Optimal stimulus shapes for neuronal excitation

The work is made available under the Creative Commons CC0 public domain dedication. The definitive version was published in PLoS Computational Biology 7 (2011): e1002089, doi:10.1371/journal.pcbi.1002089.An important problem in neuronal computation is to discern how features of stimuli control the timing of action potentials. One aspect of this problem is to determine how an action potential, or spike, can be elicited with the least energy cost, e.g., a minimal amount of applied current. Here we show in the Hodgkin & Huxley model of the action potential and in experiments on squid giant axons that: 1) spike generation in a neuron can be highly discriminatory for stimulus shape and 2) the optimal stimulus shape is dependent upon inputs to the neuron. We show how polarity and time course of post-synaptic currents determine which of these optimal stimulus shapes best excites the neuron. These results are obtained mathematically using the calculus of variations and experimentally using a stochastic search methodology. Our findings reveal a surprising complexity of computation at the single cell level that may be relevant for understanding optimization of signaling in neurons and neuronal networks.This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892 and NIH grant R01 HL718884 to DP. DBF is an AFOSR Young Investigator (FA 9550-08-01-0076)

Optimizing emergency stroke transport strategies using physiological models

Background and Purpose: The criteria for choosing between Drip and Ship (DNS) and Mothership (MS) transport strategies in emergency stroke care is widely debated. While existing data-driven probability models can inform transport decision-making at an epidemiological level, we propose a novel mathematical, physiologically derived framework that provides insight into how patient characteristics underlying infarct core growth influence these decisions. Methods: We represent the physiology of time-dependent infarct core growth within an ischemic penumbra as an exponential function with consideration to rate-determining collateral blood flow. Monte Carlo methods generate distributions of infarct core volumes, which are translated to distributions of 90-day modified Rankin Scores. We apply the model to a stroke network that serves the rural Bastrop County and urban Travis County by simulating transport strategies from thousands of potential patient pickup locations. In every pickup location, the simulation yields a distribution of outcomes corresponding to each transport strategy. A two-sample Kolmogorov-Smirnov test and student t-test determine which transport strategy provides a significantly better probability of a good outcome for a given pickup location in each respective county (P < 0.01). Results: In Travis County, DNS provides significantly better probabilities of a good outcome in 24.0% of the pickup locations, while 59.8% favor MS. In Bastrop County, 11.3% of the pickup locations favor DNS, while only 7.1% favor MS. The remaining pickup locations in each county are not statistically significant in either direction. We also reveal how differing rates of infarct core growth, the application of bypass policies, and the use of large vessel occlusion field tests impact these results. Conclusions: Modeling stroke physiology enables the use of clinically relevant metrics for determining comparative significance between DNS and MS in a given geography. This formalism can help understand and inform emergency medical service transport decision-making, as well as regional bypass policies.Bachelor of Scienc

Occult cervical spinal dural arteriovenous fistula masquerading as acute spinal cord ischemia

Acute presentation of upper and lower extremity motor weakness is commonly attributed to intracerebral ischemic infarct upon initial examination. For those that exhibit acute onset of bilateral weakness, it is important to expand the differential diagnosis to include spinal cord ischemic involvement. One cause of ischemic lesions is spinal dural arteriovenous (AV) fistulas which are generally found in the thoraco-lumbar region. They present with progressive paraplegia or quadriplegia due to changes in the spinal venous pressure and eventual myelopathy. We present a 60 year old gentleman with bilateral upper extremity weakness and right lower extremity weakness preceded by upper back and neck pain. Initial studies included both Magnetic resonance imagine (MRI) of the brain and also the cervical spine that demonstrated abnormal signal intensity within the anterior cervical cord from C3-C7 levels concerning for spinal cord infarct. In our case there were no flow voids to suggest dilated perimedullary vessels that usually prompt further diagnostic evaluation through a spinal angiogram. However, given the clinical suspicion, a spinal angiogram was obtained that demonstrated a cervical dural AV fistula supplied by a dural branch vessel originating from the left vertebral artery. We will highlight the importance of recognizing the clinical presentation of spinal dural AV fistulas; the usual findings on imaging, the value of considering further diagnostic tests if clinical suspicion is high, and provide an overview of the spinal dural AV treatment

Diagnostic Value of Lingual Tonsillectomy in Unknown Primary Head and Neck Carcinoma Identification After a Negative Clinical Workup and Positron Emission Tomography-Computed Tomography

Objective: Diagnostic rates of unknown primary head and neck carcinoma (UPHNC) using lingual tonsillectomy (LT) are highly variable. This study sought to determine the diagnostic value of LT in UPHNC identification using strict inclusion criteria and definitions to produce a more accurate estimate of diagnosis rate. Methods: In this retrospective chart review, records of patients who underwent LT for UPHNC were reviewed. Inclusion criteria included absence of suspicious findings on physical exam and positron emission tomography-computed tomography as well as negative biopsies after panendoscopy and palatine tonsillectomy. Following inclusion criteria, 16 patients were reviewed. A systematic literature review on LT for the workup of CUP was also performed. Results: LT was performed using transoral robotic surgery (TORS), transoral laser microsurgery (TLM), or transoral microsurgery with cautery (TMC). Following LT, primary tumor was identified in 4 patients out of 16. Detection rate by technique was 1/6, 2/7, and 1/3 for TORS, TLM, and TMC respectively. Postoperative bleeding occurred in three patients (19%); however, this was not related to the LT. Following literature review, 12 studies were identified; however, only 3 had enough data to compare against. All three studies had a cohort with suspicious findings on clinical exam. A total of 34 patients had a negative workup, with no suspicious findings on clinical exam and subsequently received an LT. Conclusion: This study suggests that LT should be considered initially in the diagnostic algorithm for UPHNC. This study can increase the patient size in this cohort by approximately 47%

Multidetector CT and MR Imaging of Cardiac Tumors

The purpose of this article is to provide a current review of the spectrum of multidetector CT (MDCT) and MRI findings for a variety of cardiac neoplasms. In the diagnosis of cardiac tumors, the use of MDCT and MRI can help differentiate benign from malignant masses. Especially, the use of MDCT is advantageous in providing anatomical information and MRI is useful for tissue characterization of cardiac masses. Knowledge of the characteristic MRI findings of benign cardiac tumors or thrombi can be helpful to avoid unnecessary surgical procedures. Presurgical assessment of malignant cardiac tumors with the use of MDCT and MRI may allow determination of the resectability of tumors and planning for the reconstruction of cardiac chambers

Positron emission tomography–CT prediction of occult nodal metastasis in recurrent laryngeal cancer

BackgroundThe purpose of this study was to evaluate the predictive value of positron emission tomography (PET)‐CT in identifying occult nodal metastasis in clinically and radiographically N0 patients with recurrent laryngeal cancer undergoing salvage laryngectomy.MethodsRetrospective review of 46 clinically and radiographically N0 patients with recurrent laryngeal cancer who underwent a PET‐CT examination before salvage laryngectomy with neck dissection from January 1, 2002, to December 31, 2014, was performed.ResultsTwo patients (16.7%) had true‐positive PET‐CT results, whereas 10 patients (83.3%) had false‐negative scans, 1 patient (2.9%) had a false‐positive result and 33 patients (97.1%) had a true‐negative PET‐CT. The sensitivity of PET‐CT was 16.7% (95% confidence interval [CI], 3.5% to 46.0%) with a specificity of 97.1% (95% CI, 83.8% to 99.9%), positive predictive value (PPV) of 66.7% (95% CI, 20.2% to 94.4%), and negative predictive value (NPV) of 76.7% (95% CI, 62.1% to 87.0%).ConclusionPET‐CT has poor sensitivity and NPV making PET‐CT an imperfect predictor of nodal disease in recurrent laryngeal cancer. © 2017 Wiley Periodicals, Inc. Head Neck 39: 980–987, 2017Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136682/1/hed24719.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136682/2/hed24719_am.pd

First-In-Human Study in Cancer Patients Establishing the Feasibility of Oxygen Measurements in Tumors Using Electron Paramagnetic Resonance With the OxyChip

Objective: The overall objective of this clinical study was to validate an implantable oxygen sensor, called the ‘OxyChip’, as a clinically feasible technology that would allow individualized tumor-oxygen assessments in cancer patients prior to and during hypoxia-modification interventions such as hyperoxygen breathing. Methods: Patients with any solid tumor at ≤3-cm depth from the skin-surface scheduled to undergo surgical resection (with or without neoadjuvant therapy) were considered eligible for the study. The OxyChip was implanted in the tumor and subsequently removed during standard-of-care surgery. Partial pressure of oxygen (pO2) at the implant location was assessed using electron paramagnetic resonance (EPR) oximetry. Results: Twenty-three cancer patients underwent OxyChip implantation in their tumors. Six patients received neoadjuvant therapy while the OxyChip was implanted. Median implant duration was 30 days (range 4–128 days). Forty-five successful oxygen measurements were made in 15 patients. Baseline pO2 values were variable with overall median 15.7 mmHg (range 0.6–73.1 mmHg); 33% of the values were below 10 mmHg. After hyperoxygenation, the overall median pO2 was 31.8 mmHg (range 1.5–144.6 mmHg). In 83% of the measurements, there was a statistically significant (p ≤ 0.05) response to hyperoxygenation. Conclusions: Measurement of baseline pO2 and response to hyperoxygenation using EPR oximetry with the OxyChip is clinically feasible in a variety of tumor types. Tumor oxygen at baseline differed significantly among patients. Although most tumors responded to a hyperoxygenation intervention, some were non-responders. These data demonstrated the need for individualized assessment of tumor oxygenation in the context of planned hyperoxygenation interventions to optimize clinical outcomes

Inhibition of rhythmic neural spiking by noise: the occurrence of a minimum in activity with increasing noise

The effects of noise on neuronal dynamical systems are of much current interest. Here, we investigate noise-induced changes in the rhythmic firing activity of single Hodgkin–Huxley neurons. With additive input current, there is, in the absence of noise, a critical mean value µ = µc above which sustained periodic firing occurs. With initial conditions as resting values, for a range of values of the mean µ near the critical value, we have found that the firing rate is greatly reduced by noise, even of quite small amplitudes. Furthermore, the firing rate may undergo a pronounced minimum as the noise increases. This behavior has the opposite character to stochastic resonance and coherence resonance. We found that these phenomena occurred even when the initial conditions were chosen randomly or when the noise was switched on at a random time, indicating the robustness of the results. We also examined the effects of conductance-based noise on Hodgkin–Huxley neurons and obtained similar results, leading to the conclusion that the phenomena occur across a wide range of neuronal dynamical systems. Further, these phenomena will occur in diverse applications where a stable limit cycle coexists with a stable focus

Does the Precision of a Biological Clock Depend upon Its Period? Effects of the Duper and tau Mutations in Syrian Hamsters

Mutations which alter the feedback loops that generate circadian rhythms may provide insight into their insensitivity to perturbation robustness) and their consistency of period (precision). I examined relationships between endogenous period, activity and rest (τDD, α and ρ) in Syrian hamsters using two different mutations, duper and tau, both of which speed up the circadian clock. I generated 8 strains of hamsters that are homozygous or heterozygous for the tau, duper, and wild type alleles in all combinations. The endogenous period of activity onsets among these strains ranged from 17.94+0.04 to 24.13±0.04 h. Contrary to predictions, the variability of period was unrelated to its absolute value: all strains showed similar variability of τDD when activity onsets and acrophase were used as phase markers. The τDD of activity offsets was more variable than onsets but also differed little between genotypes. Cycle variation and precision were not correlated with τDD within any strain, and only weakly correlated when all strains are considered together. Only in animals homozygous for both mutations (super duper hamsters) were cycle variation and precision reduced. Rhythm amplitude differed between strains and was positively correlated with τDD and precision. All genotypes showed negative correlations between α and ρ. This confirms the expectation that deviations in the duration of subjective day and night should offset one another in order to conserve circadian period, even though homeostatic maintenance of energy reserves predicts that longer intervals of activity or rest would be followed by longer durations of rest or activity. Females consistently showed greater variability of the period of activity onset and acrophase, and of α, but variability of the period of offset differed between sexes only in super duper hamsters. Despite the differences between genotypes in τDD, ρ was consistently more strongly correlated with the preceding than the succeeding α