial pattern of activation in response to multiple whisker stimulation was studied using high-resolution laser Doppler (LD) imaging in urethane-anesthetized rats. LD flux change representing cerebral blood flow (CBF) responses were analyzed from a single trial or after averaging a number of similar trials. CBF change in a single trial was observed predominantly over pixels having low baseline flux values (microvessels), which included diffuse circular patterns of activation 400-800 microm in diameter similar to the histological dimensions of individual barrels established in the layer IV of the rat somatosensory cortex. The overall activation pattern varied considerably between each trial (only about 9-10% overlap); however, the diffuse circular pattern of activation was reproducible in every single trial within and across all rats. With trial averaging, no significant increase was observed in the outer boundary of activation, but the number of activated pixels increased within the diffuse circular patterns of activation. Emergence of further active pixels primarily within the diffuse circular regions of activity with trial averaging indicates distinct CBF responses in the septal and barrel regions, with a lesser LD signal to noise ratio in the barrel core

BACKGROUND: Neurocognitive deficits are considered to be central to the pathophysiology of schizophrenia, and the neurodevelopmental model suggests that such deficits precede full-blown psychosis. The present study examined performance on a broad neuropsychological battery of young subjects considered to be at clinical high risk for schizophrenia, who were subsequently followed to determine clinical outcome. METHODS: Subjects were 38 clinical high-risk patients (58% male patients; mean age = 16.5) and 39 sex- and age-matched healthy control subjects. At baseline, all high-risk patients had attenuated (subpsychotic) schizophrenialike positive symptoms. Clinical follow-up data of at least 6 months duration was available on 33 patients, of whom 12 developed nonaffective psychotic disorders. RESULTS: At baseline, clinical high-risk patients had significantly impaired global cognitive performance relative to control subjects and to estimates of their own prior intellectual functioning. Measures of verbal memory and executive functioning/working memory showed significantly greater impairments; visuospatial functioning was relatively spared. Prodromal patients who later developed psychosis had significantly lower verbal memory scores at baseline compared with patients who remained nonpsychotic. CONCLUSIONS: Verbal memory deficits may be an important risk marker for the development of schizophrenia-spectrum psychotic disorders, possibly indicating the presence of a prefrontal-hippocampal neurodevelopmental abnormality. Generalized neurocognitive impairment may be a nonspecific vulnerability marker.

Young children in foster care have often experienced inadequate early care and separations from caregivers. Preclinical studies suggest that early inadequate care and separations are associated with long-term changes in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. In this study, the daytime pattern of cortisol production was examined among 55 young children who had been placed into foster care and 104 children who had not. Saliva samples were taken at wake-up, in the afternoon, and bedtime for 2 days. Average salivary cortisol values for each time of day were computed. A group (foster vs. comparison) time (morning, afternoon, night) interaction emerged, reflecting less decline in levels across the day for foster than comparison children. Daytime patterns were categorized as typical, low, or high. Children who had been in foster care had higher incidences of atypical patterns of cortisol production than children who had not. These differences suggest that conditions associated with foster care interfere with children's ability to regulate neuroendocrine functioning

Attention-deficit/hyperactivity disorder (ADHD) is a clinical disorder that may be confused with other medical and psychiatric conditions, due to overlapping symptoms. Often, symptoms suggestive of ADHD may be explained by other diagnoses. Medical 'mimics' one should consider when diagnosing a patient with ADHD include sleep deprivation, chronic and acute illness, medication effects, cognitive deficits, and other psychiatric disorders such as Asperger's syndrome, substance use disorders, and mood disorders. ADHD in both children and adults is also associated with academic performance problems, such as learning disabilities and executive functioning deficits. Learning disabilities such as math and spelling deficits are more common in children, although both age groups experience difficulties with reading and listening comprehension. Executive deficits in response inhibition and working memory have been demonstrated to be predictive of impairment in virtually every major life activity. Evaluation of both children and adults with ADHD requires screening for comorbid medical, psychiatric, and learning disorders; executive functioning; and history of school impairment. In this monograph, Russell A. Barkley, PhD, reviews the comorbidity of adult attention-deficit/hyperactivity disorder (ADHD) and learning and executive function disorders. Next, Timothy E. Wilens, MD, discusses differential diagnosis of ADHD as well as the prevalence of psychiatric comorbidity in adult ADHD. Finally, Lenard A. Adler, MD, reviews Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnostic criteria for adult ADHD and reviews the diagnostic and symptom assessment instruments available for the evaluation of ADHD in this population. (journal abstract)

BACKGROUND: The high prevalence and morbidity of obsessive compulsive disorder (OCD) in youth, the secretive nature of the disorder leading to under-recognition, and the lack of specialized child psychiatry services in many areas suggest that a simple, quick, and reliable screening tool to identify cases could be very useful to clinicians who work with children. METHOD: We used 8 items from the Child Behavior Checklist (CBCL), an empirically derived instrument free of clinician bias, to investigate the usefulness of a previously reported CBCL-based obsessive compulsive scale (OCS) by Nelson et al [Nelson EC, Hanna GL, Hudziak JJ, Botteron KN, Heath AC, Todd RD. Obsessive-compulsive scale of the Child Behavior Checklist: Specificity, sensitivity, and predictive power. Pediatrics 2001;108(1):E14] in a separate cohort of youth with OCD. We computed the psychometric properties of the OCS in our sample of youth with OCD and in psychiatric and normal controls, and compared these to the published values. RESULTS: Using the recommended cutoff between the 60th and 70th percentiles of the OCS to best predict the presence of OCD, we found very high sensitivity (92%-78%), specificity (86%-94%), negative predictive value (96%-90%), and positive predictive value (77%-86%). CONCLUSIONS: The OC scale of the CBCL shows good reliability and validity and acceptable psychometric properties to help discriminate youth with OCD.

The authors describe "collaborative problem solving," a cognitive-behavioral approach for working with aggressive children and adolescents. The model conceptualizes aggressive behavior as the byproduct of lagging cognitive skills in the domains of flexibility, frustration tolerance, and problem solving. The goal is to train staff to assess specific cognitive skills that may be contributing to challenging behavior and to teach children new skills through collaborative problem solving. The authors present results from an inpatient unit that dramatically reduced rates of seclusion and restraint.

BACKGROUND: A number of reports have shown that patients with panic disorder have greater anxiety responses to the inhalation of enhanced carbon dioxide mixtures than do well controls or patients with other psychiatric illnesses. Three earlier studies have shown that well individuals who have first-degree relatives with panic disorder also experience more anxiety following CO(2) than do controls without such a family history. The following was undertaken to confirm and extend these findings. METHODS: Well subjects at high risk for panic disorder (HR-P, n=132) had a first-degree family member with treated panic disorder but no personal history of panic attacks. Low-risk subjects (LR-C, n=85) had no such family history. All underwent a diagnostic interview with the SADS-LA and completed a battery of self-rating scales before undergoing two CO(2) challenges. One involved a single vital capacity breath of air and then of 35% CO(2) and the other 5 min of air and then 5 min of 5% CO(2). RESULTS: In comparison to the LR-C group, HR-P subjects had higher scores on various self-ratings of anxiety and depression and were more likely to have a lifetime diagnosis of MDD or of an anxiety disorder. NEO neuroticism and a history of MDD were the most important of these measures in separating the high-risk and low-risk groups. As predicted, the HR-P subjects experienced more anxiety following 35% CO(2) exposure. The removal of individuals with lifetime diagnosis of MDD or of an anxiety disorder eliminated the relationship of neuroticism to CO(2)-induced anxiety and strengthened the relationship between the CO(2) response and a family history of panic disorder. Five minutes of 5% CO(2) produced much lower increases in anxiety than did the 35% exposure, but a dose by group interaction suggested that increasing exposure increased anxiety preferentially in the high-risk subjects. CONCLUSION: The results confirm earlier findings in indicating that a family history of panic disorder conveys a liability to experience anxiety with CO(2) exposure. They also suggest that this anxiety may reflect several discrete diatheses of relevance to the heritability of panic disorder

OBJECTIVE: To develop a model of risk factors for posttraumatic stress disorder (PTSD) symptoms in parents of children with burns. METHODS: Immediately following the burn and 3 months later, parents reported on their children's and their own psychological functioning and traumatic stress responses. RESULTS: Approximately 47% of the parents reported experiencing significant posttraumatic stress symptoms 3 months after the burn. Our model indicates three independent pathways to PTSD symptoms (i.e., parent-child conflict, parents' dissociation, and children's PTSD symptoms). Additionally, parents' anxiety predicted increased parent-child conflict, conflict with extended family and size of the burn predicted parents' dissociation, and size of the burn and children's dissociation predicted children's PTSD symptoms. CONCLUSIONS: This study suggests that many parents of children with burns suffer from posttraumatic stress symptoms. Interventions that target factors such as family conflict, children's symptoms, and parents' acute anxiety and dissociation may diminish the risk for PTSD