Faculty Bibliography

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

The beneficial effect of sleep on memory has been well-established by extensive research on humans, but the neurophysiological mechanisms remain a matter of speculation. This study addresses the hypothesis that the fast oscillations known as ripples recorded in the CA1 region of the hippocampus during slow wave sleep (SWS) may provide a physiological substrate for long term memory consolidation. We trained rats in a spatial discrimination task to retrieve palatable reward in three fixed locations. Hippocampal local field potentials and cortical EEG were recorded for 2 h after each daily training session. There was an increase in ripple density during SWS after early training sessions, in both trained rats and in rats randomly rewarded for exploring the maze. In rats learning the place -reward association, there was a striking further significant increase in ripple density correlated with subsequent improvements in behavioral performance as the rat learned the spatial discrimination aspect of the task. The results corroborate others showing an experience-dependent increase in ripple activity and associated ensemble replay after exploratory activity, but in addition, for the first time, reveal a clear further increase in ripple activity related to associative learning based on spatial discrimination

Autism spectrum disorders (ASD) impact social functioning and communication, and individuals with these disorders often have restrictive and repetitive behaviors. Accumulating data indicate that ASD is associated with alterations of neural circuitry. Functional MRI (FMRI) studies have focused on connectivity in the context of psychological tasks. However, even in the absence of a task, the brain exhibits a high degree of functional connectivity, known as intrinsic or resting connectivity. Notably, the default network, which includes the posterior cingulate cortex, retro-splenial, lateral parietal cortex/angular gyrus, medial prefrontal cortex, superior frontal gyrus, temporal lobe, and parahippocampal gyrus, is strongly active when there is no task. Altered intrinsic connectivity within the default network may underlie offline processing that may actuate ASD impairments. Using FMRI, we sought to evaluate intrinsic connectivity within the default network in ASD. Relative to controls, the ASD group showed weaker connectivity between the posterior cingulate cortex and superior frontal gyrus and stronger connectivity between the posterior cingulate cortex and both the right temporal lobe and right parahippocampal gyrus. Moreover, poorer social functioning in the ASD group was correlated with weaker connectivity between the posterior cingulate cortex and the superior frontal gyrus. In addition, more severe restricted and repetitive behaviors in ASD were correlated with stronger connectivity between the posterior cingulate cortex and right parahippocampal gyrus. These findings indicate that ASD subjects show altered intrinsic connectivity within the default network, and connectivity between these structures is associated with specific ASD symptoms

ABSTRACT: BACKGROUND: Sleep problems are common in adults with attention-deficit/hyperactivity disorder (ADHD). This analysis aimed to evaluate the impact of lisdexamfetamine dimesylate (LDX) on sleep quality in adults with ADHD. METHODS: This 4-week, phase 3, double-blind, forced-dose escalation study of adults aged 18 to 55 years with ADHD randomized participants to receive placebo (n = 62), or 30 (n = 119), 50 (n = 117), or 70 (n = 122) mg/d LDX, taken once a day in the morning. The self-rated Pittsburgh Sleep Quality Index (PSQI) was administered at baseline and at week 4 to assess sleep quality. The PSQI global score assesses 7 sleep components (subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction) each scored from 0 (no difficulty) to 3 (severe difficulty). RESULTS: The mean baseline PSQI global score was 5.8 for LDX and 6.3 for placebo (P = .19) indicating poor overall sleep quality. At endpoint, least squares (LS) mean change from baseline was -0.8 for LDX vs -0.5 for placebo (P = .33). The daytime functioning component showed significant improvement in LS mean change at endpoint for LDX compared with placebo (LDX -0.4 vs placebo 0.0, P = .0001). LS mean changes for the other 6 PSQI components did not significantly differ from placebo. Sleep-related treatment-emergent adverse events with an incidence >/=2% in the active treatment and placebo groups, respectively, were insomnia (19.3% and 4.8%), initial insomnia (5.0% and 3.2%), middle insomnia (3.6% and 0%), sleep disorder (0.6% and 3.2%), somnolence (0.3% and 3.2%), and fatigue (4.7% and 4.8%), and were generally mild or moderate in severity. CONCLUSION: For most subjects, LDX was not associated with an overall worsening of sleep quality and significantly improved daytime functioning in adults with ADHD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00334880

Numerous clinical trials have demonstrated the efficacy of cognitive behavior therapy (CBT) for the treatment of childhood Separation Anxiety Disorder (SAD) and other anxiety disorders (Velting, Setzer, & Albano, 2004), yet additional research may still be needed to better access and engage anxious youth (Kendall, Suveg, & Kingery, 2006). In this study, we investigated the acceptability and preliminary utility of a group cognitive-behavioral intervention for school-aged girls with SAD provided within an intensive, 1-week setting. The development of the proposed treatment strategy, a 1-week summer treatment program, was predicated on evidence supporting the need for childhood treatments that are developmentally sensitive, allow for creative application of intervention components, incorporate a child's social context, and ultimately establish new pathways for dissemination to the community. The summer treatment program for SAD was pilot-tested using a case-series design with 5 female children, aged 8 to 11, each with a principal diagnosis of SAD. For 4 of the 5 participants, treatment gains were evidenced by changes in diagnostic status, significant reductions in measures of avoidance, and improvements on self- and parent-report measures of anxiety symptomology. Specifically, severity of SAD symptoms decreased substantially at posttreatment for each participant and, 2 months following treatment, none of the participants met diagnostic criteria for the disorder. A fifth participant experienced substantive improvement in diagnostic status prior to the onset of treatment and, though she evidenced continued improvements following treatment, the role of the intervention in such improvements is less clear

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

Monkeys separated from their mothers soon after birth and raised with peers display many disturbances in emotional behavior that are similar to human mood and anxiety disorders. In addition to emotional disturbances, both mood and anxiety disorders are often characterized by disruptions in normal sleep-wake cycles, a behavior that has not been well characterized in adversely reared non-human primates. Because polysomnographic measures are difficult to obtain in unrestrained monkeys we used 24-h actigraphy measures to assess probable sleep-wake patterns in juvenile nursery- and mother-reared rhesus macaques (Macaca mulatta, N=16) over several days in the home cage. In addition we assayed plasma cortisol in the morning, afternoon, and evening. Relative to mother-reared (MR) monkeys, actigraphic algorithms indicated that nursery-reared (NR) animals had shorter durations of nocturnal sleep, earlier morning waking, and longer periods of sleep during the active period, specifically in the mid morning. No shift in diurnal patterns of cortisol was observed, but NR animals displayed an overall elevation in cortisol. Finally a significant interaction was found between cortisol and actigraphic determination of sleep efficiency in the two groups. A strong positive relationship (r(2)>0.8) was found between mean cortisol levels and sleep efficiency for the MR monkeys, but a significant negative relationship was found between these same variables for the NR monkeys, indicating a fundamentally different relationship between waking cortisol and actigraphy patterns in these two groups.

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