Current opinion on the working mechanisms of neuromodulation
`in the treatment of lower urinary tract dysfunction
`Floor van der Pala, John P.F.A. Heesakkersa and Bart L.H. Bemelmansb
`
`Purpose of review
`Neuromodulation is a successful treatment for patients with
`refractory lower urinary tract dysfunction. In the recent
`years, more applications of various types and ways have
`been developed and put into clinical practice. It is important,
`therefore, for urologists to know the existing theories on the
`working mechanisms that explain the effect. Although much
`research has been devoted to this subject for the past
`35 years, the working mechanism is still unknown. This
`review presents an overview of the different theories
`and research into the physiological background of
`neuromodulation during the past 3 decades with emphasis
`on recent developments.
`Recent findings
`Specific receptors in the spinal cord have been identified,
`which are involved in the working mechanism of
`neuromodulation. The maximal effect of neuromodulation is
`not directly reached, indicating that neuromodulation
`induces learning changes (i.e. neural plasticity). The
`carry-over effect could be caused by negative modulation
`of excitatory synapses in the central micturition reflex
`pathway.
`Summary
`Neuromodulation in the treatment of stress incontinence
`probably induces physiological changes in the sphincter
`muscles and pelvic floor. In the treatment of overactive
`bladder syndrome, nonobstructive voiding dysfunction and
`chronic pelvic pain, the mechanism of action seems to be
`more complicated. Most likely, it is a combination of the
`different suggested modes of action, involving the neuroaxis
`at different levels.
`
`Keywords
`lower urinary tract dysfunction, mechanism of action,
`neuromodulation, review
`
`Curr Opin Urol 16:261–267. ß 2006 Lippincott Williams & Wilkins.
`
`aDepartment of Urology, Radboud University Nijmegen Medical Centre, Nijmegen,
`The Netherlands and bDepartment of Urology, Free University Medical Centre,
`Amsterdam, The Netherlands
`
`Correspondence to John P.F.A. Heesakkers MD, PhD, Department of Urology
`(659), Radboud University Nijmegen Medical Centre, P.O. Box 9101, NL-6500 HB
`Nijmegen, The Netherlands
`Tel: +31 24 3616712; fax: +31 24 3541031; e-mail: j.heesakkers@uro.umcn.nl
`
`Current Opinion in Urology 2006, 16:261–267
`
`Abbreviations
`
`PET
`photon emission tomography
`PTNS percutaneous tibial nerve stimulation
`SNS
`sacral nerve stimulation
`TENS transcutaneous electrical nerve stimulation
`
`ß 2006 Lippincott Williams & Wilkins
`0963-0643
`
`Introduction
`Patients with lower urinary tract dysfunction can have
`complaints varying from voiding disorders (impaired
`micturition or nonobstructive urinary retention) to storing
`disorders (overactive bladder wet and dry) and chronic
`pelvic pain. Lower urinary tract dysfunction in neuro-
`genic patients is caused by the injury of the peripheral or
`central nervous system, and in nonneurogenic patients, it
`is usually unknown.
`
`Neuromodulation offers an alternative treatment for
`patients who are refractory to conservative treatment
`(behavioural techniques, physiotherapy, clean intermit-
`tent catheterization or pharmacotherapy) and not ready
`for irreversible surgery. Neuromodulation is defined as
`the physiological process in which the influence of the
`activity in one neural pathway modulates the pre-existing
`activity in another
`through synaptic interaction [1].
`Different therapies, like intravesical stimulation, puden-
`dal nerve stimulation, sacral nerve stimulation (SNS) and
`lower limb stimulation, have been developed with vary-
`ing success rates [2,3]. In the recent years, more appli-
`cations of various types and ways have been developed
`and put into medical practice [4,5,6,7,8–12]. It is
`important for urologists to know the existing theories
`on the working mechanisms that explain the effect.
`Although much research has been done, the working
`mechanisms of neuromodulation are still unknown. This
`review presents an overview of the different theories and
`research into the physiological background of neuro-
`modulation in the past 3 decades, with emphasis on
`recent developments.
`
`Chronic pelvic pain
`In the treatment of pain, the working mechanism is
`believed to be a gate-control mechanism [13]. The
`gate-control theory states that pain perception does not
`depend on pain receptors sending information to the
`brain, but on the pattern of peripheral nervous input
`[14]. It is believed that a gate-control mechanism is
`
`261
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
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`Ex. 1012, p. 261
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`

`

`262 Female urology
`
`present at the spinal segmental level, which can prevent
`the sensation of pain and the reaction to it. Interneurons
`of the substantia gelatinosa of the spinal cord dorsal horn
`create gating components. Presynaptic inhibition or facili-
`tation of afferent fibres (Fig. 1) modulates the input to the
`spinal transmission neurons. Activity in A-fibres excites
`substantia gelatinosa neurons that, in turn, inhibit synap-
`tic transmission and close the gate, which results in
`hypoalgesia. Hyperalgesia is caused by C-fibre activity
`resulting in increased presynaptic transmission. Further-
`more, it is supposed that the impulses from the dorsal
`horn are controlled by a descending system containing
`fibres from the brainstem, thalamus and limbic lobes.
`
`by animal studies [24] in dogs that showed hypertrophy of
`striated external sphincter muscle fibres and increased
`urethral closure pressure during chronic SNS. Afterwards,
`it was stated that this theory is more applicable to the
`treatment of stress urinary incontinence [25]. Direct
`motor pathway stimulation and retrograde spinal motor
`neuron stimulation in Onuf’s nucleus, or central inhibi-
`tory pathway activation via afferent pudendal nerve
`stimulation could, however, suppress instable bladder
`contractions. The latter seems to be more logical as
`neuromodulation is usually applied below the threshold
`for the motor response. Up until now data supporting this
`assumption have not been presented.
`
`Another theory is activation of sensory nerves [26]. This is
`supported by research studying the latency of the motor
`response (i.e. the anal wink) to SNS demonstrating that
`the latency was approximately 10 times longer than
`would be expected if the response was mediated by
`direct motor-nerve stimulation [27]. Moreover,
`the
`latency of cortical responses is shortened during chronic
`SNS, indicating the activation of somatosensory afferent
`fibres [28].
`
`Activation of the sensory nerves supports the gate-control
`theory that has been used as the working mechanism of
`neuromodulation in the treatment of chronic pain. This
`finding is supported by animal studies [29] demonstrating
`that spino-bulbo-spinal pathways are involved in the
`normal micturition reflex. A-delta bladder afferents pro-
`ject to pontine nuclei in the brainstem, which in turn give
`rise to inhibitory and excitatory input to lumbo-sacral
`reflexes controlling bladder and sphincter
`function.
`Sensory input from the pelvic floor via large myelinated
`pudendal fibres may control erroneous bladder input
`conveyed by A-type or C-type bladder afferents ‘at the
`gate’ via sacral segmental interneurons and supraspinally
`by way of the spino-bulbo-spinal reflex system. When a
`gate-control system is attributed to the inhibitory influ-
`ences of interneurons from the somatic pudendal nuclei
`on parasympathetic pelvic nuclei within the spinal cord
`and brainstem, the cause of overactive bladder syndrome
`could be a deficiency of the inhibitory control systems
`involving the pudendal afferent nerves [30]. Therefore, it
`has been suggested that neuromodulation treats over-
`active bladder
`syndrome by restoring the balance
`between the inhibitory and excitatory control systems.
`The latter could be done at various sites in both periph-
`eral and central nervous systems [31]. This is shown in
`Fig. 2.
`
`The supraspinal involvement in the ‘the gate-control’
`theory is supported by electroencephalogram (EEG)
`studies during SNS [32]. These studies have demon-
`strated that both short and long latency cortical potentials
`can be reproduced with a maximum at the sensory
`
`The discussed gate-control mechanism is believed to be
`the working mechanism for neuromodulation in the
`treatment of chronic pelvic pain [15–17]. Neuromodu-
`lation is supposed to restore the control at the spinal
`segmental ‘gate’ as well as at supraspinal sites such as the
`brainstem and limbic system nuclei. Studies [18,19] using
`transcutaneous electrical nerve stimulation (TENS) sup-
`port the existence of descending inhibition, as is sup-
`posed in the gate-control theory of Melzack and Wall
`[14]. The rostral ventral medulla seems to be involved in
`this and serotonin and opioids are probably used to
`reduce pain. Finally, it has been suggested that the
`analgesic effects could be mediated by the modulation
`of autonomic activity [20] and that adenosine plays a role
`in the mechanism of action [21,22].
`
`Overactive bladder syndrome
`Several theories on the working mechanism of the blad-
`der have been proposed. It has been suggested that SNS
`induces pelvic floor muscle hypertrophy and changes the
`histochemical properties of the muscle, resulting in
`improved pelvic floor efficiency [23]. This is supported
`
`Figure 1 Schema of the gate-control theory
`
`+
`
`+
`
`2
`
`−+
`
`+
`
`−+
`
`1
`
`A-fiber
`
`C-fiber
`
`1Substantia gelatinosa neuron, 2Spinal cord transmission neuron
`
`(1) Substantia gelatinosa neuron and (2) spinal cord transmission
`neuron.
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`Petitioner - Avation Medical, Inc.
`Ex. 1012, p. 262
`
`

`

`Figure 2 The nervous systems that are involved in controlling the bladder and the working mechanism of neuromodulation
`
`Neuromodulation and urinary tract dysfunction van der Pal et al. 263
`
`The bladder is controlled by sympathetic
`(S), parasympathetic (PS) and somatic
`nervous systems that are regulated by
`the pontine micturition centre (PMC).
`Micturition (bladder contraction) is
`facilitated by activation of the
`parasympathetic system through the
`pelvic nerve (S2–S4). Continence is
`facilitated by both sympathetic system
`through the hypogastric nerve (T10–L2,
`bladder relaxation and internal sphincter
`contraction) and somatic system through
`the pudendal nerve (S2–S4,
`rhabdosphincter contraction). It is
`unclear if the tibial nerve (L4–S3)
`modulates the bladder function through
`the pelvic nerve or pudendal nerve or
`both.
`
`PMC
`
`S
`
`PS
`
`T10--L2
`
`S2--S4
`
`Onuf‘s
`nucleus
`
`Tibial nerve
`
`L4--S3
`
`Hypogastric nerve
`
`Pelvic nerve
`
`Bladder
`
`Pudendal nerve
`
`Rhabdosphincter
`
`Spinal cord
`
`Urethra
`
`cortical area, indicating a supraspinal-mediated site of
`modulation, most probably in sensory cortex areas. More-
`over, combined photon emission tomography (PET) and
`magnetic resonance imaging (MRI) studies have demon-
`strated that SNS has no effect on the brain areas that are
`important for the micturition itself. The activity of the
`micturition-dominant right hemisphere is, however, rela-
`tively reduced and the activity in brain areas that are
`important for general arousal, bladder filling sensation
`and the onset of micturition is decreased [33]. Further-
`more, the maximal beneficial effect of SNS is reached
`after several hours or days, indicating learning changes in
`the brain (i.e. neural plasticity) [34]. This finding is
`supported by PET studies demonstrating that only brain
`areas important for motor behaviour learning (i.e. lower
`trunk motor cortex and the cerebellum) are activated
`during the first hours of SNS. After the initial period, the
`pelvic floor and abdominal motor cortical areas are more
`easily excited and the effects of SNS are prolonged and
`pronounced [34]. Finally, these studies showed that SNS
`activates the mid cingulated gyrus, which could result in a
`temporarily increased awareness of bladder filling.
`
`Another mechanism of the action of SNS could be the
`activation of the hypogastric sympathetic nerves, which
`have an inhibitory effect on the parasympathetic fibres at
`the pelvic ganglia [35]. Furthermore, recent studies have
`indicated that non-N-methyl-D-aspartate (non-NMDA)
`receptors [36] and proton-sensitive and heat-sensitive
`vanilloid receptors [37] are involved in the working
`mechanism of SNS.
`
`For pudendal nerve stimulation, it has been demon-
`strated that spinal pathways connect somatic and auto-
`nomic reflex circuits, which have mostly an inhibitory
`mode of action. Two mechanisms have been identified
`that have their afferent limb in the pudendal nerve and
`inhibit the bladder directly. At low bladder pressure,
`bladder contractions are suppressed via sympathetic
`hypogastric nerves, whereas at high bladder pressure,
`parasympathetic pelvic excitatory neurons are activated,
`resulting in central
`inhibition [38,39]. Furthermore,
`pudendal nerve stimulation results in the activation of
`the sympathetic hypogastric nerves and inhibits the
`excitatory pelvic efferent outflow to the bladder at the
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`Petitioner - Avation Medical, Inc.
`Ex. 1012, p. 263
`
`

`

`264 Female urology
`
`ganglionic level [40]. This finding could be explained by
`the presence of a gate-control mechanism at the spinal
`cord to influence either the hypogastric or pelvic affer-
`ents. Data supporting this theory have been presented in
`patients with a complete spinal cord lesion [41]. The
`study demonstrated that the latencies of bladder neck
`responses during pudendal nerve stimulation increase
`significantly and are sensitive to a-blocking agent phen-
`tolamine, suggesting the involvement of sympathetic
`a-adrenergic fibres. Somatic afferent pudendal nerve
`fibres project to sympathetic neurons in the thoracolum-
`bar spinal cord and the sympathetic bladder neck outflow
`travels with the hypogastric nerve maintaining the blad-
`der neck tone via a-adrenergic receptors [42–44].
`
`Another suggested mechanism of action is that the sym-
`pathetic system is activated that suppresses bladder
`activity via the b-adrenergic system or spinal
`inter-
`neurons that release inhibitory neurotransmitters such
`as enkephalin, glycine, or g-aminobutyric acid [45].
`
`Pudendal nerve stimulation in healthy volunteers
`showed specific activation of the somatosensory and
`somatomotor cortex [46] on functional magnetic reson-
`ance imaging (fMRI). The first has been confirmed by
`several
`studies
`[47,48]. Furthermore,
`it has been
`suggested that the amygdala and periaqueductal grey
`are activated during pudendal nerve stimulation [46].
`Pudendal nerve stimulation-induced cortical activation
`is, however, not identical to SNS-induced cortical acti-
`vation. A larger similarity was expected as S2 and S3 roots
`contribute respectively 60.5 and 35.5%, to the overall
`pudendal afferent activity [49]. The activity of pudendal
`nerve stimulation was, however, confined to a single level
`(S2) in 18% and even to a single root in 8% of the
`participants. Direct pudendal nerve stimulation, there-
`fore, could be more effective as more afferents are
`stimulated than during SNS [6,50], as has been confirmed
`by Peters et al. [51]. To date, no results have been
`published of a comparative study on cortical activation
`during SNS and pudendal nerve stimulation in patients
`with lower urinary tract dysfunction.
`
`A carry-over effect has been shown in animal studies for
`pudendal nerve stimulation [52] and intravesical stimu-
`lation [53], in contrast to SNS in which up untill now no
`carry-over effect has been described. For intravesical
`stimulation, the carry-over effect is supposed to be
`caused by the long-term potentiation of excitatory
`synapses in the central micturition reflex pathway [53],
`analogous as has been described for other central excit-
`atory synapses [54]. It has been suggested that the carry-
`over effect of pudendal nerve stimulation could be
`caused by the negative modulation of excitatory synapses
`in the central micturition reflex pathway [52]. This theory
`is supported by the study of Bear and Malenka [55],
`
`which showed that intense activation of inhibitory input
`to target cells results in a prolonged decrease in synaptic
`efficacy of excitatory synapses (i.e. long-term depression)
`in the hippocampus. Long-term depression could be the
`mechanism of action for the carry-over effect as well as
`for TENS and percutaneous tibial nerve stimulation
`(PTNS). Although, a clear carry-over effect has not been
`described for both therapies in an animal model, it is to be
`expected as patients are successfully treated with inter-
`mittent
`therapy [56–61]. The modulatory effect of
`pudendal nerve stimulation could be prolonged by fre-
`quent stimulation sessions [52], as the carry-over effect is
`reversible and patients are treated with frequent stimu-
`lation sessions during a certain period before their symp-
`toms improve. This could be the case as well for TENS
`and PTNS; however, data supporting this assumption
`have not been presented yet.
`
`Other suggested central modes of action of pudendal
`nerve stimulation are activation of tonic inhibitory mech-
`anisms and shifts in firing threshold of involved neurons
`[62].
`
`The mechanism of action for TENS and PTNS in the
`treatment of overactive bladder syndrome is supposed to
`be a gate-control mechanism as well [25,30,63]. It has,
`however, been demonstrated for TENS that different
`stimulation frequencies have different effects. TENS at
`2 Hz is supposed to activate afferent pudendal nerve
`fibres and 50 Hz stimulation is considered to activate
`striated paraurethral muscle fibres [30,38]. TENS at
`150 Hz is supposed to influence the anterior cutaneous
`branch of the iliohypogastric nerve or to inhibit the
`afferents of the pelvic splanchnic nerves that join the
`inferior hypogastric plexus, resulting in a decreased blad-
`der contractility [56].
`
`Another suggested mode of action for TENS is that it
`provides relief from pain, resulting in increased bladder
`filling and postponed micturition [64].
`
`Tibial nerve stimulation, like SNS [65], reduces C-fos
`protein expression after chemical irritation of the bladder
`[66], indicating decrement of spinal neural cell activity
`and therefore, neuromodulative action. C-fos protein is
`the third messenger that modulates cell activity and is
`especially expressed in neurons after external stimulation
`[66] and in the spinal cord after lower urinary tract
`irritation [67].
`
`The tibial nerve is a mixed nerve containing sensory and
`motor nerve fibres. PTNS is supposed to treat overactive
`bladder syndrome by modulating the signals from and
`towards the bladder via the sacral plexus by retrograde
`afferent stimulation [61]. This has been confirmed by
`studies in anaesthetized female cats [68]. The study has
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`Petitioner - Avation Medical, Inc.
`Ex. 1012, p. 264
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`

`

`Neuromodulation and urinary tract dysfunction van der Pal et al. 265
`
`also confirmed the observation that the effect of PTNS is
`temporary and that maintenance treatment is necessary
`as PTNS reversibly modulates the micturition reflex in
`the female cat.
`
`Voiding disorders
`Different theories on the mechanism of action have been
`proposed. Direct afferent pudendal nerve stimulation
`resulting in a direct change of pelvic floor behaviour
`[69], as well as a rebound phenomenon [70], suppression
`of the guarding reflexes [3] and retuning of the L and M
`regions or ‘on–off’ switch mechanism in the brainstem
`[25], has been suggested.
`
`Conclusion
`Although many hypotheses have been given and much
`research has been performed, the exact mechanism of
`action of neuromodulation in the treatment of lower
`urinary tract dysfunction is still unclear. In the treatment
`of stress incontinence, it seems likely that neuromodu-
`lation induces physiological changes in the sphincter
`muscles and pelvic floor. In the treatment of overactive
`bladder syndrome, nonobstructive voiding dysfunction
`and chronic pelvic pain, the mechanism of action seems
`to be more complicated. The mechanism is most likely a
`combination of the different suggested modes of action,
`involving the neuroaxis at different levels.
`
`References and recommended reading
`Papers of particular interest, published within the annual period of review, have
`been highlighted as:
`
`of special interest
` of outstanding interest
`Additional references related to this topic can also be found in the Current
`World Literature section in this issue (p. 313).
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`The guarding reflex is a bladder-to-urethral reflex and is
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`thra. The reflex is excitatory and results in contraction of
`the urethral smooth muscle during the storage phase of
`the bladder [71]. The guarding reflex is activated during
`coughing
`or
`exercising
`resulting
`in momentarily
`increased bladder pressure, which prevents stress urinary
`incontinence by contraction of the external urethral
`sphincter. The reflex is activated as well by signalling
`of bladder afferents that synapse with sacral interneurons,
`which in turn activate efferent neurons of the external
`urethral sphincter [72]. Animal studies have provided
`data indicating that the guarding reflexes can be modu-
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`activity by spinal or supraspinal pathways [73–78].
`
`The retuning of the ‘on– off’ switch seems to be a more
`logical mechanism of action for neuromodulation, as
`nonobstructive bladder retention is supposed to be
`caused by a malfunction of the ‘on –off’ switch mech-
`anism due to urethral sphincter and pelvic floor spasti-
`city [79]. Evidence supporting this theory has been
`provided by PET studies, which showed pontine acti-
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`[80]. Contradicting data have been presented as well.
`Single photon emission tomography during SNS
`showed an increase in the regional cerebral blood flow
`of all brain areas, which are activated during micturition
`[81]. This study was, however, performed in healthy
`volunteers and not in patients with nonobstructive
`voiding dysfunction.
`
`Retuning of the ‘on–off’ switch could be the mechanism
`of action as well for PTNS. Up till now, no data, however,
`have presented this assumption.
`
`According to Vapnek and Schmidt [82], SNS treats non-
`obstructive retention by eliminating the spasticity of the
`urethral sphincter and pelvic floor and not by direct
`activation of the parasympathetic sacral nerves, as the
`stimulation intensity of SNS is too low for the depolar-
`ization of these unmyelinated nerve fibres.
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`Petitioner - Avation Medical, Inc.
`Ex. 1012, p. 265
`
`

`

`266 Female urology
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