Faculty Bibliography

In addition to the well-known signals of retinal image slip, floccular complex spikes (CSs) also convey nonvisual signals. We recorded eye movement and CS activity from Purkinje cells in awake rabbits sinusoidally oscillated in the dark on a vestibular turntable. The stimulus frequency ranged from 0.2 to 1.2 Hz, and the velocity amplitude ranged from 6.3 to 50 degrees /s. The average CS modulation was evaluated at each combination of stimulus frequency and amplitude. More than 75% of the Purkinje cells carried nonvisual CS signals. The amplitude of this modulation remained relatively constant over the entire stimulus range. The phase response of the CS modulation in the dark was opposite to that during the vestibulo-ocular reflex (VOR) in the light. With increased frequency, the phase response systematically shifted from being aligned with contraversive head velocity toward peak contralateral head position. At fixed frequency, the phase response was dependent on peak head velocity, indicating a system nonlinearity. The nonvisual CS modulation apparently reflects a competition between eye movement and vestibular signals, resulting in an eye movement error signal inferred from nonvisual sources. The combination of this error signal with the retinal slip signal in the inferior olive results in a net error signal reporting the discrepancy between the actual visually measured eye movement error and the inferred eye movement error derived from measures of the internal state. The presence of two error signals requires that the role of CSs in models of the floccular control of VOR adaption be expanded beyond retinal slip.

Superfusion of the squid giant synapse with artificial seawater (ASW) based on isotonic saline containing oxygen nanobubbles (RNS60 ASW) generates an enhancement of synaptic transmission. This was determined by examining the postsynaptic response to single and repetitive presynaptic spike activation, spontaneous transmitter release, and presynaptic voltage clamp studies. In the presence of RNS60 ASW single presynaptic stimulation elicited larger postsynaptic potentials (PSP) and more robust recovery from high frequency stimulation than in control ASW. Analysis of postsynaptic noise revealed an increase in spontaneous transmitter release with modified noise kinetics in RNS60 ASW. Presynaptic voltage clamp demonstrated an increased EPSP, without an increase in presynaptic ICa(++) amplitude during RNS60 ASW superfusion. Synaptic release enhancement reached stable maxima within 5-10 min of RNS60 ASW superfusion and was maintained for the entire recording time, up to 1 h. Electronmicroscopic morphometry indicated a decrease in synaptic vesicle density and the number at active zones with an increase in the number of clathrin-coated vesicles (CCV) and large endosome-like vesicles near junctional sites. Block of mitochondrial ATP synthesis by presynaptic injection of oligomycin reduced spontaneous release and prevented the synaptic noise increase seen in RNS60 ASW. After ATP block the number of vesicles at the active zone and CCV was reduced, with an increase in large vesicles. The possibility that RNS60 ASW acts by increasing mitochondrial ATP synthesis was tested by direct determination of ATP levels in both presynaptic and postsynaptic structures. This was implemented using luciferin/luciferase photon emission, which demonstrated a marked increase in ATP synthesis following RNS60 administration. It is concluded that RNS60 positively modulates synaptic transmission by up-regulating ATP synthesis, thus leading to synaptic transmission enhancement.

A combination of modified HIV-1 Tat (mTat) peptide and cationic lipids, FuGENE HD (FH), dramatically enhanced transfection efficiency across a range of cell lines when compared to mTat or FH alone (Biomaterials 35:1705-1715 2014). The efficiency of this Tat peptide combination was significantly higher than many commercial non-viral vectors. In this present study, we tested the feasibility of this non-viral vector, mTat/FH, in vivo using plasmid DNA encoding a luciferase gene. The results of the in vivo studies showed that animals administered mTat/FH/DNA intramuscularly had significantly higher and longer luciferase expression ( approximately 7 months) than those with mTat/DNA, FH/DNA, or DNA alone. Histological evaluation showed little immune response in the muscles, livers, and kidneys of mice administered with the mTat/FH. The combination of mTat with FH could significantly improve transfection efficiency, expanding the potential use of non-viral gene vectors in vivo.

BACKGROUND: Patients with nephrolithiasis and hyperoxaluria generally are advised to follow a low-oxalate diet. However, most people do not eat isolated nutrients, but meals consisting of a variety of foods with complex combinations of nutrients. A more rational approach to nephrolithiasis prevention would be to base dietary advice on the cumulative effects of foods and different dietary patterns rather than single nutrients. STUDY DESIGN: Randomized controlled trial. SETTING & PARTICIPANTS: Recurrent stone formers with hyperoxaluria (urine oxalate > 40mg/d). INTERVENTION: The intervention group was asked to follow a calorie-controlled Dietary Approaches to Stop Hypertension (DASH)-style diet (a diet high in fruit, vegetables, whole grains, and low-fat dairy products and low in saturated fat, total fat, cholesterol, refined grains, sweets, and meat), whereas the control group was prescribed a low-oxalate diet. Study length was 8 weeks. OUTCOMES: Primary: change in urinary calcium oxalate supersaturation. SECONDARY: Changes in 24-hour urinary composition. RESULTS: 57 participants were randomly assigned (DASH group, 29; low-oxalate group, 28). 41 participants completed the trial (DASH group, 21; low-oxalate group, 20). As-treated analysis showed a trend for urinary oxalate excretion to increase in the DASH versus the low-oxalate group (point estimate of difference, 9.0mg/d; 95% CI, -1.1 to 19.1mg/d; P=0.08). However, there was a trend for calcium oxalate supersaturation to decrease in the DASH versus the low-oxalate group (point estimate of difference, -1.24; 95% CI, -2.80 to 0.32; P=0.08) in association with an increase in magnesium and citrate excretion and urine pH in the DASH versus low-oxalate group. LIMITATIONS: Limited sample size, as-treated analysis, nonsignificant results. CONCLUSIONS: The DASH diet might be an effective alternative to the low-oxalate diet in reducing calcium oxalate supersaturation and should be studied more.

OBJECTIVE: A substantial proportion of children with attention-deficit/hyperactivity disorder (ADHD) also display emotion regulation deficits manifesting as chronic irritability, severe temper outbursts, and aggression. The amygdala is implicated in emotion regulation, but its connectivity and relation to emotion regulation in ADHD has yet to be explored. The purpose of this study was to examine the relationship between intrinsic functional connectivity (iFC) of amygdala circuits and emotion regulation deficits in youth with ADHD. METHOD: Bilateral amygdala iFC was examined using functional magnetic resonance imaging in 63 children with ADHD, aged 6 to 13 years. First, we examined the relationship between amygdala IFC and parent ratings of emotional lability (EL) in children with ADHD. Second, we compared amygdala iFC across subgroups of children with ADHD and high EL (n = 18), ADHD and low EL (n = 20), and typically developing children (TDC), all with low EL (n = 19). RESULTS: Higher EL ratings were associated with greater positive iFC between the amygdala and rostral anterior cingulate cortex in youth with ADHD. EL scores were also negatively associated with iFC between bilateral amygdala and posterior insula/superior temporal gyrus. Patterns of amygdala-cortical iFC in ADHD participants with low EL were not different from the comparison group, and the effect sizes for these comparisons were smaller than those for the trend-level differences observed between the high-EL and TDC groups. CONCLUSIONS: In children with ADHD and a range of EL, deficits in emotion regulation were associated with altered amygdala-cortical iFC. When comparing groups that differed on ADHD status but not EL, differences in amygdala iFC were small and nonsignificant, highlighting the specificity of this finding to emotional deficits, independent of other ADHD symptoms.

PURPOSE: Spatiotemporally Encoded (SPEN) MRI is based on progressive point-by-point refocusing of the image in the spatial rather than the k-space domain through the use of frequency-swept radiofrequency pulses and quadratic phase profiles. This technique provides high robustness against frequency-offsets including B0 inhomogeneities and chemical-shift (e.g., fat/water) distortions, and can consequently perform fMRI at challenging regions such as the orbitofrontal cortex and the olfactory bulb, as well as to improve imaging near metallic implants. This work aims to establish a comprehensive framework for the implementation and super-resolved reconstruction of SPEN-based imaging, and to accurately quantify this method's spatial-resolution and signal-to-noise ratio (SNR). THEORY AND METHODS: A stepwise formalism was laid-out for calculating the optimal experimental parameters for SPEN, followed by analytical analysis of the ensuing SNR and spatial-resolution versus conventional k-space encoding. Predictions were then confirmed using computer simulations and experimentally. RESULTS: Our findings show that SPEN is governed by the same fundamental signal-processing principles as k-space encoding, leading to similar averaging properties, and ultimately similar spatial-resolution and SNR levels as k-space encoding. CONCLUSION: Presented analysis is applicable to general multidimensional SPEN designs and provides a unified framework for the analysis of future SPEN and similar approaches based on quadratic phase encoding. Magn Reson Med, 2013. (c) 2013 Wiley Periodicals, Inc.

PURPOSE: To develop a fast and flexible free-breathing dynamic volumetric MRI technique, iterative Golden-angle RAdial Sparse Parallel MRI (iGRASP), that combines compressed sensing, parallel imaging, and golden-angle radial sampling. METHODS: Radial k-space data are acquired continuously using the golden-angle scheme and sorted into time series by grouping an arbitrary number of consecutive spokes into temporal frames. An iterative reconstruction procedure is then performed on the undersampled time series where joint multicoil sparsity is enforced by applying a total-variation constraint along the temporal dimension. Required coil-sensitivity profiles are obtained from the time-averaged data. RESULTS: iGRASP achieved higher acceleration capability than either parallel imaging or coil-by-coil compressed sensing alone. It enabled dynamic volumetric imaging with high spatial and temporal resolution for various clinical applications, including free-breathing dynamic contrast-enhanced imaging in the abdomen of both adult and pediatric patients, and in the breast and neck of adult patients. CONCLUSION: The high performance and flexibility provided by iGRASP can improve clinical studies that require robustness to motion and simultaneous high spatial and temporal resolution. Magn Reson Med, 2013. (c) 2013 Wiley Periodicals, Inc.

The dystrobrevin binding protein (DTNBP) 1 gene has emerged over the last decade as a potential susceptibility locus for schizophrenia. While no causative mutations have been found, reduced expression of the encoded protein, dysbindin, was reported in patients. Dysbindin likely plays a role in the neuronal trafficking of proteins including receptors. One important pathway suspected to be affected in schizophrenia is the fast excitatory glutamatergic transmission mediated by AMPA receptors. Here, we investigated excitatory synaptic transmission and plasticity in hippocampal neurons from dysbindin-deficient sandy mice bred on the DBA/2J strain. In cultured neurons an enhancement of AMPAR responses was observed. The enhancement of AMPAR-mediated transmission was confirmed in hippocampal CA3-CA1 synapses, and was not associated with changes in the expression of GluA1-4 subunits or an increase in GluR2-lacking receptor complexes. Lastly, an enhancement in LTP was also found in these mice. These data provide compelling evidence that dysbindin, a widely suspected susceptibility protein in schizophrenia, is important for AMPAR-mediated synaptic transmission and plasticity in the developing hippocampus.

The default network of the human brain has drawn much attention due to its relevance to various brain disorders, cognition, and behavior. However, its functional components and boundaries have not been precisely defined. There is no consensus as to whether the precuneus, a hub in the functional connectome, acts as part of the default network. This discrepancy is more critical for brain development and aging studies: it is not clear whether age has a stronger impact on the default network or precuneus, or both. We used Generalized Ranking and Averaging Independent Component Analysis by Reproducibility (gRAICAR) to investigate the lifespan trajectories of intrinsic functional networks. By estimating individual-specific spatial components and aligning them across subjects, gRAICAR measures the spatial variation of component maps across a population without constraining the same components to appear in every subject. In a cross-lifespan fMRI dataset (N=126, 7-85years old), we observed stronger age dependence in the spatial pattern of a precuneus-dorsal posterior cingulate cortex network compared to the default network, despite the fact that the two networks exhibit considerable spatial overlap and temporal correlation. These results remained even when analyses were restricted to a subpopulation with very similar head motion across age. Our analyses further showed that the two networks tend to merge with increasing age. Post-hoc analyses of functional connectivity confirmed the distinguishable cross-lifespan trajectories between the two networks. Based on these observations, we proposed a dynamic model of cross-lifespan functional segregation and integration between the two networks, suggesting that the precuneus network may have a different functional role than the default network, which declines with age. These findings have implications for understanding the functional roles of the default network, gaining insight into its dynamics throughout life, and guiding interpretation of alterations in brain disorders.

Making predictions about the rewards associated with environmental stimuli and updating those predictions through feedback is an essential aspect of adaptive behavior. Theorists have argued that dopamine encodes a reward prediction error (RPE) signal that is used in such a reinforcement learning process. Recent work with fMRI has demonstrated that the BOLD signal in dopaminergic target areas meets both necessary and sufficient conditions of an axiomatic model of the RPE hypothesis. However, there has been no direct evidence that dopamine release itself also meets necessary and sufficient criteria for encoding an RPE signal. Further, the fact that dopamine neurons have low tonic firing rates that yield a limited dynamic range for encoding negative RPEs has led to significant debate about whether positive and negative prediction errors are encoded on a similar scale. To address both of these issues, we used fast-scan cyclic voltammetry to measure reward-evoked dopamine release at carbon fiber electrodes chronically implanted in the nucleus accumbens core of rats trained on a probabilistic decision-making task. We demonstrate that dopamine concentrations transmit a bidirectional RPE signal with symmetrical encoding of positive and negative RPEs. Our findings strengthen the case that changes in dopamine concentration alone are sufficient to encode the full range of RPEs necessary for reinforcement learning.