Brian J. Wenzel

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 α‐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.

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.

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 cmH/sub 2//spl middot/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.

Closed-loop electrical control of urinary continence.

PURPOSEnIndividuals 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.nnnMATERIALS AND METHODSnIn 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.nnnRESULTSnConditional 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.nnnCONCLUSIONSnConditional electrical stimulation of inhibitory pathways is more effective than continuous stimulation. A control system triggered by PNT ENG can maintain urinary continence.

Detection of Acute Myocardial Infarction from serial ECG using multilayer support vector machine

Acute Myocardial Infarction (AMI) remains a leading cause of mortality in the United States. Finding accurate and cost effective solutions for AMI diagnosis in Emergency Departments (ED) is vital. Consecutive, or serial, ECGs, taken minutes apart, have the potential to improve detection of AMI in patients presented to ED with symptoms of chest pain. By transforming the ECG into 3 dimensions (3D), computing 3D ECG markers, and processing marker variations, as extracted from serial ECG, more information can be gleaned about cardiac electrical activity. We aimed at improving AMI diagnostic accuracy relative to that of expert cardiologists. We utilized support vector machines in a multilayer network, optimized via a genetic algorithm search. We report a mean sensitivity of 86.82%±4.23% and specificity of 91.05%±2.10% on randomized subsets from a master set of 201 patients. Serial ECG processing using the proposed algorithm shows promise in improving AMI diagnosis in Emergency Department settings.

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

Individuals with spinal cord injury or neurological disorders may develop involuntary bladder contraction at low volumes (bladder hyper-reflexia), which can lead to significant health problems. Current devices can eliminate nascent contractions through continuous stimulation, but do not have a means to detect the onset of bladder contraction to stimulate conditionally. The objective of this study is to determine the relationship between the electrical activity of the pudendal nerve (PNT) and hyper-reflexive bladder contraction, and to use the relationship to develop an algorithm to detect the onset of a bladder contraction. Bladder pressure and PNT ENG were recorded in six intact male cats. There were bursts of neuronal activity in the PNT during bladder contractions. An algorithm was developed to detect the onset of a bladder contraction using the PNT ENG activity. The algorithm calculated the onset of bladder contraction on average 2.8 seconds after the contraction started with an average increase in pressure of 14.0 cmH/sub 2/O. There existed a phasic relationship between the bladder and the PNT ENG, which enabled the algorithm to detect the onset of a bladder contraction. The PNT ENG can be used as a trigger to deliver conditional inhibitory stimulation of the bladder.

Generation of bladder contractions via electrical stimulation of urethral afferent nerves and intra-urethral stimulation

Neurological disease or spinal cord injury (SCI) can eliminate voluntary bladder control. Our long-term mission is to develop neural prostheses for restoration or neuro-rehabilitation of bladder function based on stimulation of afferent neural pathways that take advantage of native spinal neural circuitry. During voiding, urine flow in the urethra activates positive feedback reflexes that augment bladder contraction. This project sought to determine if electrical stimulation of urethral afferents could initiate bladder contractions and to develop a non-invasive method to investigate these responses in humans. In 3 cats, robust bladder contractions were generated by electrical stimulation of the urethral sensory nerves above a threshold bladder volume and at low (<5 Hz) stimulation frequencies. In 3 cats, a urethral catheter with a ring electrode was able to produce and maintain bladder contractions in the proximal and prostatic urethra via intra-urethral electrical stimulation. These results support the feasibility of the catheter-based method to investigate these effects in humans with spinal cord injury.

Algorithm for quantitative 3 dimensional analysis of ECG signals improves myocardial diagnosis over cardiologists in diabetic patients

Acute myocardial infarction (AMI) diagnosis in type II diabetes (DM2) patients is difficult and ECG findings are often non-diagnostic or inconclusive. We developed computer algorithms to process standard 12-lead ECG input data for quantitative 3-dimensional (3D) analysis (my3KGTM), and hypothesized that use of the my3KGTMs array of over 100 3D-based AMI diagnostic markers may improve diagnostic accuracy for AMI in DM2 patients. Methods: We identified 155 consecutive DM2 patients age >25 yrs with chest discomfort or shortness of breath who were evaluated at an urban emergency department (130 patients (pts)) or the cardiac catheterization laboratory (25 pts) for possible AMI. The first digital 12-lead ECG for each patient, obtained within 30 min of presentation, was evaluated by (1) 2 blinded expert cardiologists, and (2) my3KGTM. In each case, the ECG was classified as either likely AMI or likely non-AMI. “Gold standard” was the final clinical diagnosis. Statistical analysis was McNemars test with continuity correction. Results: The 155 DM2 patients were 50% male, mean age 56.8 ± 12.0 yrs; 44 pts had a final clinical diagnosis of AMI (17 ST Elevation Myocardial Infarctions (STEMI), 27 Non-ST Elevation Myocardial Infarctions (NSTEMI)) and 111 had no AMI. Conclusions: Relative to standard 12L ECG read by cardiologists, quantitative 3D ECG analysis showed significant and substantial gains in sensitivity for AMI diagnosis in DM2 patients, without loss in specificity. Sensitivity gains were particularly high in patients exhibiting NSTEMI, the most common form of AMI in DM2.

Using external anal sphincter activity to detect the onset of bladder contractions

Individuals with spinal cord injury or neurological disorders may develop, involuntary bladder contraction at low volumes (bladder hyper-reflexia), which can lead to significant health problems. Current devices can eliminate nascent contractions through continuous stimulation, but do not have a means to detect the onset of bladder contraction to stimulate conditionally. The objective of this study is to determine the relationship between the activity of the external anal sphincter (EAS) and hyper-reflexive bladder contraction, and to use the relationship to develop a model to detect the onset of a bladder contraction. Bladder pressure and EAS EMG were recorded in four intact male cats. There was little EAS activity during the bladder contraction and more activity between contractions (p<0.001). A model was developed to predict the onset of a bladder contraction using the EAS EMG activity. The model calculated the onset of bladder contraction on average 4.8 seconds after the contraction started with an average increase in pressure of 8.7 cmH/sub 2/O. There existed a phasic relationship between the bladder and the EAS, which enabled the prediction model to detect the onset of a bladder contraction. The EAS EMG can be used as a trigger to deliver conditional inhibitory stimulation of the bladder.

Event-Triggered Electrical Control of Urinary Continence

Individuals with spinal cord injury or neurological disorders may develop involuntary bladder contraction at low volumes (bladder hyper-reflexia), which can lead to significant health problems. Current devices can eliminate nascent contractions through continuous stimulation, but do not have a means to detect the onset of bladder contraction to stimulate conditionally. The pudendal nerve trunk (PNT) electroneurogram (ENG) has been shown that the ENG could be used as to detect bladder contractions and as an input to a control system to trigger conditional electrical stimulation. The objective of this study is to determine whether event-triggered electrical control of urinary continence allows the bladder to fill to greater volume than continuous control, PNT ENG was the input to the control system and served as a trigger for inhibitory stimulation to maintain continence. Conditional inhibitory stimulation controlled by the PNT ENG allowed the bladder to fill to at least the same volume as continuous stimulation before continence was lost. However, the event-triggered control system had a 65% reduction in stimulation time as compared to continuous stimulation. These results support the use of an event-triggered control system to maintain urinary continence