**2.1 Sacral anterior root stimulation**

Though this mode of urological neuromodulation is almost of historical interest in the face of current advances in the field and the dominance of sacral neuromodulation, it yet deserves honorable mention as it paved the way to utilize the sacral region for restoration of bladder function. Through stimulation of the anterior sacral nerve, both bladder parasympathetic efferents and somatic motor fibers to the external urethral sphincter are activated. This ventral activation facilitates intermittent bladder emptying [1].

Brindley in 1976 implanted intradurally and bilaterally on the ventral roots from S2 to S5 subcutaneous cables that were externally powered and would provide ondemand electromagnetic stimulation to facilitate voiding [5–7]. He later modified his procedure by performing posterior rhizotomy at the S2–S3 level during implantation of the stimulator to improve the continence outcome by eliminating the effect C-fiber bladder afferents had on amplifying the micturition reflex. This is what was later named the Brindley procedure, and its popularity phased out years later as more studies and reports demonstrated debilitating and unacceptable complications such as sacral dermatome hyperalgesia, cerebrospinal fluid leak, and damage to the anterior nerve root. The procedure, however, remains indicated for patients with complete spinal cord injury (SCI) with maintained bladder reflexes [1, 7–9].

### **2.2 Sacral neuromodulation**

The first reports describing the application of sacral neuromodulation were by Schmidt and Tanagho, the latter concentrating on its application in neurogenic lower urinary tract dysfunction [2, 3]. Since then, both experimental and approved applications and research aiming to understand the mechanism of action by which sacral neurostimulation, or more appropriately now termed sacral neuromodulation (SNM), affects and rehabilitates the functions of the lower urinary tract, both in facilitating bladder storage and voiding, has expanded. Researchers also embarked

on assessing its efficacy, particularly cost-effectiveness, when compared to other modes of treatment for its indications. SNM is, perhaps, the best studied mode of neuromodulation in urology [5].

Compared to the Brindley procedure, SNM posed numerous advantages and technical differences. The SNM procedure involves extradural electrode implantation usually in one of the paired S3 foramens. It does not require posterior rhizotomy either. This minimized the risks of nerve root injury or cerebrospinal fluid leakage. It provides continuous electrical stimulation to the nerves in its proximity and is controlled remotely without the need for subcutaneous cables as it has a built in-battery and antenna. It also modulates for restoration of normal micturition and suppresses bladder overactivity, which made it applicable to non-neurogenic voiding dysfunctions as well [1, 3].

The first SNM device made commercially available was the Interstim® (Medtronic Neuromodulation, Minneapolis USA). It was first approved in 1997 by the US Food & Drug Administration (FDA) for use in refractory urge incontinence, and later in 1999 its approval was expanded to include significant urgency, frequency, and idiopathic urinary retention. The US market was the most enthusiastic to adopt it, and back then and by the year 2004 15,000 units were implanted, the majority of which were in the USA [10, 11]. Since then, the rates of SNM implantations increased by at least 10 to 20-folds [12, 13].

Sacral neuromodulation is dedicated to the S3 foramen, targeting the S3 nerve root which is identified as the most relevant home for impulses, containing sensory fibers from the pelvic floor and parasympathetic neural fibers affecting the detrusor muscle of the bladder. This differs from the target of other neuromodulation modalities, and provides a distinct pattern of identification during implantation, which will be discussed later [14, 15].

### *2.2.1 Mechanism of action*

The goal of SNM is to modulate abnormal bladder sensations the patient may have, as well as involuntary uncontrollable reflexes in the lower urinary tract to restore the patient's voluntary control and facilitate normal function [16]. The theories on how it actually achieves these goals are vast, and expanding to date, and remain complex. This is perhaps in part due to the sophisticated interaction of higher central voiding centers in the brain and spinal cord and the peripheral nervous system in facilitating the functions of the lower urinary tract.

Investigators have assessed a multitude of concepts, from the molecular neurophysiological level to broader neurocirculatory behaviors in the brain and spine, in both animal models and human studies. Yet to date, no single theorem has been solely agreed upon. Some studies have even shown dual or multiple mechanisms through different channels by which SNM exerts its modulatory effect on the lower urinary tract, partly by studying its different effects in many neuro-urological conditions ranging from bladder overactivity to chronic pelvic pain.

SNM therapeutic effects are speculated to arise through electric stimulation of both afferent and efferent neural circuits in the pelvic viscera and connections with spinal interneurons. The stimulator produces an electrical charge in close proximity to the sacral root nerves, regenerating propagational axonal action potentials in the region. This in turn stimulates somatic afferents which modulate higher center control of micturition including the prefrontal cortex and insula, by restoring normal bladder function and perhaps suppressing reflex bladder activity such as that seen in overactive bladder (OAB). This indirect effect both on the bladder and the urinary sphincter is achieved through adaptive neural plasticity, and thus, an intact neural system, at least distally, is a neural requirement for SNM to successfully restore

**213**

*Neuromodulation in Urology: Current Trends and Future Applications*

overactivity mediated by supraspinal GABAA receptors [30].

bladder function [15–21]. The SNM device can provide different levels of stimulation, which may further modulate efferents to the bladder-sphincter complex; however, it does not have any direct effect on urethral resistance [16, 22].

Several studies have proved that SNM has modulatory effects in the brain. Earlier work has demonstrated stimulatory and inhibitory effects in specific brain regions including those responsible for alertness, sensation of bladder filling, and timing of micturition [23, 24]. Utilizing positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) of the brain, researchers were able to identify decreased function after SNM in areas like the orbitofrontal cortex, angulate gyrus, and thalamus, while stimulating the dorsolateral prefrontal cortex, and the therapeutic effect of SNM corresponded to pre-implantation increased activity in the angulate and inferior frontal gyri, insula and thalamus. Such patterns of activity in the brain were shown to predict response to SNM treatment in females with OAB. Furthermore, investigators were able to show that different SNM stimulus intensities had varied brain responses, which may have differential

On the neurophysiological level, much has been investigated to understand which neural receptors and neurotransmitters may be affected by neuromodulation, SNM in particular. Opiod receptors are shown to be inhibited by SNM, and this inhibitory effect is augmented by tramadol and other opiod receptor agonists [28]. From animal models, blockade of opiod receptors with naloxone significantly reduced bladder capacity during sacral neuromodulation for reflex bladder activity. Blockade of beta-2 receptors, however, showed the opposite response during SNM [29]. Also mediated by opiod receptors are the SNM inhibitory effects of bladder

The US Food and Drug Administration has approved four main indications for SNM application, three of which are urological: refractory urinary urgency and frequency, urge urinary incontinence (UUI), non-obstructive urinary retention (NOUR), and lastly, fecal incontinence. This has been agreed upon and resounded by multiple authorities including the International Continence Society in their best practice statements, among other bodies [4]. However, FDA approval does not indicate level of recommendation, and authoritarians and experts in the field have built on this approval to debate and set the grade and the line of therapy at which SNM serves for a number of conditions, as well as argue for and against other indications or applications the FDA has not seen the benefit of SNM for eye-to-eye with available literature and results. There are, moreover, conditions that must be met prior to justifying an implantation regardless of the aforementioned indications

The International Continence Society (ICS) assessed the evidence available for SNM in different pathological genitourinary conditions and published its recommendations based on available literature. In summary, the ICS panel found grade A evidence to support the efficacy of SNM in overactive bladder and non-obstructive urinary retention including Fowler's syndrome and voiding dysfunction; however, this high level evidence did not change their recommendation of maintaining SNM as a second or third-line mode of therapy in these disorders. For other conditions including interstitial cystitis/bladder pain syndrome (IC/BPS) and neurogenic lower urinary tract symptoms, SNM remained an option based on lower levels of

*DOI: http://dx.doi.org/10.5772/intechopen.92287*

therapeutic implications [23–27].

*2.2.2 Indications and contraindications*

and contraindications that must be observed.

evidence (grade C evidence/level III recommendations) [4, 31].

*2.2.2.1 FDA approved indications*

### *Neuromodulation in Urology: Current Trends and Future Applications DOI: http://dx.doi.org/10.5772/intechopen.92287*

*Neurostimulation and Neuromodulation in Contemporary Therapeutic Practice*

neuromodulation in urology [5].

dysfunctions as well [1, 3].

which will be discussed later [14, 15].

*2.2.1 Mechanism of action*

20-folds [12, 13].

on assessing its efficacy, particularly cost-effectiveness, when compared to other modes of treatment for its indications. SNM is, perhaps, the best studied mode of

Compared to the Brindley procedure, SNM posed numerous advantages and technical differences. The SNM procedure involves extradural electrode implantation usually in one of the paired S3 foramens. It does not require posterior rhizotomy either. This minimized the risks of nerve root injury or cerebrospinal fluid leakage. It provides continuous electrical stimulation to the nerves in its proximity and is controlled remotely without the need for subcutaneous cables as it has a built in-battery and antenna. It also modulates for restoration of normal micturition and suppresses bladder overactivity, which made it applicable to non-neurogenic voiding

The first SNM device made commercially available was the Interstim® (Medtronic Neuromodulation, Minneapolis USA). It was first approved in 1997 by the US Food & Drug Administration (FDA) for use in refractory urge incontinence, and later in 1999 its approval was expanded to include significant urgency, frequency, and idiopathic urinary retention. The US market was the most enthusiastic to adopt it, and back then and by the year 2004 15,000 units were implanted, the majority of which were in the USA [10, 11]. Since then, the rates of SNM implantations increased by at least 10 to

Sacral neuromodulation is dedicated to the S3 foramen, targeting the S3 nerve root which is identified as the most relevant home for impulses, containing sensory fibers from the pelvic floor and parasympathetic neural fibers affecting the detrusor muscle of the bladder. This differs from the target of other neuromodulation modalities, and provides a distinct pattern of identification during implantation,

The goal of SNM is to modulate abnormal bladder sensations the patient may have, as well as involuntary uncontrollable reflexes in the lower urinary tract to restore the patient's voluntary control and facilitate normal function [16]. The theories on how it actually achieves these goals are vast, and expanding to date, and remain complex. This is perhaps in part due to the sophisticated interaction of higher central voiding centers in the brain and spinal cord and the peripheral

Investigators have assessed a multitude of concepts, from the molecular neurophysiological level to broader neurocirculatory behaviors in the brain and spine, in both animal models and human studies. Yet to date, no single theorem has been solely agreed upon. Some studies have even shown dual or multiple mechanisms through different channels by which SNM exerts its modulatory effect on the lower urinary tract, partly by studying its different effects in many neuro-urological

SNM therapeutic effects are speculated to arise through electric stimulation of both afferent and efferent neural circuits in the pelvic viscera and connections with spinal interneurons. The stimulator produces an electrical charge in close proximity to the sacral root nerves, regenerating propagational axonal action potentials in the region. This in turn stimulates somatic afferents which modulate higher center control of micturition including the prefrontal cortex and insula, by restoring normal bladder function and perhaps suppressing reflex bladder activity such as that seen in overactive bladder (OAB). This indirect effect both on the bladder and the urinary sphincter is achieved through adaptive neural plasticity, and thus, an intact neural system, at least distally, is a neural requirement for SNM to successfully restore

nervous system in facilitating the functions of the lower urinary tract.

conditions ranging from bladder overactivity to chronic pelvic pain.

**212**

bladder function [15–21]. The SNM device can provide different levels of stimulation, which may further modulate efferents to the bladder-sphincter complex; however, it does not have any direct effect on urethral resistance [16, 22].

Several studies have proved that SNM has modulatory effects in the brain. Earlier work has demonstrated stimulatory and inhibitory effects in specific brain regions including those responsible for alertness, sensation of bladder filling, and timing of micturition [23, 24]. Utilizing positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) of the brain, researchers were able to identify decreased function after SNM in areas like the orbitofrontal cortex, angulate gyrus, and thalamus, while stimulating the dorsolateral prefrontal cortex, and the therapeutic effect of SNM corresponded to pre-implantation increased activity in the angulate and inferior frontal gyri, insula and thalamus. Such patterns of activity in the brain were shown to predict response to SNM treatment in females with OAB. Furthermore, investigators were able to show that different SNM stimulus intensities had varied brain responses, which may have differential therapeutic implications [23–27].

On the neurophysiological level, much has been investigated to understand which neural receptors and neurotransmitters may be affected by neuromodulation, SNM in particular. Opiod receptors are shown to be inhibited by SNM, and this inhibitory effect is augmented by tramadol and other opiod receptor agonists [28]. From animal models, blockade of opiod receptors with naloxone significantly reduced bladder capacity during sacral neuromodulation for reflex bladder activity. Blockade of beta-2 receptors, however, showed the opposite response during SNM [29]. Also mediated by opiod receptors are the SNM inhibitory effects of bladder overactivity mediated by supraspinal GABAA receptors [30].

### *2.2.2 Indications and contraindications*

### *2.2.2.1 FDA approved indications*

The US Food and Drug Administration has approved four main indications for SNM application, three of which are urological: refractory urinary urgency and frequency, urge urinary incontinence (UUI), non-obstructive urinary retention (NOUR), and lastly, fecal incontinence. This has been agreed upon and resounded by multiple authorities including the International Continence Society in their best practice statements, among other bodies [4]. However, FDA approval does not indicate level of recommendation, and authoritarians and experts in the field have built on this approval to debate and set the grade and the line of therapy at which SNM serves for a number of conditions, as well as argue for and against other indications or applications the FDA has not seen the benefit of SNM for eye-to-eye with available literature and results. There are, moreover, conditions that must be met prior to justifying an implantation regardless of the aforementioned indications and contraindications that must be observed.

The International Continence Society (ICS) assessed the evidence available for SNM in different pathological genitourinary conditions and published its recommendations based on available literature. In summary, the ICS panel found grade A evidence to support the efficacy of SNM in overactive bladder and non-obstructive urinary retention including Fowler's syndrome and voiding dysfunction; however, this high level evidence did not change their recommendation of maintaining SNM as a second or third-line mode of therapy in these disorders. For other conditions including interstitial cystitis/bladder pain syndrome (IC/BPS) and neurogenic lower urinary tract symptoms, SNM remained an option based on lower levels of evidence (grade C evidence/level III recommendations) [4, 31].
