Biomedical subjects

Warren M Grill

Publications and source records attributed to Warren M Grill.

At least 19 recordsLinked to original sources

PubMed2006

Frequency-dependent selection of reflexes by pudendal afferents in the cat.

Activation of urethral or genital afferents of the pudendal nerve can elicit or inhibit micturition, and low frequency stimulation of the compound pudendal nerve (PN) is known to produce a continence response. The present study demonstrates that PN stimulation also can elicit a micturition-like response and that the response to PN stimulation is dependent on stimulation frequency. We measured the changes in bladder pressure and external urethral sphincter (EUS) electroneurogram (ENG) evoked by PN stimulation before and up to 16 h after spinal cord transection (SCT) in cats anaesthetized with alpha-chloralose. Low frequency (10 Hz) stimulation elicited a continence-like response, including inhibition of the bladder and activation of the EUS, but mid-frequency (33 Hz) stimulation produced a micturition-like response, including excitation of the bladder without activation of the EUS. The dependence of the response on stimulus frequency was linked to interpulse interval as the same number of pulses at 10, 33 and 100 Hz produced different responses. Stimulation of the PN at 33 Hz produced bladder contractions before and 8 h after SCT provided the bladder contained a minimum volume of fluid. Only mid-range frequency stimulation with sufficient stimulus train duration produced a reduction in EUS ENG activity before and after SCT. In addition to a continence-like response, PN stimulation can also elicit a micturition-like response, and this response is dependent on stimulation frequency, stimulus train duration, and bladder volume. The ability to control the two principal functions of the bladder by pudendal nerve stimulation is an exciting prospect for neurorehabilitation.

Afferent Pathways↗

PubMed2006

Bladder emptying by intermittent electrical stimulation of the pudendal nerve.

Persons with a suprasacral spinal cord injury cannot empty their bladder voluntarily. Bladder emptying can be restored by intermittent electrical stimulation of the sacral nerve roots (SR) to cause bladder contraction. However, this therapy requires sensory nerve transection to prevent dyssynergic contraction of the external urethral sphincter (EUS). Stimulation of the compound pudendal nerve trunk (PN) activates spinal micturition circuitry, leading to a reflex bladder contraction without a reflex EUS contraction. The present study determined if PN stimulation could produce bladder emptying without nerve transection in cats anesthetized with alpha-chloralose. With all nerves intact, intermittent PN stimulation emptied the bladder (64 +/- 14% of initial volume, n = 37 across six cats) more effectively than either distention-evoked micturition (40 +/- 19%, p < 0.001, n = 27 across six cats) or bilateral intermittent SR stimulation (25 +/- 23%, p < 0.005, n = 4 across two cats). After bilateral transection of the nerves innervating the urethral sphincter, intermittent SR stimulation voided 79 +/- 17% (n = 12 across three cats), comparable to clinical results obtained with SR stimulation. Voiding via intermittent PN stimulation did not increase after neurotomy (p > 0.10), indicating that PN stimulation was not limited by bladder-sphincter dyssynergia. Intermittent PN stimulation holds promise for restoring bladder emptying following spinal injury without requiring nerve transection.

Animals↗

PubMed2006

Clinical response to varying the stimulus parameters in deep brain stimulation for essential tremor.

Deep brain stimulation (DBS) of the ventral intermediate nucleus of the thalamus for essential tremor is sometimes limited by side effects. The mechanisms by which DBS alleviates tremor or causes side effects are unclear; thus, it is difficult to select stimulus parameters that maximize the width of the therapeutic window. The goal of this study was to quantify the impact on side effect intensity (SE), tremor amplitude, and the therapeutic window of varying stimulus parameters. Tremor amplitude and SE were recorded at 40 to 90 combinations of pulse width, frequency, and voltage across 14 thalami. Posterior variable inclusion probabilities indicated that frequency and voltage were the most important predictors of both SE and tremor amplitude. The amount of tremor suppression achieved at frequencies of 90 to 100 Hz was not different from that at 160 to 170 Hz. However, the width of the therapeutic window decreased significantly and power consumption increased as frequency was increased above 90 to 100 Hz. Improved understanding of the relationships between stimulus parameters and clinical responses may lead to improved techniques of stimulus parameter adjustment.

Adult↗

PubMed2006

Detection of neurogenic detrusor contractions from the activity of the external anal sphincter in cat and human.

AIMS: Individuals with spinal cord injury or neurological disorders may develop bladder contractions at low volumes (neurogenic detrusor overactivity), which can lead to significant health problems. Present devices can inhibit unwanted contractions through continuous electrical stimulation of sensory nerves, but do not enable conditional stimulation only at the onset of bladder contractions. The objectives of this study were to determine the relationship between the electrical activity of external anal sphincter (EAS) and bladder pressure during neurogenic detrusor contractions and to determine whether EAS activity could be used to detect the onset of bladder contractions. METHODS: Bladder pressure and EAS electromyogram (EMG) were recorded in nine adult male cats. Retrospective clinical data consisting of bladder pressure and EAS EMG from 41 spinal cord injured individuals with neurogenic detrusor overactivity were analyzed. A CUSUM algorithm was used to detect the onset of bladder contractions from the EAS EMG. RESULTS: EAS EMG activity increased at the onset of bladder contractions in six cats (dyssynergic) and decreased (synergic) in three cats. The onset of bladder contractions was detected within 3 sec of the start of the contraction for both the synergic and dyssynergic data sets. The onset of bladder contractions was detected within 1 sec of the start of the bladder contraction for both synergic and dyssynergic human subjects. CONCLUSIONS: Recordings of the EAS EMG can be used to detect robustly the onset of neurogenic detrusor contractions. The EAS EMG is a suitable signal to control closed-loop inhibitory electrical stimulation to maintain urinary continence.

Anal Canal↗

PubMed2006

Closed loop electrical control of urinary continence.

PURPOSE: Individuals with spinal cord injury or neurological disorders may have neurogenic detrusor contractions at low volumes (bladder hyperreflexia), which cause incontinence and can lead to significant health problems. Bladder contractions can be suppressed by electrical stimulation of inhibitory pathways but continuous activation may lead to habituation of the inhibitory reflex and loss of continence. We determined whether conditional stimulation with electrical stimulation of inhibitory pathways applied only at the onset of nascent bladder contractions allows the bladder to fill to a greater volume before continence is lost compared with continuous stimulation. MATERIALS AND METHODS: In 6 alpha-chloralose anesthetized cats cystometry was performed to compare the volume at which continence was lost under the conditions of no stimulation, continuous stimulation and conditional electrical stimulation of inhibitory pathways. PNT ENG was used to detect the onset of bladder contractions and it served as the input to an event triggered control system that regulated conditional stimulation to maintain continence. RESULTS: Conditional stimulation controlled by PNT ENG increased bladder capacity by 36% over no stimulation and by 15% over continuous stimulation (p <0.001 and 0.027, respectively). The event triggered control system decreased stimulation time by 67% compared to continuous stimulation. CONCLUSIONS: Conditional electrical stimulation of inhibitory pathways is more effective than continuous stimulation. A control system triggered by PNT ENG can maintain urinary continence.

Animals↗

PubMed2006

Sites of neuronal excitation by epiretinal electrical stimulation.

Action potentials arising from retinal ganglion cells ultimately create visual percepts. In persons blind from retinitis pigmentosa and age-related macular degeneration, viable retinal ganglion cells remain, and the retina can be stimulated electrically to restore partial sight. However, it is unclear what neuronal elements in the retina are activated by epiretinal electrical stimulation. This study investigated the effects of cellular geometry, electrode to neuron distance, stimulus duration, and stimulus polarity on excitation of a retinal ganglion cell with an epiretinal electrode. Computer-based compartmental models representing simplified retinal ganglion cell morphology provided evidence that the threshold for excitation was lower when an electrode was located in proximity to the characteristic 90 degrees bend in the axon of the retinal ganglion cell than when it was located over a passing axon of the nerve fiber layer. This electrode-position-dependent difference in threshold occurred with both cathodic and anodic monophasic stimuli, with point source and disk electrodes, at multiple electrode-to-neuron distances, and was robust to changes in the electrical properties of the model. This finding reveals that the physical geometry of the retinal ganglion cells produces stimulation thresholds that depend strongly on electrode position. The low excitation thresholds near the bend in the axon will result in activation of cells local to the electrode at lower currents than required to excite passing axons. This pattern of activation provides a potential explanation of how epiretinal electrical stimulation results in the production of punctuate, rather than diffuse or streaky phosphenes.

Action Potentials↗

PubMed2005

Fascicular anatomy and surgical access of the human pudendal nerve.

The ability to access selectively distal nerve branches at the level of the compound pudendal nerve (PN) would allow control of multiple neural pathways and genitourinary functions at a single location. Nerve cuff electrodes can selectively stimulate individual fascicles; however the PN fascicular anatomy is unknown. The fascicular representation of distal branches was identified and traced proximally to create fascicle maps of 12 compound PNs in seven cadavers. Distal nerves were represented as groups of individual fascicles in the PN. Fascicle maps were consistent between specimens and along the PN within specimens. PN branch free length was 26+/-7.7 mm. PN cross-sections were relatively flat with major and minor diameters of 4.3+/-0.90 and 1.7+/-0.45 mm, respectively. Placing a nerve cuff on the PN is anatomically and surgically feasible. The PN fascicular anatomy, branch free length, and cross-section geometry are conducive to selective stimulation of distal nerves with a single nerve cuff electrode.

Aged↗

PubMed2005

Current density distributions, field distributions and impedance analysis of segmented deep brain stimulation electrodes.

Deep brain stimulation (DBS) electrodes are designed to stimulate specific areas of the brain. The most widely used DBS electrode has a linear array of 4 cylindrical contacts that can be selectively turned on depending on the placement of the electrode and the specific area of the brain to be stimulated. The efficacy of DBS therapy can be improved by localizing the current delivery into specific populations of neurons and by increasing the power efficiency through a suitable choice of electrode geometrical characteristics. We investigated segmented electrode designs created by sectioning each cylindrical contact into multiple rings. Prototypes of these designs, made with different materials and larger dimensions than those of clinical DBS electrodes, were evaluated in vitro and in simulation. A finite element model was developed to study the effects of varying the electrode characteristics on the current density and field distributions in an idealized electrolytic medium and in vitro experiments were conducted to measure the electrode impedance. The current density over the electrode surface increased towards the edges of the electrode, and multiple edges increased the non-uniformity of the current density profile. The edge effects were more pronounced over the end segments than over the central segments. Segmented electrodes generated larger magnitudes of the second spatial difference of the extracellular potentials, and thus required lower stimulation intensities to achieve the same level of neuronal activation as solid electrodes. For a fixed electrode conductive area, increasing the number of segments (edges) decreased the impedance compared to a single solid electrode, because the average current density over the segments increased. Edge effects played a critical role in determining the current density distributions, neuronal excitation patterns, and impedance of cylindrical electrodes, and segmented electrodes provide a means to increase the efficiency of DBS.

Animals↗

PubMed2005

Structural mechanisms to produce differential dendritic gains.

The axons of sacral parasympathetic preganglionic neurons (PGNs) originate on a primary dendrite between 10 and 110 mum from the soma. Therefore, it was hypothesized that the location of the axon origin would impact the relative efficacy of ipsilateral and contralateral synaptic inputs. The morphology of two PGNs was reconstructed, and the transfer impedance was used to quantify the influence of synaptic inputs on the transmembrane potential at the axon initial segment. The ratio of ipsilateral transfer impedance to contralateral transfer impedance (termed the relative gain) was increased by 14-29% for axons originating from the dendrite vs. axons originating from the soma. The addition of 50 synchronized "gating" synapses on the proximal dendrites increased the relative gain by 17-38% when the axon originated from the dendrite, but only by 11-15% when the axon originated from the soma. The efficacy of synaptic inputs and the ability of proximal gating synapses to regulate synaptic efficacy were strongly influenced by the site of origin of the axon. The position of axon origin is an effective structural mechanism to regulate the relative efficacy of synaptic inputs arriving at different locations on the dendritic tree.

Action Potentials↗

PubMed2005

Applied electric fields accelerate the diffusion rate and increase the diffusion distance of DiI in fixed tissue.

Lipophilic carbocyanine dyes are effective neuronal tracers in fixed tissue. However, their application has been limited by the slow diffusion, short tracing distances, and long durations of incubation in fixed tissue. We used applied dc electric fields, that exerted forces on the cationic dyes, to increase the diffusion velocity and maximal tracing distances of DiI and its analogs. Maximum diffusion distances of DiI in fixed human peripheral nerve were approximately 4 times longer then the previous reported maximum, and diffusion velocities was approximately 100 times faster in samples exposed to the electric field than in control samples. This method enabled retrograde tracing from a distal nerve branch into a proximal nerve trunk, and did not result in lateral transaxonal diffusion. Field enhanced diffusion will expand the range of uses of lipophilic dyes in fixed tissues and enable topographic mapping of peripheral nerve fascicles in post-mortem tissue.

Aged↗

PubMed2005

Functional magnetic resonance imaging of the human lumbar spinal cord.

PURPOSE: To determine whether consistent regions of activity could be observed in the lumbar spinal cord of single subjects with spin-echo functional MRI (fMRI) if several repeated experiments were performed within a single imaging session. MATERIALS AND METHODS: Repeated fMRI experiments of the human lumbar spinal cord were performed at 1.5 T with a single-shot spin-echo technique (half-Fourier single-shot turbo spin-echo (HASTE)) as used by previous investigators, and a modified method (fluid-attenuated inversion recovery (FLAIR)-HASTE) that nulled the otherwise highly variable signal from the cerebrospinal fluid (CSF). RESULTS: FLAIR-HASTE reduced the variability of the signal in the CSF region to background levels, and presumably reduced associated artifacts in the spinal cord. Consistent areas of activation in the spinal cord in response to a thermal stimulus just below the knee were not observed across the fMRI experiments with either method. CONCLUSION: FLAIR-HASTE was useful for removing artifact in the spinal cord signal induced by variability in the CSF signal. However, with the techniques used in this study, we were not able to confirm the presence of a consistent fMRI response in the lumbar spinal cord because of the signal enhancement by extravascular protons (SEEP) effect during thermal stimulation of the hindlimb.

Adult↗

PubMed2005

Polarization of a spherical cell in a nonuniform extracellular electric field.

Polarization of cells by extracellular fields is relevant to neural stimulation, cardiac pacing, cardiac defibrillation, and electroporation. The electric field generated by an extracellular electrode may be nonuniform, and highly nonuniform fields are produced by microelectrodes and near the edges of larger electrodes. We solved analytically for the transmembrane voltage (phi(m)) generated in a spherical cell by a nonuniform extracellular field, as would arise from a point electrode. Phi(m) reached its steady state value with a time constant much shorter than the membrane time constant in both uniform and nonuniform fields. The magnitude of phi(m) generated in the hemisphere of the cell toward the electrode was larger than in the other hemisphere in the nonuniform field, while symmetric polarization occurred in the uniform field. The transmembrane potential in oocytes stained with the voltage sensitive dye Di-8-ANEPPS was measured in a nonuniform field at three different electrode-to-cell distances. Asymmetric biphasic polarization and distance-dependent patterns of membrane voltage were observed in the measurements, as predicted from the analytical solution. These results highlight the differences in cell polarization in uniform and nonuniform electric fields, and these differences may impact excitation and poration by extracellular fields.

Animals↗

PubMed2005

Temporal excitation properties of paresthesias evoked by thalamic microstimulation.

OBJECTIVE: The neuronal elements mediating the effects of deep brain stimulation (DBS) are unknown. The objective was to determine the strength-duration properties of the neuronal elements that mediate paresthesias evoked by thalamic microstimulation. METHODS: The strength-duration properties of the neuronal elements causing paresthesias were measured using intraoperative microstimulation of the human thalamus. The sample included both concordant (reported in the same region as the mapped sensory receptive fields) and discordant paresthesias (reported in a region different than the mapped sensory receptive fields). RESULTS: There were no significant differences between the chronaxies of concordant and discordant paresthesias. There was no significant correlation between chronaxie and rheobase for concordant paresthesias, but a strong negative correlation existed for discordant paresthesias. CONCLUSIONS: Chronaxies did not distinguish the neuronal elements mediating concordant and discordant paresthesias, but correlations between chronaxie and rheobase suggest that concordant paresthesias were produced by activation of local cells while discordant paresthesias were caused by activation of axons of passage. SIGNIFICANCE: The similarity between the strength-duration properties of paresthesias evoked by thalamic stimulation, tremor reduction evoked by thalamic DBS, and EMG responses to thalamic DBS does not mean that these effects are caused by the same neural elements.

Chronaxy↗

PubMed2005

Detecting the onset of hyper-reflexive bladder contractions from the electrical activity of the pudendal nerve.

Individuals with a spinal cord injury or neurological disorders may develop involuntary bladder contractions at low volumes (bladder hyper-reflexia), which can lead to significant health problems. Present devices can inhibit unwanted contractions through continuous stimulation, but do not enable conditional stimulation only at the onset of bladder contractions. The objectives of this study were to determine the relationship between the electrical activity of the pudendal nerve trunk (PNT) and bladder pressure during hyper-reflexive bladder contractions and to determine whether PNT activity could be used to detect the contractions. Bladder pressure and PNT electroneurogram (ENG) were recorded in eight adult male cats. The PNT ENG activity increased at the onset of a bladder contraction and the activity during bladder contractions was greater than during the intercontraction interval (p < 0.001). Three algorithms were developed to detect the onset of a bladder contraction from the PNT ENG activity. A cumulative sum (CUSUM) algorithm performed better than either a constant threshold or a dynamic threshold algorithm, and enabled detection of reflex bladder contractions from the PNT ENG an average of 1.2 s after the contraction started with an average increase in pressure 7.1 cm H2 x O when evaluated on data not used to set detection parameters. These data demonstrated that recordings from the PNT could be used to detect hyper-reflexive bladder contractions and provide a signal to control closed-loop inhibitory stimulation.

Action Potentials↗

PubMed2005

Safety considerations for deep brain stimulation: review and analysis.

Deep brain stimulation has emerged rapidly as an effective therapy for movement disorders. Deep brain stimulation includes an implanted brain electrode and a pacemaker-like implanted pulse generator. The clinical application of deep brain stimulation proceeded in the absence of clear understandings of its mechanisms of action or extensive preclinical studies of safety and efficacy. Post mortem studies suggest that there is a loss of neurons in proximity to the active electrode, but the resulting lesions are not sufficient to treat the disorder and efficacy requires continued stimulation. Overall complication rates can exceed 25%, and permanent neurologic sequelae result in 4-6% of cases. As the application of deep brain stimulation expands, it is critical to understand the origin of adverse events and the delivery of nondamaging stimulation.

Deep Brain Stimulation↗

PubMed2004

Spinal micturition reflex mediated by afferents in the deep perineal nerve.

Reflexes mediated by urethral sensory pathways are integral to urinary function. This study investigated the changes in bladder pressure and urethral sphincter activity resulting from electrical stimulation of afferents in the deep perineal nerve (DP), which innervates the urethra and surrounding muscles, before and after acute spinal cord transection (SCT) in cats anesthetized with alpha-chloralose monitored by blood pressure and heart rate. DP stimulation elicited bladder contractions before and after SCT but only if the bladder contained a sufficient volume of fluid (78% of the volume needed to cause distention-evoked reflex contractions). The volume dependency was mediated by a neuronal mechanism in the lumbosacral spinal cord and was not attributable to length-tension properties of the detrusor muscle. Stimulation at 2-40 Hz initiated bladder contractions, but 20-40 Hz was more effective than lower frequencies in evoking and sustaining bladder contractions for the duration of the stimulus train. Decreases in urethral sphincter activity occurred during sustained bladder contractions evoked by 20- to 40-Hz stimulation before and within 16 h after SCT. After SCT, average bladder pressure increases evoked by DP stimulation were smaller than those evoked before SCT, but in some animals, bladder pressures elicited by DP stimulation continued to increase as time after SCT increased and reached pretransection amplitudes at 8-16 h posttransection. These data confirm the presence of a spinal circuit that can mediate coordinated bladder-sphincter responses and show that afferents from the DP can activate this circuit under appropriate conditions.

Afferent Pathways↗

PubMed2004

Deep brain stimulation creates an informational lesion of the stimulated nucleus.

Deep brain stimulation (DBS) is an effective treatment for movement disorders, but the mechanisms are unclear. DBS generates inhibition of neurons surrounding the electrode while simultaneously activating the output axons of local neurons. This dual effect does not explain two hallmarks of DBS effectiveness: symptom relief is dependent on using a sufficiently high-stimulation frequency, and clinical effects are analogous to those produced by lesion. The effect of DBS at different frequencies on the output of intrinsically active neurons was studied using computational models. DBS produced frequency-dependent modulation of the variability of neuronal output, and above a critical frequency stimulation resulted in regular output with zero variance. The resulting loss of information offers an explanation for the two hallmarks of DBS effectiveness.

Electric Stimulation Therapy↗

PubMed2004

A urethral afferent mediated excitatory bladder reflex exists in humans.

An excitatory reflex between urethral flow receptors and the bladder has been established in animals, but attempts to demonstrate this reflex in humans using urethral fluid flow have been inconclusive. Intraurethral electrical stimulation has recently been shown to generate bladder contractions in animals and was applied to study the presence of an excitatory urethra to bladder reflex in humans. The prostatic urethra was stimulated electrically via a catheter-based electrode in five men with complete spinal cord injury. Bladder contractions were generated in four of five individuals, however, only when the bladder volume was sufficiently large. These results demonstrate the presence of a volume dependent excitatory bladder reflex mediated by urethral afferent nerve fibers and the lumbosacral spinal cord.

Adult↗