Faculty Bibliography

A central problem in neuroscience is reconstructing neuronal circuits on the synapse level. Due to a wide range of scales in brain architecture such reconstruction requires imaging that is both high-resolution and high-throughput. Existing electron microscopy (EM) techniques possess required resolution in the lateral plane and either high-throughput or high depth resolution but not both. Here, we exploit recent advances in unsupervised learning and signal processing to obtain high depth-resolution EM images computationally without sacrificing throughput. First, we show that the brain tissue can be represented as a sparse linear combination of localized basis functions that are learned using high-resolution datasets. We then develop compressive sensing-inspired techniques that can reconstruct the brain tissue from very few (typically 5) tomographic views of each section. This enables tracing of neuronal processes and, hence, high throughput reconstruction of neural circuits on the level of individual synapses.

The subcellular locations of synapses on pyramidal neurons strongly influences dendritic integration and synaptic plasticity. Despite this, there is little quantitative data on spatial distributions of specific types of synaptic input. Here we use array tomography (AT), a high-resolution optical microscopy method, to examine thalamocortical (TC) input onto layer 5 pyramidal neurons. We first verified the ability of AT to identify synapses using parallel electron microscopic analysis of TC synapses in layer 4. We then use large-scale array tomography (LSAT) to measure TC synapse distribution on L5 pyramidal neurons in a 1.00 x 0.83 x 0.21 mm(3) volume of mouse somatosensory cortex. We found that TC synapses primarily target basal dendrites in layer 5, but also make a considerable input to proximal apical dendrites in L4, consistent with previous work. Our analysis further suggests that TC inputs are biased toward certain branches and, within branches, synapses show significant clustering with an excess of TC synapse nearest neighbors within 5-15 mum compared to a random distribution. Thus, we show that AT is a sensitive and quantitative method to map specific types of synaptic input on the dendrites of entire neurons. We anticipate that this technique will be of wide utility for mapping functionally-relevant anatomical connectivity in neural circuits.

While the plasticity of excitatory synaptic connections in the brain has been widely studied, the plasticity of inhibitory connections is much less understood. Here, we present recent experimental and theoretical findings concerning the rules of spike timing-dependent inhibitory plasticity and their putative network function. This is a summary of a workshop at the COSYNE conference 2012.

[This corrects the article on p. 3 in vol. 1, PMID: 24761224.].

Acoustic models have been used in numerous studies over the past thirty years to simulate the percepts elicited by auditory neural prostheses. In these acoustic models, incoming signals are processed the same way as in a cochlear implant speech processor. The percepts that would be caused by electrical stimulation in a real cochlear implant are simulated by modulating the amplitude of either noise bands or sinusoids. Despite their practical usefulness these acoustic models have never been convincingly validated. This study presents a tool to conduct such validation using subjects who have a cochlear implant in one ear and have near perfect hearing in the other ear, allowing for the first time a direct perceptual comparison of the output of acoustic models to the stimulation provided by a cochlear implant.

PURPOSE: To evaluate the effect of subretinal fluid (SRF), imaged with spectral-domain optical coherence tomography (SD-OCT), on visual acuity outcomes in cases of uveitic macular edema (ME), and to analyze the response of SRF and uveitic ME to therapy. DESIGN: Retrospective case series. METHODS: One hundred and one eyes of 75 patients with uveitic ME, as imaged by SD-OCT, were identified at a single tertiary-care referral center. The main outcome measures were best-corrected visual acuity, central subfield thickness (CSFT), and rates of macular edema improvement (>/=20% reduction in CSFT), and resolution (defined as reduction of CSFT to <315 mum) of ME at 3 and 6 months follow-up. RESULTS: Forty eyes of 29 patients had SRF on SD-OCT at presentation, which was associated with greater macular thickness (mean CSFT 488 mum vs 362 mum, P = .0001) and worse visual acuity than ME without SRF (20/115 vs 20/51, P = .015). However, eyes with SRF responded more favorably to treatment, and at 3 and 6 months of follow-up they achieved greater rates of improvement and resolution of ME than eyes without SRF (77% improved and 50% resolved at 6 months, vs 20% and 13%, respectively; P = .003 and P = .017, respectively) and recovered to a similar level of visual acuity (20/62 vs 20/42 at 6 months, P = .54). CONCLUSIONS: SRF in uveitic ME is associated with thicker retinas and worse visual acuity on presentation but responds more favorably to treatment and displays greater rates of edema resolution and visual acuity improvement.

IMPORTANCE: Our experience may be useful to other practitioners using compounded intravitreal agents, those suspecting infectious outbreaks, and those managing fungal endophthalmitis. OBJECTIVE: To describe a series of patients with fungal endophthalmitis following intravitreal injection of combined bevacizumab and triamcinolone acetonide prepared by the same compounding pharmacy. DESIGN AND SETTING: Noncomparative case series. PARTICIPANTS: Eight eyes of 8 patients who received an intravitreal injection of compounded combined bevacizumab-triamcinolone in a period of 3 weeks had subtle, nonspecific findings that were later diagnosed as fungal endophthalmitis. MAIN OUTCOME MEASURES: Visual acuity, response to antimicrobial therapy, and number of vitreoretinal surgical operations after diagnosis of fungal endophthalmitis. RESULTS: Eight patients developed endophthalmitis 41 to 97 days after receiving the intravitreal injection, which was prepared by the same compounding pharmacy. The injections occurred at the same location in New York. Treatment was based on clinical examination findings and knowledge of the etiology of the endophthalmitis. Eventually, all patients were treated with oral voriconazole. Five of 8 patients were initially treated with intravitreal antimicrobial agents. After 3 months of follow-up, visual acuities ranged from 20/50 to hand motions. Local, state, and federal health department officials were involved in investigating the source of the outbreak. CONCLUSIONS AND RELEVANCE: In the current study, we report a fungal endophthalmitis outbreak after intravitreal injection of contaminated, compounded combined bevacizumab-triamcinolone. In this series, Bipolaris hawaiiensis was the identified causative agent. The challenge of medical diagnosis, identification of the source of the outbreak, and management experience are highlighted in our series. Our experience may be useful to other practitioners using compounded intravitreal agents, those suspecting infectious outbreaks, and those managing fungal endophthalmitis.