Faculty Bibliography

We develop a framework for rendering photographic images by directly optimizing their perceptual similarity to the original visual scene. Specifically, over the set of all images that can be rendered on a given display, we minimize the normalized Laplacian pyramid distance (NLPD), a measure of perceptual dissimilarity that is derived from a simple model of the early stages of the human visual system. When rendering images acquired with a higher dynamic range than that of the display, we find that the optimization boosts the contrast of low-contrast features without introducing significant artifacts, yielding results of comparable visual quality to current state-of-the-art methods, but without manual intervention or parameter adjustment. We also demonstrate the effectiveness of the framework for a variety of other display constraints, including limitations on minimum luminance (black point), mean luminance (as a proxy for energy consumption), and quantized luminance levels (halftoning). We show that the method may generally be used to enhance details and contrast, and, in particular, can be used on images degraded by optical scattering (e.g., fog). Finally, we demonstrate the necessity of each of the NLPD components-an initial power function, a multiscale transform, and local contrast gain control-in achieving these results and we show that NLPD is competitive with the current state-of-the-art image quality metrics.

Nothing is more intuitive, yet more complex, than the concepts of space and time. In contrast to spacetime in physics, space and time in neuroscience remain separate coordinates to which we attach our observations. Investigators of navigation and memory relate neuronal activity to position, distance, time point, and duration and compare these parameters to units of measuring instruments. Although spatial-temporal sequences of brain activity often correlate with distance and duration measures, these correlations may not correspond to neuronal representations of space or time. Neither instruments nor brains sense space or time. Neuronal activity can be described as a succession of events without resorting to the concepts of space or time. Instead of searching for brain representations of our preconceived ideas, we suggest investigating how brain mechanisms give rise to inferential, model-building explanations.

The sequential activation of neurons has been observed in various areas of the brain, but in no case is the underlying network structure well understood. Here we examined the circuit anatomy of zebra finch HVC, a cortical region that generates sequences underlying the temporal progression of the song. We combined serial block-face electron microscopy with light microscopy to determine the cell types targeted by HVC_(RA)neurons, which control song timing. Close to their soma, axons almost exclusively targeted inhibitory interneurons, consistent with what had been found with electrical recordings from pairs of cells. Conversely, far from the soma the targets were mostly other excitatory neurons, about half of these being other HVC_(RA)cells. Both observations are consistent with the notion that the neural sequences that pace the song are generated by global synaptic chains in HVC embedded within local inhibitory networks.

Fatty acids activate GPR40 and K⁺channels to modulate β-cell function. Herein, we describe the design and synthesis ofFAAzo-10, a light-controllable GPR40 agonist based on Gw-9508.FAAzo-10is a potent GPR40 agonist in thetrans-configuration and can be inactivated on isomerization tociswith UV-A light. Irradiation with blue light reverses this effect, allowingFAAzo-10activity to be cycled ON and OFF with a high degree of spatiotemporal precision. In dissociated primary mouse β-cells,FAAzo-10also inactivates voltage-activated and ATP-sensitive K⁺channels, and allows us to control glucose-stimulated Ca²⁺oscillations in whole islets with light. As such,FAAzo-10is a useful tool to study the complex effects, with high specificity, which FA-derivatives such as Gw-9508 exert at multiple targets in mouse β-cells.

Closed-loop brain stimulation is a promising alternative to treat drug-resistant epilepsies. In contrast to optogenetic interventions, transcranial electrical stimulation (TES) does not require cellular modification of neurons to be effective, and it is less invasive compared to deep brain stimulation. Furthermore, on-demand TES of targeted brain regions allows the potential for normal function of these networks during interictal periods, a possibility that is eliminated by resective surgical treatment approaches. To further explore the translation of closed-loop TES for treatment of epilepsy, we show here for the first time that unsupervised closed-loop TES in rats can consistently interrupt seizures for 6 weeks and has the potential to control seizure activity up to 4 months (longest periods examined). On-demand TES significantly reduced the time spent in seizure and the individual seizure duration, although significantly higher seizure rate was observed during the treatment. The 6 week long stimulation had no residual adverse effects on the electrophysiologic characteristics of the brain after the termination of the treatment and did not induce glial remodelling in the brain. Our findings demonstrate the safety and effectiveness of minimally invasive, potentially lifelong TES treatment of epilepsy either alone or as a complement to drug treatments.

The progressive death of retinal ganglion cells and resulting visual deficits are hallmarks of glaucoma, but the underlying mechanisms remain unclear. In many neurodegenerative diseases, cell death induced by primary insult is followed by a wave of secondary loss. Gap junctions (GJs), intercellular channels composed of subunit connexins, can play a major role in secondary cell death by forming conduits through which toxic molecules from dying cells pass to and injure coupled neighbors. Here we have shown that pharmacological blockade of GJs or genetic ablation of connexin 36 (Cx36) subunits, which are highly expressed by retinal neurons, markedly reduced loss of neurons and optic nerve axons in a mouse model of glaucoma. Further, functional parameters that are negatively affected in glaucoma, including the electroretinogram, visual evoked potential, visual spatial acuity, and contrast sensitivity, were maintained at control levels when Cx36 was ablated. Neuronal GJs may thus represent potential therapeutic targets to prevent the progressive neurodegeneration and visual impairment associated with glaucoma.

OBJECTIVE:To assess vestibular function in patients with familial dysautonomia (FD), a hereditary sensory and autonomic neuropathy - caused by a mutation in the IKBKAP gene (c.2204 + 6 T>C) - and characterized by marked gait ataxia. METHODS:Cervical and vestibular evoked myogenic potentials (cVEMPs and oVEMPs) were recorded from the sternocleidomastoid (SCM) and extraocular muscles in 14 homozygous patients, 2 heterozygous patients, and 15 healthy controls during percussion of the forehead. RESULTS:cVEMP and oVEMP amplitudes were significantly lower, and peak latencies significantly delayed, in the FD patients. There were no differences in overall EMG during attempted maximal voluntary contractions of the SCM muscle, suggesting intact efferent function. The two heterozygotes with a minor haplotype missense (R696P) mutation in exon 19 of the IKBKAP gene had cVEMP responses less affected than the homozygous. CONCLUSIONS:The founder mutation in the IKBKAP gene affects the development of vestibular afferent pathways, leading to attenuated cVEMPs. SIGNIFICANCE/CONCLUSIONS:Vestibular abnormalities may contribute to the gait ataxia in FD.

Introduction: Increasing evidence suggests sleep can influence the risk for development of Alzheimer disease (AD), but the precise features of sleep architecture influencing this risk and the role of obstructive sleep apnea (OSA) in contributing to this risk remain only partially characterized. Current models of AD suggest that pathological changes, including the accumulation of proteins beta-amyloid (Ab) and tau, can occur years to even decades before clinical symptoms of memory impairment become evident. In this study, we examined the impact of OSA severity on longitudinal changes in Ab measured both in cerebrospinal fluid (CSF) and with brain PET imaging with Pittsburgh compound B (PiB). In subsets of individuals without significant OSA, we examined the impact of features of sleep architecture such as slow wave activity (SWA) and spindles on concentrations CSF Ab and tau at cross-section. Materials and Methods: 208 cognitively normal elderly subjects (68 +/- 7 years, CDR score = 0) received medical, neurological, and psychiatric evaluations, home polysomnography (PSG) for OSA severity, structural magnetic resonance imaging (MRI) scans, a lumbar puncture (LP) and/or PiB PET scans. A subset of 109 subjects completed a second LP 2.4 +/- 0.9 years after the first LP, and a subset of 34 subjects completed a second brain PiB PET scan 2.5 +/- 0.4 years after the first. A subset of 50 subjects without significant OSA (AHI4% < 15/hour) completed in-laboratory nocturnal PSG for measurements of sleep architecture. SWA was calculated using the average power density in the 0.5-4.0 Hz range at the F4- lead during full night EEG recordings. Spindles were isolated and quantified using DETOKS in which the EEG from the C3-lead was decomposed into oscillatory and non-oscillatory components. Oscillatory components were further scored for sleep spindles using threshold values in the frequency band of 11-16 Hz and time duration of 0.5 to 3 seconds. Results: OSA increased amyloid burden over the years, as a significant association was found between longitudinal decreases in CSF Ab42 and increasing OSA severity indices AHI-all (F1,88 = 4.26, p< .05) and AHI4% (F1,87 = 4.36, p< .05). This was corroborated by a trend toward longitudinal increases in brain PiB PET uptake positively associating with increasing OSA severity by AHI-all (F1,28 = 2.96, p=.09). At cross-section, in those subjects without significant OSA, low frontal SWA was significantly associated with high concentrations of CSF Ab42 and low sleep spindle counts and density were significantly associated with high levels of total and phosphorylated tau in the CSF