Biomedical subjects

Warren M Grill

Publications and source records attributed to Warren M Grill.

30 records · Page 2Linked to original sources

PubMed2004

Sensitivity of temporal excitation properties to the neuronal element activated by extracellular stimulation.

Measurements of the chronaxies and refractory periods with extracellular stimuli have been used to conclude that large diameter axons are responsible for the effects of deep brain stimulation (DBS). We hypothesized that because action potential initiation by extracellular stimulation occurs in the axons of central nervous system (CNS) neurons, the chronaxies and refractory periods determined using extracellular stimulation would be similar for cells and axons. Computer simulation was used to determine the sensitivity of chronaxie and refractory period to the neural element stimulated. The results demonstrate that chronaxies and refractory periods were dependent on the polarity of the extracellular stimulus and the electrode-to-neuron distance, and indicate that there is little systematic difference in either chronaxies or refractory periods between local cells or axons of passage with extracellular stimulation. This finding points out the difficulty in drawing conclusions regarding which neuronal elements are activated based on extracellular measurements of temporal excitation properties.

Action Potentials↗

PubMed2004

Electrical localization of neural activity in the dorsal horn of the spinal cord: a modeling study.

Intraspinal microstimulation is a means of eliciting coordinated motor responses for restoration of function. However, detailed maps of the neuroanatomy of the human spinal cord are lacking, and it is not clear where electrodes should be implanted. We developed an electrical approach to localize active neurons in the spinal cord using potentials recorded from the surface of the spinal cord. We evaluated this localization method using an analytical model of the spinal cord and two previously developed inverse algorithms (standardized low resolution brain electromagnetic tomography (sLORETA) and a locally optimal source (LOS) method). The results support electrical source localization as a feasible imaging approach for localizing (within 300 microm) active neurons in the spinal cord. The LOS method could localize the source when 16 recording electrodes were placed on the dorsolateral aspect of the cord and the noise level was 2%. When recording electrodes were positioned around the entire circumference of the spinal cord, either localization method could localize the source, even at 15% noise. Finally, localization error was not sensitive to inaccuracies in the expected electrode positions or the electrical parameters of the forward model, but was sensitive to a geometrical modification of the forward model in one case.

Animals↗

PubMed2004

Selection of stimulus parameters for deep brain stimulation.

OBJECTIVE: To provide an analysis of stimulation parameters for deep brain stimulation (DBS). METHODS: Synthesis of theoretical and empirical findings is used to provide guidance for the selection of stimulus parameters. Finite element modeling is used to investigate the effects of contact location and electrode geometry on the electric field, and to estimate the effects of current density distribution on the limit for non-damaging stimulation. RESULTS: Anatomical targeting of DBS electrodes is complicated by the uncertainty of which neural elements are targeted and differences in the electric field distribution in fiber tracts and nuclei. Electrical targeting by selection of electrode geometry and stimulus waveform can alter the distribution of the electric field and control neural activation. The recommended charge density limit for DBS represents a liberal estimate for non-damaging stimulation. Short duration stimulus pulses reduce charge injection and increase the therapeutic window between therapeutic effects and side effects. CONCLUSIONS: There are several challenges to developing rational methods of selecting stimulus parameters including a large number of degrees of freedom, the unknown effects of stimulation, and the complexity of the responses. SIGNIFICANCE: Understanding the fundamentals of electrical stimulation of the nervous system enables rational selection of stimulus parameters.

Brain↗

PubMed2004

Prediction of myelinated nerve fiber stimulation thresholds: limitations of linear models.

Computer models of neurons are used to simulate neural behavior, and are important tools for designing neural prostheses. Computation time remains an issue when simulating large numbers of neurons or applying models to real time applications. Warman et al. developed a method to predict excitation thresholds for axons using linear models and a predetermined critical voltage. We calculated threshold prediction error as a function of the location of an extracellular electrode using two different axon models to examine further threshold prediction using linear models. Threshold prediction error was low (<3% error) under the conditions examined by Warman et al., but under more general conditions, threshold prediction error was as high as 23.6%. Linear models were limited as effective tools for single fiber threshold prediction because accuracy was dependent on the nonlinear and linear models used, and any parameter that affected the extracellular potential distribution. Threshold prediction could be improved by appropriately choosing the membrane conductance of the linear model, but determination of an optimal conductance was computationally expensive. Finally, although single fiber threshold prediction error was partially masked when considering the input-output (I/O) properties of populations of axons, relatively large errors still occurred in population I/O curves generated with linear models.

Axons↗

PubMed2003

Cellular effects of deep brain stimulation: model-based analysis of activation and inhibition.

Deep brain stimulation (DBS) is an effective therapy for medically refractory movement disorders. However, fundamental questions remain about the effects of DBS on neurons surrounding the electrode. Experimental studies have produced apparently contradictory results showing suppression of activity in the stimulated nucleus, but increased inputs to projection nuclei. We hypothesized that cell body firing does not accurately reflect the efferent output of neurons stimulated with high-frequency extracellular pulses, and that this decoupling of somatic and axonal activity explains the paradoxical experimental results. We studied stimulation using the combination of a finite-element model of the clinical DBS electrode and a multicompartment cable model of a thalamocortical (TC) relay neuron. Both the electric potentials generated by the electrode and a distribution of excitatory and inhibitory trans-synaptic inputs induced by stimulation of presynaptic terminals were applied to the TC relay neuron. The response of the neuron to DBS was primarily dependent on the position and orientation of the axon with respect to the electrode and the stimulation parameters. Stimulation subthreshold for direct activation of TC relay neurons caused suppression of intrinsic firing (tonic or burst) activity during the stimulus train mediated by activation of presynaptic terminals. Suprathreshold stimulation caused suppression of intrinsic firing in the soma, but generated efferent output at the stimulus frequency in the axon. This independence of firing in the cell body and axon resolves the apparently contradictory experimental results on the effects of DBS. In turn, the results of this study support the hypothesis of stimulation-induced modulation of pathological network activity as a therapeutic mechanism of DBS.

Action Potentials↗

PubMed2003

Modularity of motor output evoked by intraspinal microstimulation in cats.

We studied the forces produced at the cat's hindpaw by microstimulation of the ipsi- and contralateral lumbar spinal cord in spinal intact alpha-chloralose anesthetized (n = 3) or decerebrate (n = 3) animals. Isometric force and EMG responses were measured at 9-12 limb configurations, with the paw attached to a force transducer and with the hip and femur fixed. The active forces elicited at different limb configurations were summarized as force fields representing the sagittal plane component of the forces produced at the paw throughout the workspace. The forces varied in amplitude over time but the orientations were stable, and the pattern of an active force field was invariant through time. The active force fields divided into four distinct types, and a few of the fields showed convergence to an equilibrium point. The fields were generally produced by coactivation of the hindlimb muscles. In addition, some of the fields were consistent with known spinal reflexes and the stimulation sites producing them were in laminae where the interneurons associated with those reflexes are known to be located. Muscle activation produced by intraspinal stimulation, as assessed by intramuscular EMG activity, was modified with limb configuration, suggesting that the responses were not fixed, but were modified by position-dependent sensory feedback. The force responses may represent basic outputs of the spinal circuitry and may be related to similar spinal primitives found in the frog and rat.

Anesthetics, Intravenous↗

PubMed2003

A catheter based method to activate urethral sensory nerve fibers.

PURPOSE: The ability to control bladder activity would provide a valuable tool to assist individuals with neurological disorders or spinal cord injury (SCI). Recent studies in animal models have shown that bladder contractions can be evoked by electrical stimulation of urethral afferent nerves. We developed and validated in cats a minimally invasive method to stimulate electrically the sensory nerve fibers that innervate the urethra. MATERIALS AND METHODS: The urethra was stimulated electrically along its length via a catheter mounted circumferential electrode in 6 cats. The urethra was similarly stimulated in a male individual with complete SCI. RESULTS: Robust bladder contractions were generated via intraurethral electrical stimulation in all cat experiments. Peak responses were obtained in the proximal and prostatic urethra. In the individual with SCI bladder contractions were generated via intraurethral stimulation at a position 4 cm distal to the bladder. Responses in cats and the human depended on bladder volume. CONCLUSIONS: To our knowledge this study provides the first documentation of generating bladder contractions via intraurethral electrical stimulation in cats and humans. This method provides a research tool for future studies to investigate these pathways in humans. Preliminary human results suggest that urethral afferent mediated neural pathways demonstrated in animal models exist in humans and support the development of neural prostheses using electrical stimulation of these nerves to restore control of bladder function in individuals with neurological disorders or SCI.

Adult↗

PubMed2002

Effects of stochastic sodium channels on extracellular excitation of myelinated nerve fibers.

The effects of the stochastic gating properties of sodium channels on the extracellular excitation properties of mammalian nerve fibers was determined by computer simulation. To reduce computation time, a hybrid multicompartment cable model including five central nodes of Ranvier containing stochastic sodium channels and 16 flanking nodes containing detenninistic membrane dynamics was developed. The excitation properties of the hybrid cable model were comparable with those of a full stochastic cable model including 21 nodes of Ranvier containing stochastic sodium channels, indicating the validity of the hybrid cable model. The hybrid cable model was used to investigate whether or not the excitation properties of extracellularly activated fibers were influenced by the stochastic gating of sodium channels, including spike latencies, strength-duration (SD), current-distance (IX), and recruitment properties. The stochastic properties of the sodium channels in the hybrid cable model had the greatest impact when considering the temporal dynamics of nerve fibers, i.e., a large variability in latencies, while they did not influence the SD, IX, or recruitment properties as compared with those of the conventional deterministic cable model. These findings suggest that inclusion of stochastic nodes is not important for model-based design of stimulus waveforms for activation of motor nerve fibers. However, in cases where temporal fine structure is important, for example in sensory neural prostheses in the auditory and visual systems, the stochastic properties of the sodium channels may play a key role in the design of stimulus waveforms.

Action Potentials↗

PubMed2002

Evaluation of command algorithms for control of upper-extremity neural prostheses.

Five new command control algorithms were created to enable increased control over grasp force in upper-extremity neural prostheses. Most of these algorithms took advantage of the ability to lock or assign a steady command value to the hand neural prosthesis. Five able-bodied subjects tested the algorithms by using a shoulder controller that controlled a video-simulated hand to repeatedly complete a consistent evaluation task. A generalized estimating equations-based linear model was used to analyze the data. The algorithms were ranked via contrast analyses between the coefficient values from the linear model of the proportional control with lock algorithm, which is the algorithm presently used in neural prostheses, and each of the other algorithms. The algorithms that allowed adjustment of the command value after the hand was locked as well as algorithms that allowed a decrease in controller gain after the hand was locked performed better than the proportional control with lock algorithm. Algorithms that changed command as a function of time performed worse than the proportional control with lock algorithm. Further, the computer-based video simulator proved to be useful as a first-pass evaluation tool for neural prosthesis control.

Adult↗

PubMed2002

Modeling the excitability of mammalian nerve fibers: influence of afterpotentials on the recovery cycle.

Human nerve fibers exhibit a distinct pattern of threshold fluctuation following a single action potential known as the recovery cycle. We developed geometrically and electrically accurate models of mammalian motor nerve fibers to gain insight into the biophysical mechanisms that underlie the changes in axonal excitability and regulate the recovery cycle. The models developed in this study incorporated a double cable structure, with explicit representation of the nodes of Ranvier, paranodal, and internodal sections of the axon as well as a finite impedance myelin sheath. These models were able to reproduce a wide range of experimental data on the excitation properties of mammalian myelinated nerve fibers. The combination of an accurate representation of the ion channels at the node (based on experimental studies of human, cat, and rat) and matching the geometry of the paranode, internode, and myelin to measured morphology (necessitating the double cable representation) were needed to match the model behavior to the experimental data. Following an action potential, the models generated both depolarizing (DAP) and hyperpolarizing (AHP) afterpotentials. The model results support the hypothesis that both active (persistent Na(+) channel activation) and passive (discharging of the internodal axolemma through the paranodal seal) mechanisms contributed to the DAP, while the AHP was generated solely through active (slow K(+) channel activation) mechanisms. The recovery cycle of the fiber was dependent on the DAP and AHP, as well as the time constant of activation and inactivation of the fast Na(+) conductance. We propose that experimentally documented differences in the action potential shape, strength-duration relationship, and the recovery cycle of motor and sensory nerve fibers can be attributed to kinetic differences in their nodal Na(+) conductances.

Action Potentials↗

PubMed2002

Extracellular stimulation of central neurons: influence of stimulus waveform and frequency on neuronal output.

The objective of this project was to examine the influence of stimulus waveform and frequency on extracellular stimulation of neurons with their cell bodies near the electrode (local cells) and fibers of passage in the CNS. Detailed computer-based models of CNS cells and axons were developed that accurately reproduced the dynamic firing properties of mammalian motoneurons including afterpotential shape, spike-frequency adaptation, and firing frequency as a function of stimulus amplitude. The neuron models were coupled to a three-dimensional finite element model of the spinal cord that solved for the potentials generated in the tissue medium by an extracellular electrode. Extracellular stimulation of the CNS with symmetrical charge balanced biphasic stimuli resulted in activation of fibers of passage, axon terminals, and local cells around the electrode at similar thresholds. While high stimulus frequencies enhanced activation of fibers of passage, a much more robust technique to achieve selective activation of targeted neuronal populations was via alterations in the stimulus waveform. Asymmetrical charge-balanced biphasic stimuli, consisting of a long-duration low-amplitude cathodic prepulse phase followed by a short-duration high-amplitude anodic stimulus phase, enabled selective activation of local cells. Conversely, an anodic prepulse phase followed by a cathodic stimulus phase enabled selective activation of fibers of passage. The threshold for activation of axon terminals in the vicinity of the electrode was lower than the threshold for direct activation of local cells, independent of the stimulus waveform. As a result, stimulation induced trans-synaptic influences (indirect depolarization/hyperpolarization) on local cells altered their neural output, and this indirect effect was dependent on stimulus frequency. If the indirect activation of local cells was inhibitory, there was little effect on the stimulation induced neural output of the local cells. However, if the indirect activation of the local cells was excitatory, attempts to activate selectively fibers of passage over local cells was limited. These outcomes provide a biophysical basis for understanding frequency-dependent outputs during CNS stimulation and provide useful tools for selective stimulation of the CNS.

Animals↗

PubMed2002

Electrical stimulation for the treatment of bladder dysfunction: current status and future possibilities.

Electrical stimulation of peripheral nerves can be used to cause muscle contraction, to activate reflexes, and to modulate some functions of the central nervous system (neuromodulation). If applied to the spinal cord or nerves controlling the lower urinary tract, electrical stimulation can produce bladder or sphincter contraction, produce micturition, and can be applied as a medical treatment in cases of incontinence and urinary retention. This article first reviews the history of electrical stimulation applied for treatment of bladder dysfunction and then focuses on the implantable Finetech-Brindley stimulator to produce bladder emptying, and on external and implantable neuromodulation systems for treatment of incontinence. We conclude by summarizing some recent research efforts including: (a) combined sacral posterior and anterior sacral root stimulator implant (SPARSI), (b) selective stimulation of nerve fibers for selective detrusor activation by sacral ventral root stimulation, (c) microstimulation of the spinal cord, and (d) a newly proposed closed-loop bladder neuroprosthesis to treat incontinence caused by bladder overactivity.

Animals↗