James E. Skinner - US grants

sudden cardiac death; ventricular fibrillation; behavioral medicine;

The use of nonlinear mathematical dynamics is claimed to be revolutioning some sciences, because deterministic models can be made of unresolved physical and chemical phenomena (e.g., Brownian motion, turbulent flow, etc.). Several laboratories have attempted to apply nonlinear dynamics, th t is, the correlation dimension (D2) to the electroencephalogram of humans. Our laboratory, being skeptical, tested some of their claims on surface potentials in a simple model system, the olfactory bulb). The bulb has the same cell types and intrinsic neurochemistry as neocortex, but has a much simpler and better understood neurophysiology. Algorithms were developed t estimate D2, which led to the conviction that low-dimentional chaos DOES EXIST in the bulb. Using brief epochs and behavioral control, stationarity was observed; by eliminating spurious autocorrelations, linear correlation- integrals were achieved to calculate D2; by studying known chaotic attractors, rules were developed for sampling the attractor. Following thi experience, we now propose to determine whether or not the nonlinear dynamical analyses can be applied to real neocortex. Our first Specific Ai is to evalute D2 during various normal cortical conditions: quiet wakefulness, sleep and event-related reactions. Because of the sensitivity of the D2-meausre and its potential clinical application, Specific Aim 2 is to evalute D2 during known pathological conditions in the cortex: hypernoradrenergic reactivity (hypertension in SHR and renovascular rat models) and hypernoradrenergic innervation (epilepsy in the tottering-mouse model). Specific Aim 3 is to determine whether or not D2-values are sensitive to therapeutic interventions. If D2 is found to be sensitive to normal and abnormal cortical functioning, then its use can be developed for the diagnosis of cerebral (and perhaps preclinical) pathology and the evaluation of therapies. Because of its process-specific signature, D2 can be used to map anatomical loci which contribute to the singular dynamical system. Furthermore, the integer and fractional portions of D2 have theoretical implications regarding the number of independent variables in t e stationary process and whether or not it may factal. (key words: nonlinea dynamics, chaos, fractals, cerebral cortex, event-related potentials, sleep epilepsy, hypertension, noradrenergic response).

DESCRIPTION (adapted from the applicant's abstract): The applicant's long-term goal is to understand the neurocardiac mechanism underlying sudden cardiac death. The applicant states that neurocardiological approaches over the past two decades, in both animal and human studies, have clearly shown that psychosocial stressors, higher cerebral integrative-centers, and the autonomic nerves have important regulatory roles, perhaps even causal ones, in the process of lethal ventricular fibrillation (VF). The heart rate variability (HRV) is primarily regulated by the nervous system. An altered range, synchrony or pattern of HRV is predictive of risk in prospective clinical studies. Of these, the applicant believes the altered pattern of variability, represented by a reduction in the chaotic dimension of the heartbeats, seems to best predict VF, but this measure has only been studied in high-risk patient groups. The applicant now wishes to study this HRV measure, along with other promising stochastic and deterministic candidate-measures, in data collected during experimental ischemia in the conscious pig, a preparation in which the neurocardiac variables regulating vulnerability to VF can be systematically controlled. The applicant also wishes to integrate his studies of HRV with a mathematical theory of heartbeat generation and arrhythmogenesis. The applicant developed a strategy in which he can remap the variables of the theoretical model into the QT and RR-QT subintervals of each heartbeat. In support of this strategy the applicant has found 1) a predicted exclusion area of the QT vs RR-QT dynamics; 2) a breakdown of this exclusion area by neurocardiac variables known to increase risk of VF, and 3) evoked arrhythmias when the QT vs RR-QT dynamics enter the exclusion area. The applicant's final aim is to model these phenomena, using a mathematical simulation of an excitable medium that has T-waves.

DESCRIPTION (provided by applicant): A large unmet need exists in medical markets for a product to assist the Emergency Department physician in the rapid triage of high-risk cardiac-patients. A new cutting-edge device is proposed to reduce physician error as well as hospital costs. The Phase-1 aim is to develop user-friendly analytic software to be used on conventional digital ECG's to predict risk of arrhythmic death. The proposal is supported by results from two independent prospective studies which show that the analysis of heart rate variability (HRV) by the Company's proprietary algorithm is highly predictive of arrhythmic death in ER patients and of all cause mortality in survivors of myocardial infarction. ECG analysis by this proprietary algorithm currently requires experts in signal analysis. The goal of this proposal is to develop software meeting FDA specifications that can be used by actual hospital personnel in an actual clinical situation. The two Specific Aims of this fast-track proposal are 1) the creation of user-friendly software for use by hospital personnel, and 2) the testing and establishment of "good medical practice" through wide experimental use of this software at different Emergency Room sites. Both aims are pivotal for commercialization.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Understanding the molecular structure and dynamics of condensed phases is a major goal of chemists. Infrared (IR) spectroscopy is a powerful technique used to study the structures of substances via analysis of characteristic absorption bands. Recent advances in laser techniques and ultrafast nonlinear IR spectroscopy enable researchers to obtain valuable structural and dynamic information on systems in the condensed phase. One of our research groups focuses is the theory and simulation of condensed phase spectroscopy. Previous work utilizing the facility at SDSC has allowed us to modify the GROMACS code to output frequency trajectories on-the-fly for the amide-I spectra calculation of a tetrameric peptide bundle, CD3-zeta. We are extending the method we have developed to investigate the spectral signature accompanying the amyloid aggregation. Large and fast computational environments provided by the TeraGrid sites will facilitate the computation and understanding of FT-IR and 2D-IR spectra of amyloid monomer/aggregates. In addition, we are currently developing an output data manipulation for instantaneous lineshape calculation and extending our methodology to coupled-chromophore systems.