Biomedical subjects
Publications and source records attributed to C C McIntyre.
Recent work shows that two molecules with major roles in synaptic plasticity--CaMKII and the NMDA receptor--bind to each other. This binding activates CaMKII and triggers its autophosphorylation. In this state, it may act as a memory switch and strengthen synapses through enzymatic and structural processes.
Electrical stimulation via implanted microelectrodes permits excitation of small, highly localized populations of neurons, and allows access to features of neuronal organization that are not accessible with larger electrodes implanted on the surface of the brain or spinal cord. As a result there are a wide range of potential applications for the use of microelectrodes in neural engineering. However, little is known about the current-density and electric field generated by microelectrodes. The objectives of this project were to answer three fundamental questions regarding electrical stimulation with metal microelectrodes using geometrically and electrically accurate finite elements models. First, what is the spatial distribution of the current density over the surface of the electrode? Second, how do alterations in the electrode geometry effect neural excitation? Third, under what conditions can an electrode of finite size be modeled as a point source? Analysis of the models showed that the current density was concentrated at the tip of the microelectrode and at the electrode-insulation interface. Changing the surface area of the electrode, radius of curvature of the electrode tip, or applying a resistive coating to the electrode surface altered the current-density distribution on the surface of the electrode. Changes in the electrode geometry had little effect on neural excitation patterns, and modeling the electric field generated by sharply tipped microelectrodes using a theoretical point source was valid for distances > approximately 50 microm from the electrode tip. The results of this study suggest that a nearly uniform current-density distribution along the surface of the electrode can be achieved using a relatively large surface area electrode (500-1000 microm2), with a relatively blunt tip (3-6 microm radius of curvature), in combination with a thin (approximately 1 microm) moderately resistive coating (approximately 50 omega m).
The excitation and conduction properties of computer-based cable models of mammalian motor nerve fibres, incorporating three different myelin representations, are compared. The three myelin representations are a perfectly insulating single cable (model A), a finite impedance single cable (model B) and a finite impedance double cable (model C). Extracellular stimulation of the three models is used to study their strength-duration and current-distance (I-X) relationships, conduction velocity (CV) and action potential shape. All three models have a chronaxie time that is within the experimental range. Models B and C have increased threshold currents compared with model A, but each model has slope to the I-X relationship that matches experimental results. Model B has a CV that matches experimental data, whereas the CV of models A and C are above and below the experimental range, respectively. Model C is able to produce a depolarising afterpotential (DAP), whereas models A and B exhibit hyperpolarising afterpotentials. Models A and B are determined to be the preferred models when low-frequency stimulation (< approximately 25 Hz) is used, owing to their efficiency and accurate excitation and conduction properties. For high frequency stimulation (approximately 25 Hz and greater), model C, with its ability to produce a DAP, is necessary accurately to simulate excitation behaviour.
The goal of this study was to identify stimulus parameters and electrode geometries that were effective in selectively stimulating targeted neuronal populations within the central nervous system (CNS). Cable models of neurons that included an axon, initial segment, soma, and branching dendritic tree, with geometries and membrane dynamics derived from mammalian motoneurons, were used to study excitation with extracellular electrodes. The models reproduced a wide range of experimentally documented excitation patterns including current-distance and strength-duration relationships. Evaluation of different stimulus paradigms was performed using populations of fifty cells and fifty fibers of passage randomly positioned about an extracellular electrode(s). Monophasic cathodic or anodic stimuli enabled selective stimulation of fibers over cells or cells over fibers, respectively. However, when a symmetrical charge-balancing stimulus phase was incorporated, selectivity was greatly diminished. An anodic first, cathodic second asymmetrical biphasic stimulus enabled selective stimulation of fibers, while a cathodic first, anodic second asymmetrical biphasic stimulus enabled selective stimulation of cells. These novel waveforms provided enhanced selectivity while preserving charge balancing as is required to minimize the risk of electrode corrosion and tissue injury. Furthermore, the models developed in this study can predict the effectiveness of electrode geometries and stimulus parameters for selective activation of specific neuronal populations, and in turn represent useful tools for the design of electrodes and stimulus waveforms for use in CNS neural prosthetic devices.
The goal of this study was to determine which neural elements are excited by microstimulation of the central nervous system. A cable model of a neuron including an axon, initial segment, axon hillock, soma, and simplified dendritic tree was used to study excitation with an extracellular point source electrode. The model reproduced a wide range of experimentally documented extracellular excitation patterns. The site of action potential initiation (API) was a function of the electrode position, stimulus duration, and stimulus polarity. The axon or initial segment was always the site of API at threshold. When the electrode was positioned near the cell body, the site of excitation was dependent on the stimulus amplitude. With the electrode in close proximity to the neuron, short-duration cathodic pulses produced lower thresholds with the electrode positioned over the axon than over the cell body, and long-duration stimuli produced opposite relative thresholds. This result was robust to alterations in either the maximum conductances or the intracellular resistivities of the model. The site of maximum depolarization was not always an accurate predictor of the site of API, and the temporal evolution of the changes in membrane potential played a strong role in determining the site of excitation.
The sensitivity of the strength-duration (S-D) relationship to changes in the parameters describing the sodium channel of mammalian neuronal membrane was determined by computer simulation. A space-clamped patch of neuronal membrane was modeled by a parallel nonlinear sodium conductance, linear leakage conductance, and membrane capacitance. Each parameter that governs the activation (m) and inactivation (h) variables of the sodium channel was varied from -50% to +50% of its default value, and for each variation a S-D relationship was generated. Individual changes in six of the eleven parameters (alpha mA, alpha mD, alpha hA, beta mA, beta mB, and beta hB) generated substantial changes in the rheobase current and chronaxie time (Tch) of the model. Changing the parameter values individually did not correct for the model's failure to generate excitation after the release from a long duration hyperpolarization (anode break excitation). Scaling a combination of five parameters (alpha mA, alpha mB, alpha hA, beta mA, and beta hB) by an equal amount produced a model that generated anode break excitation and increased Tch, but also decreased the amplitude of the action potential. To reproduce the amplitude of the action potential, the maximum sodium conductance and sodium Nernst potential were increased. These modifications generated a model that had S-D properties closer to experimental results, could produce anode break excitation, and reproduced the action potential amplitude.