Automated objective surgical planning for lateral skull base tumors.

PURPOSE: Surgical removal of pathology at the lateral skull base is challenging because of the proximity of critical anatomical structures which can lead to significant morbidity when damaged or traversed. Pre-operative computed surgical approach planning has the potential to aid in selection of the optimal approach to remove pathology and minimize complications. METHODS: We propose an automated surgical approach planning algorithm to derive the optimal approach to vestibular schwannomas in the internal auditory canal for hearing preservation surgery. The algorithm selects between the middle cranial fossa and retrosigmoid approach by utilizing a unique segmentation of each patient's anatomy and a cost function to minimize potential surgical morbidity. RESULTS: Patients who underwent hearing preservation surgery for vestibular schwannoma resection (n = 9) were included in the cohort. Middle cranial fossa surgery was performed in 5 patients, and retrosigmoid surgery was performed in 4. The algorithm favored the performed surgical approach in 6 of 9 patients. CONCLUSION: We developed a method for computing morbidity costs of surgical paths to objectively analyze surgical approaches at the lateral skull base. Computed pre-operative planning may assist in surgical decision making, trainee education, and improving clinical outcomes.

Choice of control tissue impacts designation of germline variants in a cohort of papillary thyroid carcinoma patients.

BACKGROUND: The term germline is commonly used to refer to any non-tumor control sample analyzed in tumor-normal paired sequencing experiments. Blood is the most commonly utilized control, and variants found in both tumor and blood are considered germline. However, somatic variants accumulate within an organism from embryogenesis throughout life. The resultant mosaicism is extensive and calls into question the assumption that blood, or any somatic tissue, represents the germline. Misclassification of germline and somatic variants has critical consequences for individual patient care and enormous impact on our health care system, given potential screening, counseling, and treatment implications of misidentifying germline variants. PATIENTS AND METHODS: Whole-exome sequencing was performed on six separate specimens from each of two patients with papillary thyroid carcinoma, and three specimens each from eight additional patients forming a validation cohort. Tumor variants were compared with each individual non-tumor control and with composite control sets generated as approximations of true germline. For the index patient, parental blood was also sequenced to assess whether patient-only samples could approximate a trio-derived germline. RESULTS: Using different non-tumor control tissues results in altered germline-somatic designation of tumor variants. In patient 1, 82% of variants are labeled germline using blood control, compared with 75.8%, 61.5%, and 49.6% using lymph node, thyroid, and thymus, respectively. In patient 2, the thyroid control resulted in the greatest percentage of germline calls (70.0%), followed by thymus (56.0%), lymph node (50.1%), and blood (44.1%). Composite control sets built from multiple samples can approximate the germline, even in the absence of parental DNA. CONCLUSIONS: Misclassification of germline-somatic origin has potential consequences for patient care, informing screening, trial eligibility, prophylactic interventions, and family planning. This study demonstrates the need for caution in interpreting germline-somatic designation if these data are to inform clinical decisions and suggests that improved design of controls can overcome current limitations.

Generalized trisections in all dimensions.

This paper describes a generalization of Heegaard splittings of 3-manifolds and trisections of 4-manifolds to all dimensions, using triangulations as a key tool. In particular, every closed piecewise linear n-manifold can be divided into [Formula: see text] n-dimensional 1-handlebodies, where [Formula: see text] or [Formula: see text], such that intersections of the handlebodies have spines of small dimensions. Several applications, constructions, and generalizations of our approach are given.

Processing of Cryo-EM Movie Data.

Direct detector device (DDD) cameras dramatically enhance the capabilities of electron cryomicroscopy (cryo-EM) due to their improved detective quantum efficiency (DQE) relative to other detectors. DDDs use semiconductor technology that allows micrographs to be recorded as movies rather than integrated individual exposures. Movies from DDDs improve cryo-EM in another, more surprising, way. DDD movies revealed beam-induced specimen movement as a major source of image degradation and provide a way to partially correct the problem by aligning frames or regions of frames to account for this specimen movement. In this chapter, we use a self-consistent mathematical notation to explain, compare, and contrast several of the most popular existing algorithms for computationally correcting specimen movement in DDD movies. We conclude by discussing future developments in algorithms for processing DDD movies that would extend the capabilities of cryo-EM even further.

INDUCED SEISMICITY. High-rate injection is associated with the increase in U.S. mid-continent seismicity.

An unprecedented increase in earthquakes in the U.S. mid-continent began in 2009. Many of these earthquakes have been documented as induced by wastewater injection. We examine the relationship between wastewater injection and U.S. mid-continent seismicity using a newly assembled injection well database for the central and eastern United States. We find that the entire increase in earthquake rate is associated with fluid injection wells. High-rate injection wells (>300,000 barrels per month) are much more likely to be associated with earthquakes than lower-rate wells. At the scale of our study, a well's cumulative injected volume, monthly wellhead pressure, depth, and proximity to crystalline basement do not strongly correlate with earthquake association. Managing injection rates may be a useful tool to minimize the likelihood of induced earthquakes.

A mathematical model for the progression of dental caries.

A model for the progression of dental caries is derived. The analysis starts at the microscopic reaction and diffusion process. The local equations are averaged to derive a set of macroscopic equations. The global system includes features such as anisotropic diffusion and local changes in the geometry due to the melting of the enamel. The equations are then solved numerically. The simulations highlight the effect of anisotropy. In addition, we draw conclusions on the progression rate of caries, and discuss them in light of a number of experiments.

Evoked cortical activity and speech recognition as a function of the number of simulated cochlear implant channels.

OBJECTIVES: (1) To determine if consonant-vowel-consonant (CVC) syllables [Hillenbrand J, Getty L, Clark M, Wheeler K. Acoustic characteristics of American English vowels. J Acoust Soc Am 1995;97:3099-3111] could be used to evoke cortical far field response patterns in humans, (2) to characterize the effects of cochlear implant-simulated channel number on the perception and physiological detection of these same CVC stimuli, and (3) to define the relationship between perception and the morphology of the physiological responses evoked by these speech stimuli. METHODS: Ten normal hearing monolingual English speaking adults were tested. Unprocessed CVC naturally spoken syllables, containing medial vowels, as well as processed versions (2, 4, 8, 12, and 16 spectral channels) were used for behavioral and physiological testing. RESULTS: (1) CVC stimuli evoked a series of overlapping P1-N1-P2 cortical responses. (2) Amplitude of P1-N1-P2 responses increased as neural conduction time (latency) decreased with increases in the number of spectral channels. Perception of the CVC stimuli improved with increasing number of spectral channels. (3) Coinciding changes in P1-N1-P2 morphology did not significantly correlate with changes in perception. CONCLUSIONS: P1-N1-P2 responses can be recorded using CVC syllables and there is an effect of channel number on the latency and amplitude of these responses, as well as on vowel identification. However, the physiological detection of the acoustic changes does not fully account for the perceptual performance of these same syllables. SIGNIFICANCE: These results provide evidence that it is possible to use vocoded CVC stimuli to learn more about the physiological detection of acoustic changes contained within speech syllables, as well as to explore brain-behavior relationships.

Genotype-phenotype correlations in Rubinstein-Taybi syndrome.

Rubinstein-Taybi syndrome (RTS) is a rare multiple congenital anomaly/intellectual impairment syndrome. Loss of function in CREBBP or EP300 genes has been found in about 50% of patients with RTS. Genotype-phenotype correlations were investigated in 93 patients meeting diagnostic criteria for RTS during 2 international RTS family conferences. Mutation analysis of CREBBP was performed on all 31 coding exons and exon-intron junctions; a subset of patients had FISH analysis for large deletions. A total of 64 different variations were observed in the DNA sequence, and determined to be definitive mutations in 52 patients (56%). Mutations detected included: 10 missense mutations; 36 truncating or splice-site mutations; and 6 large deletions detectable by FISH. Fourteen patients had synonymous changes of unknown significance. The majority of mutations affected the HAT domain of CREBBP or predicted termination of the protein before the HAT region. Extensive phenotypic data were collected on each patient and analyzed to determine correlations with mutation types, that is, truncating, large deletions, single amino acid substitutions, or no CREBBP mutation. All four groups displayed the characteristic facial and thumb dysmorphology. Growth retardation in height and weight was seen more frequently in patients with no CREBBP mutation; seizure disorder was more frequent in those with CREBBP mutations. Degree of mental retardation was similar in all groups, although there was a trend toward lower IQ and autistic features in patients with large deletions. Similarity in phenotype between the groups implies that the several genes involved in causing RTS likely have effects through the same pathway.

Bifurcation diagram and pattern formation of phase slip centers in superconducting wires driven with electric currents.

We provide here new insights into the classical problem of a one-dimensional superconducting wire exposed to an applied electric current using the time-dependent Ginzburg-Landau model. The most striking feature of this system is the well-known appearance of oscillatory solutions exhibiting phase slip centers (PSC's) where the order parameter vanishes. Retaining temperature and applied current as parameters, we present a simple yet definitive explanation of the mechanism within this nonlinear model that leads to the PSC phenomenon and we establish where in parameter space these oscillatory solutions can be found. One of the most interesting features of the analysis is the evident collision of real eigenvalues of the associated PT-symmetric linearization, leading as it does to the emergence of complex elements of the spectrum.

Two theorems in catoptrics.

Two general theorems in the theory of mirrors are presented. The first one asserts that a mirror that reflects a parallel beam into a beam with zero mean curvature must be harmonic. The second one provides a universal characterization of the spot diagram of rays from a reflected parallel beam as they intersect a plane orthogonal to their direction of propagation.

Development of a biophysical model for vestibular prosthesis research.

Physiologic properties of primary vestibular neurons are compared and contrasted with properties of primary auditory neurons. The differences and similarities suggest possible coding strategies for a vestibular implant. The degree of spike rate variability, or coefficient of variation (CV), is a prominent physiological property of vestibular neurons with undetermined functional significance. At the very least, CV is highly correlated with threshold to electrical stimulation in the intact vestibular labyrinth. If CV is also important for vestibular coding, then electrical stimulation strategies should be designed to restore relatively physiologic patterns of CV. Simulations using a stochastic model of primary afferent vestibular neurons reveal that this should be possible using combinations of low and high-rate pulsatile stimulation. They also demonstrate that differences in the number and independence of synaptic inputs can significantly affect CV.

Analysis of monophasic and biphasic electrical stimulation of nerve.

In an earlier study, biphasic and monphasic electrical stimulation of the auditory nerve was performed in cats with a cochlear implant. Single-unit recordings demonstrated that spikes resulting from monophasic and biphasic stimuli have different thresholds and latencies. Monophasic thresholds are lower and latencies are shorter under cathodic stimulation. Results from stochastic simulations of a biophysical model of electrical stimulation are similar. A simple analysis of a linear, "integrate to threshold" membrane model accounts for the threshold and latency differences observed experimentally and computationally. Since biphasic stimuli are used extensively in functional electrical stimulation, this analysis greatly simplifies the biophysical interpretation of responses to clinically relevant stimuli by relating them to the responses obtained with monophasic stimuli.

Executive control of cognitive processes in task switching.

In 4 experiments, participants alternated between different tasks or performed the same task repeatedly. The tasks for 2 of the experiments required responding to geometric objects in terms of alternative classification rules, and the tasks for the other 2 experiments required solving arithmetic problems in terms of alternative numerical operations. Performance was measured as a function of whether the tasks were familiar or unfamiliar, the rules were simple or complex, and visual cues were present or absent about which tasks should be performed. Task alternation yielded switching-time costs that increased with rule complexity but decreased with task cuing. These factor effects were additive, supporting a model of executive control that has goal-shifting and rule-activation stages for task switching. It appears that rule activation takes more time for switching from familiar to unfamiliar tasks than for switching in the opposite direction.

Acoustic neuromas in the elderly.

OBJECTIVE: To determine if an "observation" protocol with serial scanning is a safe and effective management paradigm for acoustic neuromas in the elderly. STUDY DESIGN: A retrospective case review was performed. SETTING: This study was performed in an academic, tertiary care center. PATIENTS: Forty-one patients over the age of 65 years were identified with the primary diagnosis of unilateral acoustic neuroma, without prior treatment or observation. INTERVENTION: The patients were followed with serial, gadolinium-enhanced magnetic resonance imaging (MRI) scans performed at 6 months and then yearly, if no significant growth occurred. MAIN OUTCOME MEASURES: The patients were monitored for tumor growth, cranial nerve deficits, and hydrocephalus. RESULTS: The patients were followed for an average of 3.5 years (range, 6 months to 9 years). The average tumor size at presentation was 1.14 cm, with a range of growth rates from 0 to 1.2 cm per year. Twenty-one patients demonstrated tumor growth at an average rate of 0.322 cm per year. Only five patients (12%) required further intervention. Three patients underwent translabyrinthine excision, and two patients were treated with radiation. No patients developed significant complications during the observation period. CONCLUSIONS: Acoustic neuromas in the older population can be managed safely using serial MRI scanning. No correlation could be made between initial tumor size and subsequent growth rate.

The effects of interpulse interval on stochastic properties of electrical stimulation: models and measurements.

It is known that some cochlear implant users have improved speech perception using higher rates of interleaved pulsatile stimulation. There are, however, significant limitations on their performance presumably due in part to temporal and spatial interactions. To address these limitations, we have examined refractory characteristics of the auditory nerve using experimental animal models and computational simulations. A stochastic model of the node of Ranvier modified for mammalian sodium channel kinetics has been developed to calculate the masked input-output (I/O) functions for different interpulse intervals (IPI) [26]. The model is based upon 1000 voltage-gated sodium channels and incorporates parameters such as nodal resistance and capacitance. The relative spread (RS) [35] calculated from the I/O functions was typically 0.03 for 17 different IPIs between 450 micros and 6 ms for cathodal stimuli. For IPI = 830 and 870 micros, the RS was ten times greater than those for other IPIs. Although it is not fully understood how the electrically evoked compound action potential (EAP) data are related to single fiber data, the RS of single fibers is a partial contributor [19]. We have measured the EAP using a monopolar intracochlear stimulating electrode and a recording electrode placed directly on the nerve and have observed changes in slope of EAP growth functions consistent with the theoretical RS values. These results have significant implications for speech coding in a cochlear implant since they suggest an increased membrane noise for pulse trains of specific rates.

Auditory nerve responses to monophasic and biphasic electric stimuli.

Charge-balanced, biphasic stimulus pulses are commonly used in implantable cochlear prostheses as they can be safely delivered to living tissue. However, monophasic stimuli are more efficient (i.e. producing lower thresholds) and likely provide more spatially selective excitation of nerve fibers. We examined the neural responses to monophasic, 'pseudomonophasic', and biphasic stimuli to better understand the inherent tradeoffs of these stimuli. Using guinea pig and cat animal models, we compared the auditory nerve responses to both 40 micros monophasic and 40 micros/phase biphasic stimuli using both electrically evoked compound action potential and single-fiber recordings. We also made comparisons using a computational model of the feline auditory nerve fiber. In all cases, our stimuli were cathodic monophasic and cathodic-first biphasic pulses. As expected, monophasic stimuli provided lower thresholds relative to biphasic stimuli. They also evoked responses with relatively longer latencies. We also examined responses to charge-balanced biphasic pulses composed of two phases of differing duration (i.e. pseudomonophasic stimuli). The first phase was fixed at 40 micros, while the second phase was systematically varied from 40 to 4000 micros. With a relatively long second phase, we hypothesized that these stimuli would provide some of the beneficial features of monophasic stimuli. Both the gross-potential and single-fiber data confirmed this and indicate that the largest incremental effects of changing the second-phase duration occur for durations less than 500 micros. Consideration of single-fiber data and computer simulations suggest that these results are consistent with the neural membrane acting as a leaky integrator. The computer simulations also suggest that the integrative properties at least partially account for the difference between our monophasic-biphasic results and previously published data. Our results apply to cathodic-leading stimuli; due to differing patterns of membrane depolarization, they may not be applicable to situations using anodic-leading stimuli. Finally, we observed differences between the guinea pig and cat response patterns. Compared to cats, guinea pigs produced smaller monophasic vs. biphasic threshold differences. This interspecies disparity may be due to differences in cochlear anatomy.

Semiautomatic segmentation of the cochlea using real-time volume rendering and regional adaptive snake modeling.

The human cochlea in the inner ear is the organ of hearing. Segmentation is a prerequisite step for 3-dimensional modeling and analysis of the cochlea. It may have uses in the clinical practice of otolaryngology and neuroradiology, as well as for cochlear implant research. In this report, an interactive, semiautomatic, coarse-to-fine segmentation approach is developed on a personal computer with a real-time volume rendering board. In the coarse segmentation, parameters, including the intensity range and the volume of interest, are defined to roughly segment the cochlea through user interaction. In the fine segmentation, a regional adaptive snake model designed as a refining operator separates the cochlea from other anatomic structures. The combination of the image information and expert knowledge enables the deformation of the regional adaptive snake effectively to the cochlear boundary, whereas the real-time volume rendering provides users with direct 3-dimensional visual feedback to modify intermediate parameters and finalize the segmentation. The performance is tested using spiral computed tomography (CT) images of the temporal bone and compared with the seed point region growing with manual modification of the commercial Analyze software. Our method represents an optimal balance between the efficiency of automatic algorithm and the accuracy of manual work.

Three-dimensional geometric modeling of the cochlea using helico-spiral approximation.

In this paper, the three-dimensional geometry of the human cochlea is modeled by the helico-spiral seashell model. The 3-D helico-spiral model, the generalized representation of the Archimedian spiral model, provides a framework for measuring cochlear features based on consistent estimation of model parameters. Nonlinear least square minimization based algorithms are developed for the identification of rotation, center and intrinsic parameters of the helico-spiral representation. Two algorithms are designed for the rotation axis aligned to the modiolar axis: one is more susceptible in the presence of noise, while the other allows applicability to two-dimensional data sets. The estimated center and intrinsic parameters allow the calculation of length, height and angular positions needed for frequency mapping of multichannel cochlear implant electrodes. Model performance is evaluated with numerically synthesized curves with different levels of added random noise, histologic data and real human cochlear spiral computed tomography data.