Totts Gap

Nonprofit Medical Research Laboratories

James E. Skinner, PhD, was trained in Neuroscience by Donald B. Lindsley at the Brain Research Institute of UCLA. His dissertation (1967) involved animal research concerned with the regulation of sensory input to primary cortex by the frontocortico-thalamic gating system; it won an award from the American Institutes of Research. After 2 additional years as a USPHS Postdoctoral Fellow, he left the BRI in Los Angeles and became an Assistant Professor of Physiology, and later of Neurology and Neuroscience, at Baylor College of Medicine in Houston. He worked under the aegis of Peter Kellaway, a clinical neurophysiologist interested in cerebral disorders and Michael E. DeBakey, a surgeon interested in cardiovascular pathologies. After a 23 year career as a Professor at BCM, he moved to the Totts Gap Institute, near New York City, and become its Associate Director in 1993. In recognition of his research achievements, he was presented the Laufberger Award (1994) by the Czech National Academy of Science.

Skinner began a research career in a new field he helped to pioneer, Neurocardiology. From the beginning he has been supported by research grants from the National Institutes of Health. Initially he showed how the frontal lobes simultaneously orchestrate sensory input and autonomic output during behavioral reactions to novel and conditioned stimuli. During such reactions he demonstrated the noradrenergic activation of a slow outward potassium current in frontocortical neurons that, in turn, selectively excite the 40-80 Hz activities in the thalamic reticular neurons that, in turn, determine the pattern of inhibition that controls the ascent of primary sensory information relayed through the thalamus. Simultaneously the frontocortical neurons that project to the brainstem cardiovascular centers activate both sympathetic and parasympathetic efferents in their control of the viscera. Walter B. Cannon, in the 1930's, had proposed that such an "orchestrator" existed and furthermore that it was the focus of natural selection that led to the rapid encephalization of the higher mammalian brain.

To fill the gap that lay between these initial findings and the clinical disorders of sudden cardiac death and hypertension, Skinner performed a series of studies to demonstrate, in a conscious pig model of experimental myocardial infarction, that behavioral stress-reduction, intracerebral beta-blockade, or bilateral cryoblockade of the frontocortical-brainstem pathways would prevent the occurrence of lethal cardiac arrhythmias following acute coronary artery constriction. These same cerebral interventions were also found to normalize the blood-pressure elevations in various models of experimental hypertension.

In parallel with the neurocardiac experiments in the pig, and in collaboration with gifted students and fellows (Roberto Seidner, Charles Yingling, Jane Reed, Gregory King, Mitchell Feldman, Mark Molnar, Saeed Moradi, Charles Gray, Marie Montaron, Stanley Beder, Julie Szilagyi, Jodie Litowitz, Michael Evans, Carol Landisman, Keith Fulton, Gerald Parker, Clara Carpeggiani, Tomas Vybirol), the Skinner Lab also focussed on the higher-cognitive components of the underlying neurocardiac mechanism. After all it was activity in the higher cerebral centers that was indicated to be the root cause of sudden cardiac death.

Because of the technical complexity of studying the widely distributed structures of the thalamic gating system that controlled the 40-80 Hz cellular activities during the selective sensory input, a model system was adopted, the olfactory bulb of the conscious rabbit. In this simple system model, which was known to have the same basic cell types, neurochemicals, and connectivities as those in the neocortex, it was possible to record what was happening to the output neurons on a grand scale, that is, by observing the surface potentials recorded by a densely-packed array of electrodes. As in the neocortex, a noradrenergic mechanisms was observed and found to underlie the reactive neural process stimulated by novel and conditioned odors.

But the amplitudes and frequencies observed in the spatial potentials of the bulb were not well behaved. So instead of presuming that the trial to trial variations in the surface potentials were stochastic, and therefore noise, the team hypothesized that they were determined, and perhaps were the signal. This hypothesis opened a whole new approach to the problem of biological signal analysis, and has led to considerable excitement in the Lab.

First a deterministic analytic measure (the PD2i) was developed, based in Chaos Theory, and with it the Lab showed that indeed stable patterns among the bulbar output neurons could be observed, and furthermore that the learning-altered pattern stayed fixed in time to bridged the so-called "time-gap" between associated stimuli and between trials. Thus the foundation was layed for the current interests of the Lab in the 40 to 80 Hz activities that have recently been found by a former member (Charles Gray) in the visual cortex and interpreted to "bind" feature detectors during the acquired perception of an "object."

In 1993 the Skinner Lab moved from Balyor College of Medicine to the Totts Gap Institute near New York City. This enabled the rapid expansion of the research interests into new territories, the clinical applications.

Because the new algorithm could easily be applied to the study of heart rate variability, a research subarea in clinical cardiology, the PD2i was used in the analysis of serial heartbeat intervals recorded from high-risk cardiac patients. It was found that this deterministic measure, unlike the stochastic ones (e.g., running 5-min standard deviation, power spectrum, etc.), could discriminate imminent risk of fatal arrhythmias with high sensitivity and individual specificity. Because of its important clinical significance, this type of PD2i-analysis has become an active area of study in the new Lab.

Other recent work at Totts Gap has been devoted to determining just what it is that the PD2i measures in a biological system. For sure, the algorithm, like other dimensional algorithms, reconstructs from the data stream just how many independent variables or minimum number of degrees of freedom exist in the generator, but additionally it has been proven that the PD2i can accurately track nonstationary changes in the data. Its application to many different types of biological data reveals a consistant result--- each biological generator, whether in the brain or the heart, changes as it "adapts" to its stimulus environment and metamorphically becomes to a NEW system.

To pursue this new understanding about the biological systems not being fixed in time, that is, evolving into a new entity with perhaps the same components but a new internal organization, a simple biological model was again adopted, the isolated rabbit heart with its intrinsic nervous system. The nonstationary shifts in the heartbeat data were found to occur in relation to changes in the organization ("self-organization") of the components of the system that control rate and strength of contraction. After the "re-organization" is completed, the complexity (i.e., PD2i) is reduced and a new stable attractor is formed, which specifies the new dynamics (i.e., the new behavioral function) of the system.

This recent finding has important implications for how "learning" may occur and how information may be "stored" in a massively parallel nervous system, like that of the simplified neurocardiac preparation. It is the attractor, not the individual pathways, that appears to be sculptured in time by the neuroplastic mechanisms. With only small modifications in the structure of the attractor, that is, after the re-organization in the system, enormous amounts of previously "stored" specific information existing in the parallel afferent-efferent loops is observed to be modified. How this happens is not yet known, but evidence suggests that the G-proteins may be involved, at least in the heart and its attached neurons.

In another clinical pursuit, behaviorally-released neuropeptides are being isolated and identified by the Lab, with the intention of using them as 3-dimensional models for "silver-bullet" drugs (i.e., drugs without side- effects). There are 10,000 neuropeptides stored in the brain, some of which are co-released along with aminergic neuromodulators. In comparison to their co-released companions, the neuropeptides have a more specific spatial effect on the modification of synaptic efficacy. The release-sites and receptors for single aminergic compounds are widely distributed in the brain and periphery (e.g., norepinephrine and the beta-receptors), whereas those of the neuropeptides generally are not. Using a specific behavior to release one or more specific neuropeptides into the interstitial space of the brain (and eventually into the serum), the Lab has isolated a small neuropeptide (NLX) that, when re-injected into the brain or blood, will normalize blood-pressure elevations in most experimental models of hypertension. NLX does not have the untoward side-effects of the beta- blockers (memory loss, impotency), which are drugs widely used to treat hypertension and to prevent sudden cardiac death. Therefore, the future NLX-based drug is expected to be more effective, because of this lack of dose-limiting side-effects.

Other behaviorally-released neuropeptides of interest to the Lab are those that suppress appetite in monkeys, inhibit malignant tumor growth in dogs, and recycle the nitrogen from blood urea in rats. These pursuits are somewhat of a distraction from the neurocardiac and cognitive researches, but they are very important because obesity, cancer, and kidney failure are national health problems that can be approached easily with the new collection of technologies.

The Skinner Lab at the Totts Gap Institute now has collaborative arrangements with other laboratories: in Cardiovascular Science (J Yasha Kresh, Hahneman University and Medical College of Pennsylvania), in Cognitive Neuroscience (Neils Birbaumer, University of Teubingen), in Physiological Psychology (George Karmos and Mark Molnar, National Academy of Science, Budapest) and Molecular Biology (D Scott Linthicum, Texas A&M University). Current financial support is from both the public (National Institutes of Health, Totts Gap Institute) and private sectors (Neurotech Laboratories, Inc., Greer Industries, Inc.).