Faculty Bibliography

Transient subthreshold-activating somato-dendritic A-type K(+) currents (I(SA)s) have fundamental roles in neuronal function. They cause delayed excitation, influence spike repolarization, modulate the frequency of repetitive firing, and have important roles in signal processing in dendrites. We previously reported that DPPX proteins are key components of the channels mediating these currents (Kv4 channels) (Nadal, M.S., Ozaita, A., Amarillo, Y., Vega-Saenz, E., Ma, Y., Mo, W., Goldberg, E.M., Misumi, Y., Ikehara, Y., Neubert, T.A., Rudy, B., 2003. The CD26-related dipeptidyl aminopeptidase-like protein DPPX is a critical component of neuronal A-type K+ channels. Neuron 37, 449-461). The DPPX gene encodes alternatively spliced transcripts that generate single-spanning transmembrane proteins with a short, divergent intracellular domain and a large extracellular domain. We characterized the modulatory effects on Kv4.2-mediated currents and the rat brain distribution of three splice variants of the DPPX subfamily of proteins. These three splice isoforms--DPPX-S, DPPX-L, and DPPX-K--are expressed in adult rat brain and modify the voltage dependence and kinetic properties of Kv4.2 channels expressed in Xenopus oocytes. Analysis of a deletion mutant that lacks the variable N-terminus showed that the N-terminus is not necessary for the modulation of Kv4 channels. Using in situ hybridization analysis, we found that the three splice variants are prominently expressed in brain regions where Kv4 subunits are also expressed. DPPX-K and DPPX-S mRNAs have a widespread distribution, whereas DPPX-L transcripts are concentrated in few specific areas of the rat brain. The emerging diversity of DPPX splice variants, differing only in the N-terminus of the protein, opens up intriguing possibilities for the modulation of Kv4 channels

Functional brain imaging of pain over the last years has provided insight into a distributed anatomical matrix involved in pain processing which includes multiple cortical areas. EEG/MEG-based imaging studies have mostly relied on settings of evoked nociception. We report here the spontaneous presence of enhanced activations in the pain matrix of the patient group on the basis of continuous EEG and functional Low Resolution Electromagnetic Tomography (LORETA) from 16 chronic neurogenic pain patients and 16 healthy controls. These overactivations occurred predominantly within the high theta (6-9 Hz) and low beta frequency ranges (12-16 Hz). Theta and beta overactivations were localized to multiple pain-associated areas, primarily to insular (IC), anterior cingulate (ACC), prefrontal, and inferior posterior parietal cortices, as well as to primary (S1), secondary (S2), and supplementary somatosensory (SSA) cortices. After a therapeutic lesion in the thalamus (central lateral thalamotomy, CLT), we followed a subgroup of 6 patients. Twelve months after surgery, activation in cingulate and insular cortices was significantly reduced. The presence of rhythmic processes in multiple, partially overlapping areas of the cortical pain matrix concur with the concept of thalamocortical dysrhythmia (TCD) that predicts increased thalamocortical low and high frequency oscillations ensuing from thalamic desactivation. These spontaneous, ongoing, frequency-specific overactivations may therefore serve as an anatomo-physiological hallmark of the processes underlying chronic neurogenic pain

In this paper, we investigate the decoding of flashed, full-field visual stimuli while recording from a population of retinal ganglion cells. We present a direct statistical method for determining the likelihood that a response was evoked by a particular stimulus, and use this method to estimate stimuli based on microelectrode array recordings in the turtle retina. This method uses the well-known time-varying Poisson model of neural firing, along with extensions to accommodate neural refractory periods. Unlike other approaches commonly used for Poisson processes, the specific formulation presented here is bin free and requires few user-specified parameters. Statistical dependency issues and the effects of stationarity on the estimation method are also discussed.

RATIONALE AND OBJECTIVES: The aim of the study is to develop a theory-based signal calibration approach to be used for the conversion of signal-time curves to absolute contrast concentration-time curves for first-pass contrast-enhanced quantitative myocardial perfusion studies. MATERIALS AND METHODS: A normalization procedure was used to obtain a theoretical relationship between image signal and T1 and perform rapid single-point T1 measurements. T1 measurements were compared with reference T1 measurements. The method also was used in preliminary in vivo contrast-enhanced first-pass perfusion studies, and its applicability for dual-delay-time acquisitions was shown. A theory-based error sensitivity analysis was used to characterize the robustness of the method. RESULTS: The normalization procedure was implemented with minimal noise enhancement and insensitivity to small misregistrations through postprocessing techniques. The rapid T1 measurements are in excellent agreement with the reference measurements (R = 0.99, slope = 1.05, bias = -5.96 milliseconds). For in vivo studies, it is possible to simultaneously calibrate the arterial input function and myocardial enhancement curves acquired with different effective trigger delays through appropriate use of the theory-based signal calibration model. With this method, errors of in vivo baseline T1 estimates are large, but the effect of these large errors on the accuracy of contrast agent concentration estimates is limited. CONCLUSION: This theory-based signal calibration approach can be used to perform rapid T1 mapping and provides flexibility for in vivo calibration of signal-time curves resulting from dual-delay-time first-pass contrast-enhanced acquisitions

We propose the concept of quality-aware image, in which certain extracted features of the original (high-quality) image are embedded into the image data as invisible hidden messages. When a distorted version of such an image is received, users can decode the hidden messages and use them to provide an objective measure of the quality of the distorted image. To demonstrate the idea, we build a practical quality-aware image encoding, decoding and quality analysis system, which employs: 1) a novel reduced-reference image quality assessment algorithm based on a statistical model of natural images and 2) a previously developed quantization watermarking-based data hiding technique in the wavelet transform domain

The kinetics of activity-dependent, extracellular alkaline transients, and the buffering of extracellular pH (pH(e)), were studied in rat hippocampal slices using a fluorescein-dextran probe. Orthodromic stimuli generated alkaline transients < or = 0.05 pH units that peaked in 273 +/- 26 ms and decayed with a half-time of 508 +/- 43 ms. Inhibition of extracellular carbonic anhydrase (ECA) with benzolamide increased the rate of rise by 25%, doubled peak amplitude, and prolonged the decay three- to fourfold. The slow decay in benzolamide allowed marked temporal summation, resulting in a severalfold increase in amplitude during long stimulus trains. Addition of exogenous carbonic anhydrase reduced the rate of rise, halved the peak amplitude, but had no effect on the normalized decay. A simulation of extracellular buffering kinetics generated recoveries from a base load consistent with the observed decay of the alkaline transient in the presence of benzolamide. Under control conditions, the model approximated the observed decays with an acceleration of the CO2 hydration-dehydration reactions by a factor of 2.5. These data suggest low endogenous ECA activity, insufficient to maintain equilibrium during the alkaline transients. Disequilibrium implies a time-dependent buffering capacity, with a CO2/HCO3- contribution that is small shortly after a base load. It is suggested that within 100 ms, extracellular buffering capacity is about 1% of the value at equilibrium and is provided mainly by phosphate. Accordingly, in the time frame of synaptic transmission, small base loads would generate relatively large changes in interstitial pH

There is substantial evidence that a bioenergetic defect may play a role in the pathogenesis of Huntington's Disease (HD). A potential therapy for remediating defective energy metabolism is the mitochondrial cofactor, coenzyme Q10 (CoQ10). We have reported that CoQ10 is neuroprotective in the R6/2 transgenic mouse model of HD. Based upon the encouraging results of the CARE-HD trial and recent evidence that high-dose CoQ10 slows the progressive functional decline in Parkinson's disease, we performed a dose ranging study administering high levels of CoQ10 from two commercial sources in R6/2 mice to determine enhanced efficacy. High dose CoQ10 significantly extended survival in R6/2 mice, the degree of which was dose- and source-dependent. CoQ10 resulted in a marked improvement in motor performance and grip strength, with a reduction in weight loss, brain atrophy, and huntingtin inclusions in treated R6/2 mice. Brain levels of CoQ10 and CoQ9 were significantly lower in R6/2 mice, in comparison to wild type littermate control mice. Oral administration of CoQ10 elevated CoQ10 plasma levels and significantly increased brain levels of CoQ9, CoQ10, and ATP in R6/2 mice, while reducing 8-hydroxy-2-deoxyguanosine concentrations, a marker of oxidative damage. We demonstrate that high-dose administration of CoQ10 exerts a greater therapeutic benefit in a dose dependent manner in R6/2 mice than previously reported and suggest that clinical trials using high dose CoQ10 in HD patients are warranted.

A magnetic resonance imaging (MRI) method is presented for estimating the magnetic field correlation (MFC) associated with magnetic field inhomogeneities (MFIs) within biological tissues. The method utilizes asymmetric spin echoes and is based on a detailed theory for the effect of MFIs on nuclear magnetic resonance (NMR) signal decay. The validity of the method is supported with results from phantom experiments at 1.5 and 3 T, and human brain images obtained at 3 T are shown to demonstrate the method's feasibility. The preliminary results suggest that MFC imaging may be useful for the quantitative assessment of iron within the brain

In order to identify and understand mechanistically the cortical circuitry of sensory information processing estimates are needed of synaptic input fields that drive neurons. From intracellular in vivo recordings one would like to estimate net synaptic conductance time courses for excitation and inhibition, g(E)(t) and g(I)(t), during time-varying stimulus presentations. However, the intrinsic conductance transients associated with neuronal spiking can confound such estimates, and thereby jeopardize functional interpretations. Here, using a conductance-based pyramidal neuron model we illustrate errors in estimates when the influence of spike-generating conductances are not reduced or avoided. A typical estimation procedure involves approximating the current-voltage relation at each time point during repeated stimuli. The repeated presentations are done in a few sets, each with a different steady bias current. From the trial-averaged smoothed membrane potential one estimates total membrane conductance and then dissects out estimates for g(E)(t) and g(I)(t). Simulations show that estimates obtained during phases without spikes are good but those obtained from phases with spiking should be viewed with skeptism. For the simulations, we consider two different synaptic input scenarios, each corresponding to computational network models of orientation tuning in visual cortex. One input scenario mimics a push-pull arrangement for g(E)(t) and g(I)(t) and idealized as specified smooth time courses. The other is taken directly from a large-scale network simulation of stochastically spiking neurons in a slab of cortex with recurrent excitation and inhibition. For both, we show that spike-generating conductances cause serious errors in the estimates of g(E) and g(I). In some phases for the push-pull examples even the polarity of g(I) is mis-estimated, indicating significant increase when g(I) is actually decreased. Our primary message is to be cautious about forming interpretations based on estimates developed during spiking phases

In the long germ insect Drosophila, the gene tailless acts to pattern the terminal regions of the embryo. Loss of function of this gene results in the deletion of the anterior and posterior terminal structures and the eighth abdominal segment. Drosophila tailless is activated by the maternal terminal system through Torso signaling at both poles of the embryo, with additional activation by Bicoid at the anterior. Here, we describe the expression and function of tailless in a long germ Hymenoptera, the wasp Nasonia vitripennis. Despite the morphological similarities in the mode of development of these two insects, we find major differences in the regulation and function of tailless between Nasonia and Drosophila. In contrast to the fly, Nasonia tll appears to rely on otd for its activation at both poles. In addition, the anterior domain of Nasonia tll appears to have little or no segmental patterning function, while the posterior tll domain has a much more extensive patterning role than its Drosophila counterpart.