Faculty Bibliography

BACKGROUND: There is a virtual avalanche of medical information available to clinicians and researchers. The traditional 'search' can be substantially augmented by proactive 'harvesting.' AIMS: To describe how to search and harvest the medical literature. MATERIALS & METHODS: Survey of selected resources available on the internet. RESULTS: PubMed remains the backbone of the traditional literature search. The availability of automated delivery of electronic tables of contents ('eTOCs'), electronic feeds of targeted search results, and workflow tools allows relevant articles to find the reader. Electronic storage and retrieval tools make it possible to manage this information and make day-to-day clinical and research activities more efficient. DISCUSSION: Searching and harvesting the medical literature is made easier with the advent of the internet and email. In addition, there are internet resources that screen and filter potential articles of interest. Managing one's electronic library of PDF documents requires attention to appropriately naming files and the use of indexing programs. CONCLUSION: In addition to readers searching for relevant citations, these citations themselves can be searching for readers. Clinicians and researchers can take advantage of this and efficiently harvest the medical literature with a modest investment of time

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.

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.

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.

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 authors examined the association of serum perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with self-reported pregnancy outcome in Mid-Ohio Valley residents (2000-2006) highly exposed to PFOA. Data on 1,845 pregnancies within the 5 years preceding exposure measurement were analyzed for PFOA, and data on 5,262 pregnancies were analyzed for PFOS. Generalized estimating equations were used to calculate adjusted odds ratios and 95% confidence intervals. Neither PFOA nor PFOS showed any association with miscarriage or preterm birth. Preeclampsia was weakly associated with PFOA (adjusted odds ratio = 1.3, 95% confidence interval: 0.9, 1.9) and PFOS (adjusted odds ratio = 1.3, 95% confidence interval: 1.1, 1.7) exposures above the median. PFOA was not associated with an increase in low birth weight, but PFOS showed an increased risk above the median (adjusted odds ratio = 1.5, 95% confidence interval: 1.1, 1.9) and a dose-response gradient. Birth defects were weakly associated with PFOA exposures above the 90th percentile (adjusted odds ratio = 1.7, 95% confidence interval: 0.8, 3.6). This study identified modest associations of PFOA with preeclampsia and birth defects and of PFOS with preeclampsia and low birth weight, but associations were small, limited in precision, and based solely on self-reported health outcomes.

BACKGROUND: Childhood sexual abuse (CSA) has been associated with alterations in brain morphology using region of interest analyses that have focused on stress-sensitive target regions. This study was designed to ascertain the effects on gray matter volume (GMV) of exposure to CSA in healthy young adult college students selected based on exposure history regardless of psychiatric outcome. Voxel-based morphometry (VBM) provided unbiased delineation of the most significantly affected brain regions. METHODS: High-resolution T1-weighted magnetic resonance imaging (MRI) datasets were obtained for 23 unmedicated female subjects with CSA and 14 healthy female control subjects of equivalent age and socioeconomic status with no history of trauma. Cortical surface-based analysis (FreeSurfer) was performed to verify VBM results. RESULTS: Gray matter volume was reduced by 12.6% and 18.1% in right and left primary visual (V1) and visual association cortices of abused subjects. This reduction was directly related to duration of CSA before age 12. Gray matter volume of left and right V1 correlated with measure of visual memory (r = .353, p = .032 and r = .448, p = .005). Cortical surface-based analysis indicated that GMV of abused subjects was reduced in the left fusiform (p = .004), left middle occipital (p = .04), and right lingual (p = .002) gyri. CONCLUSIONS: Early visual experience exerts a strong influence on the developing mammalian visual cortex. Present findings indicate that exposure to CSA may also affect the development of this region and are apparent even in a population of subjects who are sufficiently healthy to matriculate

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