Faculty Bibliography

Unintended consequences of participating in research studies are not well characterized, particularly in veterans who are frequent study participants. Our objective, then, was to assess the rate of and variables associated with distress resulting from veterans' participation in a study on a sensitive subject. Veterans Administration (VA) hospital outpatients were administered questionnaires with three increasingly severe scenarios of a U.S. soldier abusing a detainee. Distress--upset requiring clinical intervention--was assessed, as were sociodemographic characteristics, post-traumatic stress disorder (PTSD), depression, and locus of control (LOC). Three hundred fifty-one veterans participated. Forty-three (12%) became distressed. Modeling indicated distress was associated with minority status (odds ratio [OR] = 5.72, 95% confidence interval [CI] = 1.59, 20.58), PTSD (OR = 2.66, 95% CI = 1.12, 6.29), and external LOC (OR = 6.27, 95% CI = 2.82, 13.90). Distress related to study participation was high in this veteran sample. Higher rates in some subgroups suggested that some individuals may not be able to accurately anticipate risk for harm in sensitive studies.

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study was funded by the National Institute of Mental Health to compare the effectiveness of drugs for schizophrenia. The focus here is not on its conclusions but on the knotty issues of design and methods, in order to support appropriate clinical interpretation of the conclusions, and on using the CATIE experience to indicate directions for improvement of future clinical trials. While many of the CATIE design and implementation decisions are excellent and serve as models for future research, other decisions resulted in a study with a large study group but inadequate power. Multiple treatment interventions, unbalanced randomization within and across clinical sites, and multiple secondary outcomes are among the issues that require even more serious consideration in future large multisite clinical trials. Moreover, it is crucial to clarify whether the intent of a study is to establish superiority of some treatments or to establish equivalence, for the appropriate designs and analyses differ in these situations. If the study is designed, as was CATIE, to demonstrate some treatments' superiority, statistically nonsignificant results should not be misinterpreted as evidence of "equivalence." For establishing either superiority or equivalence, future treatment comparisons might better be designed with fewer sites, more subjects per site, fewer treatments, and fewer outcomes, in order to have the power for definitively establishing superiority or equivalence at a lower cost.

Behavioral inhibition (BI) is characterized by a pattern of extreme social reticence, risk for internalizing behavior problems, and possible protection against externalizing behavior problems. Parenting style may also contribute to these associations between BI and behavior problems (BP). A sample of 113 children was assessed for BI in the laboratory at 14 and 24 months of age, self-report of maternal parenting style at 7 years of age, and maternal report of child internalizing and externalizing BP at 4, 7, and 15 years. Internalizing problems at age 4 were greatest among behaviorally inhibited children who also were exposed to permissive parenting. Furthermore, greater authoritative parenting was associated with less of an increase in internalizing behavior problems over time and greater authoritarian parenting was associated with a steeper decline in externalizing problems. Results highlight the importance of considering child and environmental factors in longitudinal patterns of BP across childhood and adolescence.

The lateral nucleus of the amygdala (LA) has been implicated in the formation of long-term associative memory (LTM) of stimuli associated with danger through fear conditioning. The current study aims to detect genes that are expressed in LA following associative fear conditioning. Using oligonucleotide microarrays, we monitored gene expression in rats subjected to paired training where a tone co-terminates with a footshock, or unpaired training where the tone and footshock are presented in a non-overlapping manner. The paired protocol consistently leads to auditory fear conditioning memory formation, whereas the unpaired protocol does not. When the paired group was compared with the unpaired group 5 h after training, the expression of genes coding for the limbic system-associated membrane protein (Lsamp), kinesin heavy chain member 2 (Kif2), N-ethylmaleimide-sensitive fusion protein (NSF) and Hippocalcin-like 4 protein (Hpcal4) was higher in the paired group. These genes encode proteins that regulate neuronal axonal morphology (Lsamp, Kif2), presynaptic vesicle cycling and release (Hpcal4 and NSF), and AMPA receptor maintenance in synapses (NSF). Quantitative real-time PCR (qPCR) showed that Kif2 and Lsamp are expressed hours following fear conditioning but minutes after unpaired training. Hpcal4 is induced by paired stimulation only 5 h after the training. These results show that fear conditioning induces a unique temporal activation of molecular pathways involved in regulating synaptic transmission and axonal morphology in LA, which is different from non-associative stimulation

BACKGROUND:Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease. METHODS:Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers. RESULTS:All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. CONCLUSIONS:Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson's disease.

Levels of extra-synaptic dopamine in the brain vary as a function of polymorphisms at the val158met locus of the catechol-O-methyltransferase (COMT) gene. In vivo studies of this polymorphism in the human brain have typically measured patterns of neural activation during dopamine-mediated tasks in adults. This study is the first to investigate the effects of COMT on brain physiology during rest and in children. We used flow-sensitive arterial spin-labeling (ASL) magnetic resonance imaging to examine brain blood flow (CBF) in 42 children. Compared with val-allele carriers, met-allele homozygotes exhibited greater CBF in mesolimbic, mesocortical, and nigrostriatal dopamine (DA) pathways. Higher CBF in DA-rich brain structures reflects COMT-related baseline differences that (1) underlie the selective behavioral advantages associated with each genotype; (2) affect interpretations of previously reported genotype differences in BOLD signal changes; and (3) serve as a foundation for future studies on the effects of COMT on brain development.

The emotional significance of objects and events depends on the context in which they occur. Using functional magnetic resonance imaging, we examined the modulation of neural responses to monetary outcomes while subjects performed a decision-making task in a positive and a negative economic context. Neural responses indicated a relative regional specialization in the neural coding of outcome valence and followed three distinct patterns. The nucleus accumbens (NAc) and orbital frontal cortex (OFC) appeared to code the most extreme outcome in each context, with a potentiated response for favorable outcomes by a positive context. The amygdala and insula appeared to also code highly salient outcomes, but showed a potentiated response to unfavorable outcomes occurring in a negative context. The medial prefrontal cortex (medPFC), on the other hand, only coded favorable responses occurring in a positive context. Moreover, the medPFC showed large inter-individual variability when responding to outcomes in a negative context, suggesting that its role in a negative context may depend on a number of individual factors. The results of this work provide evidence of complex valence-based regional dissociations that are influenced by contextual factors.

Recent neuroimaging studies investigating neural correlates of psychological stress employ cognitive paradigms that induce a significant hormonal stress response in the scanner. The Montreal Imaging Stress Task (MIST) is one such task that combines challenging mental arithmetic with negative social evaluative feedback. Due to the block design nature of the MIST, it has not been possible thus far to investigate which brain areas respond specifically to the key components of the MIST (mental arithmetic, failure, negative social evaluation). In the current study, we developed an event-related MIST (eventMIST) in order to investigate which neural activation patterns are associated with performing mental arithmetic vs. processing of social evaluative threat. Data was available from twenty healthy university students. The eventMIST induced a significant stress response in a subsample of subjects, called the responders (n=7). Direct comparison between brain activity changes in responders vs. non-responders, in response to challenging math, revealed increased activity bilaterally in dorsomedial prefrontal cortex (PFC), left temporal pole, and right dorsolateral PFC. In response to negative social evaluation, responders showed reduction of brain activity in limbic system regions (medial orbitofrontal cortex and hippocampus), which was largely lacking in non-responders. Direct comparison between the groups for this contrast did not reveal any significant difference, probably due to small number of events available. This is the first study to use an event-related paradigm to investigate brain activity patterns in relation to challenging math and social evaluative threat separately

The ability of positive and negative facial signals to influence attention orienting is crucial to social functioning. Given the dramatic developmental change in neural architecture supporting social function, positive and negative facial cues may influence attention orienting differently in relatively young or old individuals. However, virtually no research examines such age-related differences in the neural circuitry supporting attention orienting to emotional faces. We examined age-related correlations in attention-orienting biases to positive and negative face emotions in a healthy sample (N=37; 9-40 years old) using functional magnetic resonance imaging and a dot-probe task. The dot-probe task in an fMRI setting yields both behavioral and neural indices of attention biases towards or away from an emotional cue (happy or angry face). In the full sample, angry-face attention bias scores did not correlate with age, and age did not correlate with brain activation to angry faces. However, age did positively correlate with attention bias towards happy faces; age also negatively correlated with left cuneus and left caudate activation to a happy bias fMRI contrast. Secondary analyses suggested age-related changes in attention bias to happy faces. The tendency in younger children to direct attention away from happy faces (relative to neutral faces) was diminished in the older age groups, in tandem with increasing neural deactivation. Implications for future work on developmental changes in attention-emotion processing are discussed.

The cognitive division of anterior cingulate cortex (ACC-cd) plays an important role in cognitive control via a distributed attention network. The structural hemispheric asymmetries of ACC have been revealed by several neuroimaging studies. However potential functional hemispheric asymmetries of ACC remain less clear. Investigating the functional hemispheric asymmetries of ACC helps for a better understanding of ACC function. The aim of this study was to use resting-state functional magnetic resonance imaging (fMRI) to examine hemispheric differences in the functional networks associated with ACC-cd in the two hemispheres. ROI-based functional connectivity analysis was performed on a group of 49 right-handed healthy volunteers. The left and right ACC-cd showed significant differences in their patterns of connectivity with a variety of brain regions, including the dorsolateral prefrontal cortex, inferior parietal lobule, superior parietal lobule and dorsal posterior cingulate cortex in their ipsilateral cerebral cortex, as well as cerebellar tonsil and inferior semilunar lobule in their contralateral cerebellar hemisphere. Specifically, for these areas, we found significantly greater connectivity strength with ACC-cd in the right hemisphere than the left, regardless of whether the connection was positive or negative. The current results highlight the presence of clear asymmetries in functional networks associated with ACC-cd. Future functional imaging studies are needed to give greater attention to the lateralized ACC functional networks which are observed