Application of Signal Advance Technology to Electrophysiology

Medical instrumentation used in diagnosis and treatment relies on the accurate detection and processing of various physiological events and signals. While signal detection technology has improved greatly in recent years, there remain inherent delays in signal detection/ processing. These delays may have significant negative clinical consequences during various pathophysiological events. Reducing or eliminating such delays would increase the ability to provide successful early intervention in certain disorders thereby increasing the efficacy of treatment. In recent years, a physical phenomenon referred to as Negative Group Delay (NGD), demonstrated in simple electronic circuits, has been shown to temporally advance the detection of analog waveforms. Specifically, the output is temporally advanced relative to the input, as the time delay through the circuit is negative. The circuit output precedes the complete detection of the input signal. This process is referred to as signal advance (SA) detection. An SA circuit model incorporating NGD was designed, developed and tested. It imparts a constant temporal signal advance over a pre-specified spectral range in which the output is almost identical to the input signal (i.e., it has minimal distortion). Certain human patho-electrophysiological events are good candidates for the application of temporally-advanced waveform detection. SA technology has potential in early arrhythmia and epileptic seizure detection and intervention. Demonstrating reliable and consistent temporally advanced detection of electrophysiological waveforms may enable intervention with a pathological event (much) earlier than previously possible. SA detection could also be used to improve the performance of neural computer interfaces, neurotherapy applications, radiation therapy and imaging. In this study, the performance of a single-stage SA circuit model on a variety of constructed input signals, and human ECGs is investigated. The data obtained is used to quantify and characterize the temporal advances and circuit gain, as well as distortions in the output waveforms relative to their inputs. This project combines elements of physics, engineering, signal processing, statistics and electrophysiology. Its success has important consequences for the development of novel interventional methodologies in cardiology and neurophysiology as well as significant potential in a broader range of both biomedical and non-biomedical areas of application.

Motile response patterns and ultrastructural observations of the isolated outer hair cell

The tonotopic organization of the mammalian cochlea is accompanied by structural gradients which include the somatic lengths of outer hair cells (OHCs). These receptors rest upon the vibrating portion of the basilar membrane and have been reported to exhibit motile responses following chemical and electrical stimulation. These movements were examined in detail in this dissertation. It was found that isolated OHCs cultured in vitro respond to chemical depolarization with slow tonic movements, and to electrical waveforms with bi-directional, frequency following movements extending from DC to at least 10 kHz.^ Slow contractions were also elicited following electrical stimulation, bath incubation in carbachol (a cholinergic agonist), and increases in extracellular K+ concentration as little as 50 mM.^ Isolated OHCs display anatomical features which are remarkable when contrasted with those prepared from intact receptor organs. A complex structure located between the cuticular plate and the nuclear membrane was consistently observed and was examined by serial cross-sections which revealed a network of non-membrane bound densities. This corresponded to a granular complex seen at the light microscope level. The complex was composed of dense regions of organelles, striated structures embedded within the core, and a circumferential network of microtubules residing in the peri-nuclear portion of the cell. In cells which had lost their nuclear attachment to the terminal synaptic body, the granular complex could be made to contract without effecting any change in cellular length, implying that the complex may be the driving force behind certain aspects of the motile response.^ Most cells displayed movements which revealed asymmetries analogous to those reported for OHC receptor potentials in vivo. The contraction phase (for longer cells) was shown to have a small time constant (approximately 400 microseconds) and saturated with limited displacements. The expansion phase had time constants as large as 1.3 milliseconds but yielded displacements as much as 60 percent larger than those seen for contractions.^ Additional waveform characteristics seen in the in vivo response could be emulated either by biasing the cell's resting length with either direct current, triggering contractions via large electrical displacements, or incubation with depolarizing compounds.^ Alternatively, short (20-30 um) cells revealed more linear response characteristics to the probe stimulus. Partial saturation was achieved and revealed a DC component which was opposite in polarity to that seen in longer cells. (Abstract shortened with permission of author.) ^

APPLICATION OF THE BRAINSTEM EVOKED RESPONSE (BER) TO NEUROTOXICITY EVALUATION OF THE AUDITORY SYSTEM: ASSESSMENT OF INORGANIC LEAD-INDUCED OTOTOXICITY

An experimental procedure was developed using the Brainstem Evoked Response (BER) electrophysiological technique to assess the effect of neurotoxic substances on the auditory system. The procedure utilizes Sprague-Dawley albino rats who have had dural electrodes implanted in their skulls, allowing neuroelectric evoked potentials to be recorded from their brainstems. Latency and amplitude parameters derived from the evoked potentials help assess the neuroanatomical integrity of the auditory pathway in the brainstem. Moreover, since frequency-specific auditory stimuli are used to evoke the neural responses, additional audiometric information is obtainable. An investigation on non-exposed control animals shows the BER threshold curve obtained by tests at various frequencies very closely approximates that obtained by behavioral audibility tests. Thus, the BER appears to be a valid measure of both functional and neuroanatomical integrity of the afferent auditory neural pathway.^ To determine the usefulness of the BER technique in neurobehavioral toxicology research, a known neurotoxic agent, Pb, was studied. Female Sprague-Dawley rats were dosed for 45 days with low levels of Pb acetate in their drinking water, after which BER recordings were obtained. The Pb dosages were determined from the findings of an earlier pilot study. One group of 6 rats received normal tap water, one group of 7 rats received a solution of 0.1% Pb, and another group of 7 rats received a solution of 0.2% Pb. After 45 days, the three groups exhibited blood Pb levels of 4.5 (+OR-) 0.43 (mu)g/100 ml, 37.8 (+OR-) 4.8 (mu)g/100 ml and 47.3 (+OR-) 2.7 (mu)g/100 ml, respectively.^ The results of the BER recording indicated evoked response waveform latency abnormalities in both the Pb-treated groups when midrange frequency (8 kHz to 32 kHz) stimuli were used. For the most part, waveform amplitudes did not vary significantly from control values. BER recordings obtained after a 30-day recovery period indicated the effects seen in the 0.1% Pb group had disappeared. However, those anomalies exhibited by the 0.2% Pb group either remained or increased in number. This outcome indicates a longer lasting or possibly irreversible effect on the auditory system from the higher dose of Pb. The auditory pathway effect appears to be in the periphery, at the level of the cochlea or the auditory (VIII) nerve. The results of this research indicate the BER technique is a valuable and sensitive indicator of low-level toxic effects on the auditory system.^