Faculty Bibliography

OBJECTIVE: The sociocommunicative abnormalities of young children with Williams syndrome (WS) with limited language were compared with those of children with clinical diagnoses of autism, Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS), or nonspectrum developmental disability. METHOD: Participants were 30 children with WS and individually matched groups of participants with autism (n = 28), PDD-NOS (n = 17), and mixed etiology nonspectrum developmental disabilities (n = 16). The autism, PDD-NOS, and mixed etiology groups were matched individually to the children with WS for age, sex, and developmental level. All participants were administered the Autism Diagnostic Observation Schedule Module 1 and the Mullen Scales of Early Learning. RESULTS: As a group, children with WS with limited language showed fewer sociocommunicative abnormalities than children with autism, about the same level as children with PDD-NOS, and more abnormalities in reciprocity social interaction than participants in the mixed etiology group. Examination of the subgroup of participants with WS matched and compared with children with PDD-NOS indicated that half of the children showed fewer abnormalities than their individual matches with PDD-NOS, whereas half of the children with WS showed more abnormalities than their matches with PDD-NOS. CONCLUSION: Sociocommunicative difficulties are present for many children with WS and overlap with the autism spectrum. The results of this investigation suggest that these abnormalities are not accounted for by developmental delay alone, and care should be taken to avoid diagnostic overshadowing in young children with WS

BACKGROUND: Increased systemic cytokine levels, modulators of the immune system, have been repeatedly documented in adult and adolescent major depressive disorder (MDD). This preliminary study extends this work to test the role of cytokines in suicidal symptomatology in adolescent MDD. Hypotheses were that acutely suicidal depressed adolescents would have: (1) increased plasma levels of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1beta, and (2) a proinflammatory/antiinflammatory cytokine imbalance (indexed by plasma IFN-gamma/IL-4), compared to nonsuicidal depressed adolescents and healthy controls. METHODS: Twelve suicidal adolescents with MDD (7 females [58%]; 5 medication-free/naive), 18 nonsuicidal adolescents with MDD (12 females [67%]; 8 medication-free/naive), and 15 controls (8 females [53%]) were enrolled. MDD had to be of at least 6 weeks duration, with a minimum severity score of 40 on the Children's Depression Rating Scale-Revised. Plasma cytokines were examined using enzyme-linked immunosorbent assays. Nonparametric tests were used to compare subject groups. RESULTS: Unexpectedly, suicidal adolescents with MDD had significantly decreased plasma TNF-alpha concentrations compared to nonsuicidal adolescents with MDD (1.33 +/- 2.95 pg/mL versus 30.9 +/- 110.9 pg/mL; p = 0.03). IFN-gamma was increased in both suicidal and nonsuicidal adolescents with MDD compared to controls (2.14 +/- 6.22 and 4.20 +/- 14.48 versus 0.37 +/- 0.64; p < 0.02, p = 0.005). Findings remained evident when controlled for age and gender. CONCLUSIONS: Our preliminary findings suggest that immune system dysregulation may be associated with suicidal symptomatology in adolescent MDD. These findings should be replicated in larger samples with medication-free adolescents

This study tested the hypothesis that very young children who received more morphine for acute burns would have larger decreases in posttraumatic symptoms 3 to 6 months later. This has never before been studied in very young children, despite the high frequency of burns and trauma in this age group. Seventy 12- to 48-month-old nonvented children with acute burns admitted to a major pediatric burn center and their parents participated. Parents were interviewed at three time points: during their child's hospitalization, 1 month, and 3 to 6 months after discharge. Measures included the Child Stress Disorders Checklist - Burn Version (CSDC-B). Chart reviews were conducted to obtain children's morphine dosages during hospitalization. Mean equivalency dosages of morphine (mg/kg/d) were calculated to combine oral and intravenous administrations. Eleven participants had complete 3 to 6-month data on the CSDC. The correlation between average morphine dose and amount of decrease in posttraumatic stress disorder symptoms on the CSDC (r = -0.32) was similar to that found in studies with older children. The correlation between morphine dose and amount of decrease in symptoms on the arousal cluster of the CSDC was significant (r = -0.63, P < .05). Findings from the current study suggest that, for young children, management of pain with higher doses of morphine may be associated with a decreasing number of posttraumatic stress disorder symptoms, especially those of arousal, in the months after major trauma. This extends, with very young children, the previous findings with 6- to 16-year olds

OBJECTIVE: As perinatally human immunodeficiency virus (HIV)-infected (PHIV+) youths enter adolescence, they are at high risk for poor behavioral and health outcomes. This study examines relations between youth mental health problems and sexual and substance use risk behavior, the impact of caregiver mental health and family functioning on youth mental health and risk behavior outcomes, and the role of youth HIV status in this process. METHOD: Participants were recruited from four medical centers. Individual interviews were administered to 193 PHIV+ and 127 perinatally HIV exposed but uninfected (PHIV-) 9- to 16-year-old boys and girls and their primary caregivers. Participants were primarily African American and Latino. The interview assessed child sexual and drug risk behavior, child and caregiver mental health, and family functioning. RESULTS: Exploratory latent-variable structural equation modeling revealed no differences in rates of sexual risk behavior or substance use between PHIV+ and PHIV- youths. However, adolescent mental health was significantly associated with sexual risk behavior and substance use. Caregiver mental health was associated with youth mental health and indirectly with sexual risk behavior and drug use through its impact on youth mental health. Family functioning did not significantly predict youth outcomes. CONCLUSIONS: Over and above other key environmental factors and family functioning, youth and caregiver mental health problems are related to sex and drug use risk behaviors in PHIV+ and PHIV- youths. Given high rates of youth and caregiver mental health problems in this population, family-based mental health interventions may be a key component of HIV prevention programs for perinatally HIV-exposed youth.

Addiction is increasingly understood as a neurobiological illness where repetitive substance abuse corrupts the normal circuitry of rewarding and adaptive behaviors causing drug-induced neuroplastic changes. The addictive process can be examined by looking at the biological basis of substance initiation to the progression of substance abuse to dependence to the enduring risk of relapse. Critical neurotransmitters and neurocircuits underlie the pathological changes at each of these stages. Enhanced dopamine transmission in the nucleus accumbens is part of the common pathway for the positively rewarding aspects of drugs of abuse and for initiation of the addictive process. F-Aminobutyric acid,opioid peptides, serotonin, acetylcholine, the endocannabinoids, and glutamate systems also play a role in the initial addictive process. Dopamine also plays a key role in conditioned responses to drugs of abuse, and addiction is now recognized as a disease of pathological learning and memory. In the path from substance abuse to addiction, the neurochemistry shifts from a dopamine-based behavioral system to a predominantly glutamate-based one marked by dysregulated glutamate transmission from the prefrontal cortex to the nucleus accumbens in relation to drug versus biologically oriented stimuli. This is a core part of the executive dysfunction now understood as one of the hallmark features of addiction that also includes impaired decision making and impulse dysregulation.Understanding the neurobiology of the addictive process allows for a theoretical psychopharmacological approach to treating addictive disorders,one that takes into account biological interventions aimed at particular stages of the illness

The alpha-2-adrenoreceptor agonist, medetomidine, which exhibits dose-dependent sedative effects and is gaining acceptance in small-animal functional magnetic resonance imaging (fMRI), has been studied. Rats were examined on the bench using the classic tail-pinch method with three infusion sequences: 100 microg/kg/h, 300 microg/kg/h, or 100 microg/kg/h followed by 300 microg/kg/h. Stepping the infusion rate from 100 to 300 microg/kg/h after 2.5 h resulted in a prolonged period of approximately level sedation that cannot be achieved by a constant infusion of either 100 or 300 microg/kg/h. By stepping the infusion dosage, experiments as long as 6 h are possible. Functional MRI experiments were carried out on rats using a frequency dependent electrical stimulation protocol-namely, forepaw stimulation at 3, 5, 7, and 10 Hz. Each rat was studied for a four-hour period, divided into two equal portions. During the first portion, rats were started at a 100 microg/kg/h constant infusion. During the second portion, four secondary levels of infusion were used: 100, 150, 200, and 300 microg/kg/h. The fMRI response to stimulation frequency was used as an indirect measure of modulation of neuronal activity through pharmacological manipulation. The frequency response to stimulus was attenuated at the lower secondary infusion dosages 100 or 150 microg/kg/h but not at the higher secondary infusion dosages 200 or 300 microg/kg/h. Parallel experiments with the animal at rest were carried out using both electroencephalogram (EEG) and functional connectivity MRI (fcMRI) methods with consistent results. In the secondary infusion period using 300 microg/kg/h, resting-state functional connectivity is enhanced.

Numerous studies in animals and humans have shown that the hippocampus (HP) is involved in spatial navigation and memory. Blind subjects, in particular, must memorize extensive information to compensate for their lack of immediate updating of spatial information. Increased demands on spatial cognition and memory may be associated with functional and structural HP plasticity. Here we examined local size and shape differences in the HP of blind and sighted individuals. A 3D parametric mesh surface was generated to represent right and left HPs in each individual, based on manual segmentations of 3D volumetric T1-weighted MR images of 22 blind subjects and 28 matched controls. Using a new surface mapping algorithm described in (Shi, Y., Thompson, P.M., de Zubicaray, G.I., Rose, S.E., Tu, Z., Dinov, I., Toga, A.W., Direct mapping of hippocampal surfaces with intrinsic shape context, NeuroImage, Available online May 24, (In Press).), we created an average hippocampal surface for the controls, and computed its normal distance to each individual surface. Statistical maps were created to visualize systematic anatomical differences between groups, and randomization tests were performed to correct for multiple comparisons. In both scaled and unscaled data, the anterior right HP was significantly larger, and the posterior right HP significantly smaller in blind individuals. No significant differences were found for left HP. These differences may reflect adaptive responses to sensory deprivation, and/or increased functional demands on memory systems. They offer a neuroanatomical substrate for future correlations with measures of navigation performance or functional activations related to variations in cognitive strategies

Non-specific responses to treatment (commonly known as placebo response) are pervasive when treating mental illness. Subjects treated with an active drug may respond in part due to non-specific aspects of the treatment, i.e, those not related to the chemical effect of the drug. To determine the extent a subject responds due to the chemical effect of a drug, one must disentangle the specific drug effect from the non-specific placebo effect. This paper presents a unique statistical model that allows for the separate prediction of a specific effect and non-specific effects in drug treated subjects. Data from a clinical trial comparing fluoxetine to a placebo for treating depression is used to illustrate this methodology.

BACKGROUND: Positron emission tomography (PET) can localize and quantify neurokinin-1 (NK(1)) receptors in brain using the nonpeptide antagonist radioligand, [(18)F]SPA-RQ. We sought to determine if patients with panic disorder have altered density of NK(1) receptors in brain because of their history of recurrent panic attacks. We also sought to determine if a drug-induced panic attack releases substance P in brain, as measured by decreased binding of [(18)F]SPA-RQ. METHODS: Positron emission tomography scans with [(18)F]SPA-RQ were performed in 14 patients with panic disorder and 14 healthy subjects. Of these two groups, 7 patients and 10 healthy subjects were scanned twice, once at baseline and once after injection of doxapram, a drug that induces panic attacks. RESULTS: NK(1) receptor binding in patients (n = 14) compared with that in healthy subjects (n = 14) was significantly decreased by 12% to 21% in all brain regions. Doxapram effectively produced panic attacks in 6 of 7 patients with panic disorder but only 2 of 10 healthy subjects. Doxapram caused no significant change of [(18)F]SPA-RQ binding in either patients or healthy subjects. CONCLUSIONS: Although induction of a panic attack has no significant effect on [(18)F]SPA-RQ binding to NK(1) receptors, patients with panic disorder have widespread reduction of NK(1) receptor binding in brain.

BACKGROUND: Uncontrollability and unpredictability are key concepts related to re-experiencing, avoidance, and hypervigilance symptoms of posttraumatic stress disorder (PTSD). However, little is known about the differential sensitivity of PTSD individuals to unpredictable stressors, relative to either healthy individuals or individuals with other anxiety disorders. This study tested the hypothesis that elevated anxious reactivity, specifically for unpredictable aversive events, is a psychophysiological correlate of PTSD. METHODS: Sixteen patients with PTSD (34.5 +/- 12.4 years) were compared with 18 patients with generalized anxiety disorder (GAD) (34.0 +/- 10.5 years) and 34 healthy control subjects (30.2 +/- 8.5 years). Participants were exposed to three conditions: one in which predictable aversive stimuli were signaled by a cue, a second in which aversive stimuli were administered unpredictably, and a third in which no aversive stimuli were anticipated. Startle magnitude was used to assess anxious responses to the threat cue and to contexts associated with each condition. RESULTS: Posttraumatic stress disorder and GAD patients showed normative enhancement of fear to the predictable threat cue, but the PTSD group displayed elevated anxiety during the unpredictable condition compared with participants with GAD and healthy control subjects. CONCLUSIONS: Anxious reactivity to unpredictable aversive events was heightened in PTSD but not in GAD and healthy subjects. Prior works also found signs of increased reactivity to unpredictable threat in panic disorder (PD), suggesting that PTSD and PD may involve shared vulnerability. As such, the current results inform understandings of classification, pathophysiology, and psychopharmacology of anxiety disorders, generally, and PTSD and panic disorder specifically.