Faculty Bibliography

Background: Complex ventricular-arterial (VA) relationships in patients with double outlet right ventricle (DORV) make preoperative assessment of potential repair pathways challenging. The relationship of the ventricular septal defect (VSD) to one or both great arteries must be understood and this influences the choice of surgical procedure [1] In neonates and infants with DORV, Computed Tomography (CT) is often performed due to the ability to get high spatial resolution and ECG gated images [2], however it is possible to get the necessary information from Magnetic Resonance (MR) imaging with an added advantage of avoiding exposure to ionizing radiation. Both CT and MR allow image acquisition in three dimensions (3D) but traditional viewing of the anatomy using the multiplanar reformatting is actually done in two dimensions (2D). Volume rendering from either modality may also be performed, but typically only the external vascular anatomy is depicted. We hypothesized that it is possible to accurately define the intracardiac anatomy in infants with DORV using virtual and physical 3D printed (rapid prototyped) models created from either MR or CT and this can both aid in better defining potential VA pathways and may assist in surgical decision making. Methods: Virtual and physical 3D models were generated for three patients with DORV. Non-ECG-gated 3D spoiled fast gradient echo sequence MR angiography was used for two patients. Retrospective ECG gated CT angiography images acquired in diastole were used in the third patient (to better define the coronary arteries given the suspicion of a single coronary artery by echocardiography). Blood pool segmentation (Figure 1a) was performed in all the three patients (Mimics, Materialise, Leuven, Belgium). A 2 mm shell was added to the blood pool and it was hollowed to create a patient specific heart replica (3-matic, Materialise, Leuven, Belgium). All virtual models were cut to best demonstrate the VA relationships and the models were printed. Results: The VSD and VA relationships were well visualized in all three patients using both the virtual and physical models (Figure 1b,c). The models helped the surgeons better understand the anatomy in all patients: in two patients the surgical plan was altered while the plan was confirmed in the third patient (Table 1). Conclusions: Construction of 3D models in patients with DORV is feasible and allows for extensive examination and surgical planning. This may facilitate a focused and informed surgical procedure and improve the potential for successful outcome. For purposes of DORV, non-gated MRA is sufficient to delineate the VA relationships adequately for 3D printing and enhanced clinical decision-making. CT imaging should be reserved for only those patients where additional information like coronary artery anatomy is desired

Functional analysis of a clinical microbiome facilitates the elucidation of mechanisms by which microbiome perturbation can cause a phenotypic change in the patient. The direct approach for the analysis of the functional capacity of the microbiome is via shotgun metagenomics. An inexpensive method to estimate the functional capacity of a microbial community is through collecting 16S rRNA gene profiles then indirectly inferring the abundance of functional genes. This inference approach has been implemented in the PICRUSt and Tax4Fun software tools. However, those tools have important limitations since they rely on outdated functional databases and uncertain phylogenetic trees and require very specific data pre-processing protocols. Here we introduce Piphillin, a straightforward algorithm independent of any proposed phylogenetic tree, leveraging contemporary functional databases and not obliged to any singular data pre-processing protocol. When all three inference tools were evaluated against actual shotgun metagenomics, Piphillin was superior in predicting gene composition in human clinical samples compared to both PICRUSt and Tax4Fun (p<0.01 and p<0.001, respectively) and Piphillin's ability to predict disease associations with specific gene orthologs exhibited a 15% increase in balanced accuracy compared to PICRUSt. From laboratory animal samples, no performance advantage was observed for any one of the tools over the others and for environmental samples all produced unsatisfactory predictions. Our results demonstrate that functional inference using the direct method implemented in Piphillin is preferable for clinical biospecimens. Piphillin is publicly available for academic use at http://secondgenome.com/Piphillin.

We measured saccadic latencies in a large sample (total n = 459) of individuals with amblyopia or risk factors for amblyopia, e.g., strabismus or anisometropia, and normal control subjects. We presented an easily visible target randomly to the left or right, 3.5 degrees from fixation. The interocular difference in saccadic latency is highly correlated with the interocular difference in LogMAR (Snellen) acuity-as the acuity difference increases, so does the latency difference. Strabismic and strabismic-anisometropic amblyopes have, on average, a larger difference between their eyes in LogMAR acuity than anisometropic amblyopes and thus their interocular latency difference is, on average, significantly larger than anisometropic amblyopes. Despite its relation to LogMAR acuity, the longer latency in strabismic amblyopes cannot be attributed either to poor resolution or to reduced contrast sensitivity, because their interocular differences in grating acuity and in contrast sensitivity are roughly the same as for anisometropic amblyopes. The correlation between LogMAR acuity and saccadic latency arises because of the confluence of two separable effects in the strabismic amblyopic eye-poor letter recognition impairs LogMAR acuity while an intrinsic sluggishness delays reaction time. We speculate that the frequent microsaccades and the accompanying attentional shifts, made while strabismic amblyopes struggle to maintain fixation with their amblyopic eyes, result in all types of reactions being irreducibly delayed.

It is well known that hormones affect both brain and behavior, but less is known about the extent to which hormones affect economic decision-making. Numerous studies demonstrate gender differences in attitudes to risk and loss in financial decision-making, often finding that women are more loss and risk averse than men. It is unclear what drives these effects and whether cyclically varying hormonal differences between men and women contribute to differences in economic preferences. We focus here on how economic rationality and preferences change as a function of menstrual cycle phase in women. We tested adherence to the Generalized Axiom of Revealed Preference (GARP), the standard test of economic rationality. If choices satisfy GARP then there exists a well-behaved utility function that the subject's decisions maximize. We also examined whether risk attitudes and loss aversion change as a function of cycle phase. We found that, despite large fluctuations in hormone levels, women are as technically rational in their choice behavior as their male counterparts at all phases of the menstrual cycle. However, women are more likely to choose risky options that can lead to potential losses while ovulating; during ovulation women are less loss averse than men and therefore more economically rational than men in this regard. These findings may have market-level implications: ovulating women more effectively maximize expected value than do other groups.

Introduction: Delayed sleep and meal timing promote metabolic dysregulation and obesity. Altered coordination of sleep and eating may impact food reward valuation in the brain; yet the independent and collective contribution of sleep and meal times remains unknown. This pilot, randomized crossover study manipulates both sleep and meal times while preserving normal sleep duration (8 h time in bed for 5 nights) to test how misalignment of sleeping and eating behaviors affects intrinsic functional connectivity (iFC) across reward and interoception-related brain circuitry. Methods: Resting state functional MRI scans (3T Siemens Skyra; TR = 2.5s; 2 x ~5-minute runs) were obtained for 4 participants (3 males; 25.3 +/- 4.6 years) who completed all 4 phases (normal sleep/normal meal; late sleep/normal meal; normal sleep/late meal; late sleep/late meal). Normal meal times were 1, 5, 11, and 12.5 h after awakening and late meal times were 4.5, 8.5, 14.5 and 16 h after awakening. For a priori selected regions-of-interest (seeds) relevant to food reward and interoception, each seed's iFC was calculated as the correlation between its time-series and that of every voxel, and then contrasted between conditions. Standard preprocessing and seed-based correlations used the Configurable Pipeline for the Analysis of Connectomes v0.3.9. Results: Statistically significant (p late) additionally significantly modulated iFC between left ventral striatum and precuneus. Other significant iFC modulations of components of reward and interoception circuitry will also be presented. Conclusion: These pilot findings provide support that misalignment of sleep and food timing alters iFC in regions relevant to food reward and interoception, motivating examination in a larger sample

The hippocampus is critical for the storage of new autobiographical experiences as memories. Following an initial encoding stage in the hippocampus, memories undergo a process of systems-level consolidation, which leads to greater stability through time and an increased reliance on neocortical areas for retrieval. The extent to which the retrieval of these consolidated memories still requires the hippocampus is unclear, as both spared and severely degraded remote memory recall have been reported following post-training hippocampal lesions. One difficulty in definitively addressing the role of the hippocampus in remote memory retrieval is the precision with which the entire volume of the hippocampal region can be inactivated. To address this issue, we used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), a chemical-genetic tool capable of highly specific neuronal manipulation over large volumes of brain tissue. We find that remote (>7 weeks after acquisition), but not recent (1-2 days after acquisition) contextual fear memories can be recalled after injection of the DREADD agonist (CNO) in animals expressing the inhibitory DREADD in the entire hippocampus. Our data demonstrate a time-dependent role of the hippocampus in memory retrieval, supporting the standard model of systems consolidation.

In recent years, tau immunotherapy has advanced from proof-of-concept studies [Sigurdsson EM, NIH R01AG020197, 2001; Asuni AA, et al: J Neurosci 2007;27:9115-9129], which have now been confirmed and extended by us and others. Phase I clinical trials on active and passive tau immunizations are being conducted, with several additional passive tau antibody trials likely to be initiated in the near future for Alzheimer's disease and other tauopathies. Because tau pathology correlates better with the degree of dementia than amyloid-beta (Abeta) pathology, greater clinical efficacy may be achieved by clearing tau than Abeta aggregates in the later stages of the disease, when cognitive impairments become evident. Substantial insight has now been obtained regarding which epitopes to target, mechanism of action and potential toxicity, but much remains to be clarified. All of these factors likely depend on the model/disease or stage of pathology and the immunogen/antibody. Interestingly, tau antibodies interact with the protein both extra- and intracellularly, but the importance of each site for tau clearance is not well defined. Some antibodies are readily taken up into neurons, whereas others are not. It can be argued that extracellular clearance may be safer but less efficacious than intraneuronal clearance and/or sequestration to prevent secretion and further spread of tau pathology. Development of therapeutic tau antibodies has led to antibody-derived imaging probes, which are more specific than the dye-based compounds that are already in clinical trials. Such specificity may give valuable information on the pathological tau epitope profile, which could then guide the selection of therapeutic antibodies for maximal efficacy and safety. Hopefully, tau immunotherapy will be effective in clinical trials, and further advanced by mechanistic clarification in experimental models with insights from biomarkers and postmortem analyses of clinical subjects.

How stem cells produce the huge diversity of neurons that form the visual system, and how these cells are assembled in neural circuits are a critical question in developmental neurobiology. Investigations in Drosophila have led to the discovery of several basic principles of neural patterning. In this chapter, we provide an overview of the field by describing the development of the Drosophila visual system, from the embryo to the adult and from the gross anatomy to the cellular level. We then explore the general molecular mechanisms identified that might apply to other neural structures in flies or in vertebrates. Finally, we discuss the major challenges that remain to be addressed in the field.