A Decade of Functional Brain Imaging Applied to Bladder Control

Neurourology and Urodynamics 29:49 55 (2010) REVIEW ARTICLE A Decade of Functional Brain Imaging Applied to Bladder Control Clare J. Fowler 1 * and Derek J. Griffiths 1,2 1 Institute of Neurology, UCL, London 2 University of Pittsburgh, Pittsburgh, PA Over the last 10 years functional brain imaging has emerged as the most powerful technique for studying human brain function. Although the literature is now vast, including studies of every imaginable aspect of cortical function, the number of studies that have been carried out examining brain control of bladder function is relatively limited. Nevertheless those that have been reported have transformed our thinking. This article reviews that development in the context of emerging ideas of interoception and a working model of brain activity during bladder filling and emptying is proposed. Some studies have also been carried out using functional imaging methods to examine pathophysiological bladder conditions or the effect of treatments and these are reviewed and future work anticipated. Neurourol. Urodynam. 29:49 55, 2010. ß 2009 Wiley-Liss, Inc. Key words: bladder control; brain imaging; neurourology BACKGROUND Functional brain imaging is the use of neuroimaging technology to measure an aspect of brain function, with a view to understanding the relationship between activity in certain brain areas and specific functions. The science of functional brain imaging first appeared in the mid 1990s with the advent of improved scanning of whole brain images and powerful computer tomographic analysis. First single photon computerized tomography (SPECT) which used gamma-ray photons and subsequently positron emission tomography (PET) which relies on the fact that a positron is emitted when isotopes decay, were used. Both techniques required injection of a radioactive substance which was concentrated in a metabolically active brain region. The spatial resolution of PET was twice that of SPECT and furthermore its temporal resolution was superior, so that this method proved very valuable and it was with PET that much of the early functional brain imaging discoveries were made. In due course PET was complemented by functional MRI which has the advantage of being completely non-invasive but the signal to noise ratio is low so that repeated captures of the event related data are necessary. For studies of bladder function using fmri this has meant subjects have been required to do repeated pelvic floor contractions with either full or empty bladder 1 4 or had alternating bladder infusions and fluid removal via a catheter. 5,6 The science of functional brain imaging has grown explosively in the last decade and a Pubmed search, using terms which identify the various methods that have been used in humans, reveals a literature which now totals approximately a quarter of a million papers. These have looked at brain activation with movement, language, emotion, working memory, attention, sensory modalities such as pain, vision, hearing and olfaction and most recently decision making, social behavior, reward, and empathy. This new science has transformed our understanding of that wondrous organ which is the human brain. However amongst this enormous literature the number of studies that have focused on brain control of bladder function is minute. The complete literature on this topic containing new data (rather than review articles) is shown in Table I and amounts to a total of 24 papers. Nevertheless, as in other disciplines where the power of functional brain imaging has been harnessed, even from this relatively tiny contribution, our thinking about brain control of the bladder has been fundamentally changed. TOWARDS CURRENT CONCEPTS OF BRAIN AND BLADDER CONTROL The very first attempt to use functional brain imaging to examine the neural control of the bladder was by Fukuyama et al. 7 from Japan, who in 1996 performed SPECT imaging and showed areas of brain activation during micturition in healthy male volunteers. Despite the relatively poor spatial resolution of this technique activity was seen in the upper pons, the left sensorimotor cortex, the right frontal cortex, and bilateral supplementary motor areas. But the same year Holstege s group in Groningen published their first PET study of brain activation during filling and voiding in men, accompanied by a highly illuminating discussion of their findings. 8 Of the 17 male subjects who had received special training to be able to void supine, only half were able to do so on command following the injection of radioactive isotope. 8 In fact the difference between those who could and could not void proved to be of considerable interest in the analysis. The Conflicts of interest: none. *Correspondence to: Prof. Clare J. Fowler, Box 71, Queen Square, London WC1N 3BG, UK. E-mail: c.fowler@ion.ucl.ac.uk Received 8 January 2009; Accepted 13 March 2009 Published online 1 May 2009 in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/nau.20740 ß 2009 Wiley-Liss, Inc.

50 Fowler and Griffiths TABLE I. Functional Brain Imaging and Bladder Control Literature to Date References Method Method and aim Fukuyama et al. 7 SPECT Voiding in men Blok et al. 8 PET Voiding in men Blok et al. 39 PET Pelvic floor contraction in women Blok et al. 15 PET Voiding in women Nour et al. 40 PET Filling and emptying with pressure measurements Athwal et al. 13 PET Bladder filling in men Matsuura et al. 14 PET Bladder filling in men with saline and with ice cold water Dasgupta et al. 34 PET Effects of SNS in women with retention Zhang et al. 1 fmri Filling and pelvic floor contraction Griffiths et al. 5 fmri Filling in controls and subjects with overactive bladder Kuhtz-Buschbeck et al. 2 fmri Urge to void induced by pelvic floor contraction Seseke et al. 3 fmri Voluntary pelvic floor control Kitta et al. 35 PET In Parkinson s disease PD Yin et al. 41 SPECT Bladder filling with new analysis method Herzog et al. 36 PET Effect of subthalamic stimulation in PD Di Gangi Herms et al. 38 fmri Changes following pelvic floor exercises in women with stress incontinence Blok et al. 33 PET Acute and chronic effects of sacral neuromodulation in urgency Griffiths and Tadic 11 fmri Controls and urgency incontinence Kuhtz-Buschbeck et al. 4 fmri Pelvic floor contraction Griffiths and Tadic 11 fmri Urgency Tadic et al. 19 fmri Physiophysiological interactions Mehnert et al. 6 fmri Filling and clitoral stimulation Herzog et al. 37 PET Effect of subthalamic stimulation in PD Seseke et al. 16 fmri Gender differences in voluntary control of micturition findings of that study were not only entirely novel and exciting but also proved to be important in establishing a framework of thinking which has informed all studies in this area ever since. At the time the result was considered remarkable because sufficient spatial resolution had been achieved to show activation in the pontine region, in an area referred to as the M region in the cat (because of its more medial location) by Holstege s group, but also known as the pontine micturition center (PMC) or Barrington s nucleus from animal studies. The PMC was seen in the subjects who were able to void in the scanner, whereas those who could not showed more lateral activation in a region that was postulated to be the equivalent to the L region in cats and important in storage. 9 This led to the hypothesis that bladder control was effected by switching between these two centers in the pontine region, the M and the L, to effect voiding and storage respectively, a theory that led thinking about human neural control of the bladder for some while but which has subsequently been the subject of some controversy. The animal experimental basis for the L region rested on the findings of a single experimental animal which was severely incontinent after lesioning in the L region, 10 other animals in that series having perished, probably as a result of a lesion in the closely associated respiratory center. Subsequent human functional brain imaging experiments have often not visualized the L region in circumstances when it might have been expected and current thinking is that the pontine micturition center (PMC) is active in both storage and voiding, being actively inhibited during storage and activated by input from the periaqueductal gray (PAG) during voiding. (Note that functional imaging may not distinguish between activation and inhibition.) The recent meta-analysis of the literature by Griffiths and Tadic 11 summarizes the subcortical locations of activation that have been found and is shown in Figure 1. Prior to the first PET imaging article, experiments in cats had shown that the major destination of afferents from the sacral region was the PAG, a region which played a critical role in what Holstege termed the emotional motor system. This, it was hypothesized, has an important role in homeostasis and reproductive function. 12 The demonstration of PAG activation on bladder filling and with micturition in their PET imaging experiments confirmed that group s scientific predictions and showed a similarity between the neural control of cats and humans. Subsequent studies which focused on brain activation and bladder filling by both Athwal et al. 13 and Matsuura et al. 14 showed prominent activation of the PAG on bladder filling. Interestingly the same experimental paradigm as had been used in Groningen in male subjects showed much less activation of the PAG in women 15 a finding not replicated in a recent fmri study which found gender differences only in (sub)cortical structures, not in pons or midbrain. 16 Bladder Sensation and the Emerging Concepts of Interoception Functional brain imaging has contributed vastly to our understanding of the nature of human interoception. Fig. 1. Reported locations of peak activation (deactivation in a few cases) of brainstem areas activated during withholding of urine or full bladder, or during voiding, projected on a medial section of the brain (based on PET, fmri and SPECT studies in healthy controls). Reprinted with permission from Ref. 11

A Decade of Functional Brain Imaging 51 Interoception can be defined as the sense of the physiological condition of the entire body and in recent years Craig has emphasized that it includes the sensations of pain and temperature, formerly regarded together with touch, as exteroceptive sensations. 17 This reassignment of pain and temperature represented a significant change in thinking as previously interoception had been considered to relate simply to visceral sensation. However the better understanding of the central processing of interoception that this reappraisal brought, has led to significant conceptual advances. The cardinal feature characterizing the interoceptive system is that the afferent input is through small-diameter (A d and C) fibers which enter the spinal cord through lamina 1. Lamina 1 neurones represent many aspects of physiological conditions of the tissues of the body and relate to homeostatic information. 17 Bladder afferents fit neatly into this model. Homeostatic afferents are now regarded as the missing sensory limb of the efferent autonomic nervous system. These afferents project via the spinothalamic tracts to subcortical homeostatic centers including the hypothalamus and PAG and, in humans and higher order primates, relay in the thalamus and converge on the non-dominant anterior insula. The insula, an island of cortex, lies buried deep to the lateral sulcus which separates the temporal lobe from the fronto-parietal cortices. The insula has come to be regarded as the homeostatic afferent cortex 18 and has been shown to be activated by a range of modalities associated with visceral sensation. Insula activation was seen in PET studies by Blok et al., 8 but recently has been more extensively studied in the fmri experiments carried out by the Pittsburgh group. 5,11,19 They have been able to show a correlation between the degree of bladder filling and insula activation in healthy controls with an exaggerated increase in activation at high volumes in a group comprising almost entirely women with urgency incontinence 5 (Fig. 2). A key feature of bodily or interoceptive sensations is their association with an affective, motivational aspect and hence their value in homeostasis. The anterior cingulate cortex (ACC) is the cortical region associated with motivation and, if the insula is regarded as the limbic sensory cortex, the ACC can be considered as the limbic motor cortex, 20 the two being frequently seen to be co-activated in functional brain imaging studies. 21 A wide range of cerebral functions has been attributed to the ACC over the years as its activation is seen with many different executive tasks 22 but the demonstration that output was correlated with sympathetic activation lead to the hypothesis that the ACC mediates context-driven modulation of bodily arousal states. 23 Furthermore there is a suggestion that the location of activation in the ACC, a widely distributed area, depends on the nature of the task to be performed; stimuli with a largely emotional content activating the ventral ACC whilst tasks involving cognitive processing activate a more dorsal region. 24 ACC activation has been demonstrated in all functional imaging bladder experiments, although as shown in Figure 3, the precise location has been quite varied. Prefrontal Cortex and Bladder Control The prefrontal cortex is that part of the frontal cortex anterior to the motor strip and supplementary motor areas. It is the part of the brain which most distinguishes humans from subprimates, ventral regions being involved in aspects of cognition and inferior lateral parts, emotions. The orbitofrontal or prefrontal lateral cortex (PFLC) has extensive interconnections with the limbic system the hypothalamus, amygdala, insula, and ACC. Subjective evaluation of gustatory, thermal and pain stimuli is thought to depend on sequential processing in the insula and orbitofrontal cortex, the latter providing hedonic valence that is, feelings of pleasantness or unpleasantness according to the body s homeostatic needs while intensity correlates with amygdale activation. 25 The importance of the prefrontal cortex in bladder control was established from clinical studies both by Ueki 26 and subsequently by Andrew and Nathan, 27 who published their celebrated paper in Brain in 1964. Interestingly, that paper Fig. 2. Brain responses to bladder infusion in normal subjects with good bladder control and in subjects with poor control (urgency incontinence or overactive bladder), measured at small bladder volume (weak bladder sensation) and at large volume (strong sensation) and plotted on an axial cross-section. The marked bilateral activation seen in every section corresponds to the insula. In subjects with normal control, activation increases slightly but not markedly with increasing bladder volume. In those with poor control, activation is weaker than normal at low volume, but much stronger and more widespread than normal at high volume. Reprinted with permission from Ref. 5 Fig. 3. Reported locations of peak activation (deactivation in a few cases) of the anterior cingulate gyrus activated during withholding of urine or full bladder, or during voiding, projected on a medial section of the brain (based on PET, fmri, and SPECT studies in healthy controls). Reprinted with permission from Ref. 11 The cyan filled circle refers to that region in the frontal lobes identified by Andrew and Nathan 27 as being critical for bladder control.

52 Fowler and Griffiths highlights that the location of lesions which were clinically demonstrated to have long-term effects on bladder function was in white matter tracts (connecting pathways consisting of myelinated axons) in the medial frontal regions. Functional imaging detecting brain activation reflecting neuronal metabolic activity, inevitably detects only gray matter (containing neural cell bodies). This led to some difficulty reconciling the reported clinical and imaging data, only recently clarified by Griffiths (Fig. 4). In the original PET experiments by Blok et al. 8 the medial prefrontal area was seen to be activated in those who could successfully void in the scanner. It was hypothesized that this is the region which is involved in making the decision whether or not micturition should take place. Many subsequent experiments have shown lateral prefrontal areas of activation during withholding of urine or a full bladder with the summary analysis shown in Figure 5. Brain Bladder Control Matrix In 2005 it was possible to illustrate a review article on Brain and Bladder control with diagrams showing a meta-analysis of the regions of brain activation on bladder filling as revealed by PET scanning 28 and this was subsequently updated for a second review article in 2007 with the additional data that had become available from the fmri experiments 29 (Fig. 6a). It was also possible in 2005 to propose an illustrative scheme for a bladder control matrix, which was a flat map showing brain centers that were known to be activated on bladder filling, linked by connecting lines. It was not possible at that time to suggest directions for connectivity but in the last year the Pittsburgh group 19 has made a significant advance. Tadic and coworkers introduced a new method ( physiophysiological interaction; PPI) to the analysis of their fmri results. Based on their findings it now became possible to show probable directions of connectivity Fig. 5. Reported locations of peak activation (deactivation in a few cases) of frontal lobes areas activated during withholding of urine or full bladder, or during voiding, projected on a lateral view of the brain (based on PET, fmri, and SPECT studies in healthy controls). Reprinted with permission from Ref. 11 and the diagram changed to that shown in Figure 6b. 30 The central role of the PAG is evident, as it both receives sacral afferents and (via the PMC) transmits efferent signals to the sacral spinal cord. During storage it is chronically suppressed by a net inhibition from the many other regions shown in the figure. These include prefrontal cortex and hypothalamus, as well as insula and anterior cingulate cortex. Inhibition of the PAG by the prefrontal cortex may be particularly important, because lesions in this pathway lead to incontinence, as shown by Andrew and Nathan 27 (Fig. 4). The PAG has multiple connections that enable it to coordinate and control all essential bodily functions, not just voiding 31 and it appears to perform much of the required signal processing. The PMC however is the ultimate arbiter of lower urinary tract function, acting as a switch between the storage and voiding phases. It is believed that, for voiding to occur, the PMC requires both an excitatory signal from the PAG and a safe signal from the hypothalamus 8 as suggested by Figure 6B. In accordance with neuroanatomical observations in the cat, 32 Figure 6b suggests that the PAG (rather than the PMC) receives sacral afferent input. Correspondingly, in humans, neuroimaging studies show increasing activation on bladder filling in PAG but not in PMC. 5,13,14 Other regions shown in Figure 6b include basal ganglia and cerebellum. Activation of the cerebellum and the basal ganglia (especially putamen) is often reported in imaging studies but has not been systematically studied. Transposing the data from Figure 6 back to a structural brain, Figure 7 has been proposed as a summary illustration of current thinking about brain control of the bladder during filling and emptying respectively. APPLICATION OF FUNCTIONAL IMAGING TO PATHOPHYSIOLOGICAL CONDITIONS Several attempts have now been made to use functional brain imaging to study pathophysiological conditions, and they are of interest not only for their own sake, but also because they form a set of natural experiments that shed light on normal physiology by showing how it can go wrong. Fig. 4. Location of lesions causing incontinence (or occasionally retention) in the group of patients studied by Andrew and Nathan. 27 The red ellipse shows where white-matter lesions caused lasting urinary tract dysfunction. The cyan ellipse shows the location of gray-matter lesions that caused transient dysfunction [Nathan, personal communication with CJF]. Urgency (Urge) Incontinence Blok et al. 33 looked at the acute and chronic effects of sacral neural modulation (SNM) when used to treat urgency incontinence associated with detrusor overactivity (DO), both

A Decade of Functional Brain Imaging 53 Fig. 6. Brain areas involved in the regulation of urine storage. a: A meta-analysis 29 of PET and functional MRI studies that investigated which brain areas are involved in the regulation of micturition reveals that the thalamus, the insula, the prefrontal cortex, the anterior cingulate, the periaqueductal gray (PAG), the pons, the medulla and the supplementary motor area (SMA) are activated during urinary storage. b: Following the PPI study of the Pittsburgh group 19 it was possible to show probable connections between forebrain and brainstem structures that are involved in the control of the bladder and the sphincter in humans. Arrows show probable directions of connectivity but do not preclude connections in the opposite direction. In spite of this complexity, the PMC remains the origin of the final common pathway from brain to spinal cord. Reprinted with permission from Ref. 30 studies using PET. A most interesting finding was that the brain responses to SNM in treatment-naïve subjects, who were examined when their implanted stimulator was switched on for the first time, were different from those in subjects who had already received SNM via an implant for several years. This suggests that, via neuroplasticity, the brain is gradually reorganized by chronic SNM. Since the naïve subjects had presumably all shown an acute therapeutic response during a brief trial of percutaneous stimulation some months earlier, it is likely that the neuroplastic changes in the chronic subjects represent a learned reaction to successful therapy, not the mechanism of therapy itself. Consistent with this postulate, chronic changes included decreases in neural activity in brain regions concerned with Fig. 7. A preliminary working model of lower urinary tract control by higher brain centers. A: During storage, ascending afferents (yellow) synapse on the midbrain periaqueductal gray (PAG); they are relayed via the hypothalamus (H) and thalamus (TH) to the dorsal anterior cingulate cortex (ACC) and to the right insula (RI) and to the lateral prefrontal cortex (LPFC); in the storage phase they pass to the medial prefrontal cortex (MPFC, red arrow) where the decision to void or not maybe made. In this phase the decision is not to void, and this situation is maintained by chronic inhibition of the PAG via a long pathway (red arrows) from the MPFC; consequently the pontine micturition center (PMC) is also suppressed, and voiding does not occur. B: When the decision to void is made, the MPFC relaxes its inhibition of the PAG (green arrow) and the hyothalamus (H) also provides a safe signal; consequently the PAG excites the PMC which in turn sends descending motor output (green arrow) to the sacral spinal cord that ultimately relaxes the urethral sphincter and contracts the detrusor, so that voiding occurs. Voiding is continued to completion by continuing afferent input, probably to the PAG.

54 Fowler and Griffiths the emotions, such as cingulate gyrus, ventromedial orbitofrontal cortex, midbrain, and amygdala/hippocampal complex. This suggests that after long-term successful treatment patients showed a more relaxed attitude to bladder events. In contrast, the responses during the first hours of stimulation were nearly all activations, and the authors suggested that they included areas concerned with sensorimotor learning. However, one would expect that these acute responses should mediate the therapeutic effect of SNM, and indeed they included the right insula and the medial prefrontal cortex, known to be involved in bladder control (see Fig. 6). However, the mechanism of therapy remained obscure. The studies of the Pittsburgh group, based on fmri during repetitive infusion and withdrawal of liquid in and out of the bladder, have shown that brain responses to bladder filling (infusion) are abnormal in women with urgency incontinence, even when no detrusor overactivity is present (Fig. 2). 11 The regions involved PMC, PAG, thalamus, insula, dorsolateral prefrontal cortex, ACG, hypothalamus are familiar from Figure 6, although there are also activations in other areas frontoparietal regions, posterior brain, and cerebellum. In such women there is a pattern of exaggerated activation at high volume (associated with strong bladder sensation but in the absence of detrusor overactivity) that is particularly prominent in the ACC, suggesting a strong emotional reaction to threatened leakage. This pattern may therefore be characteristic of the sensation of urgency, a critical symptom that has proved difficult to define in practice. It seems likely that this approach will lead to an understanding of what is now termed idiopathic detrusor overactivity or urgency incontinence, and to new therapies. Urinary Retention Dasgupta et al. 34 explored how SNM restores voiding in young women with urinary retention due to a primary disorder of sphincter relaxation (Fowler s syndrome). Using PET, they compared brain activity with full versus empty bladder, in patients versus healthy controls. In patients scans were run with stimulator on and also after the stimulator had been off for at least 3 days. All had already been successfully treated by SNM, and so the changes associated with stimulation may represent chronic (learned) as well as acute effects. A significant finding was that, in patients, SNM restored both bladder sensation and the midbrain (PAG) response to bladder filling. This is consistent with the view that in Fowler ssyndromethere is a deficit in the afferent signals from the bladder; SNM improves the deficient afferents, which are received by the PAG and relayed onward to give rise to sensation, in accordance with Figure 7A. Parkinson s Disease PET was also used to study detrusor overactivity in patients with Parkinson s disease. 35 Measurements made during detrusor overactivity, with full bladder, were compared with those made with empty bladder and no detrusor overactivity. Brain regions significantly activated during detrusor overactivity included the PAG and (left) insula, consistent with their respective roles in receiving and relaying bladder afferents and efferents, and in recording bladder sensations. No activation of the pontine micturition center was detected, although it had been activated in an earlier study of normal volunteers by the same group. The significance of this finding is not clear: it requires further investigation. In another PET study of Parkinson s disease the effect of deep brain (subthalamic nucleus) stimulation on bladder function and brain responses was investigated. 36 The acute effects included reduction in sensation signaled by marked increases in bladder volume at first desire to void and strong desire to void. Detrusor overactivity, observed in some subjects, was not affected however. During stimulation with full bladder there was increased neural activity in the basal ganglia and decreased activity in some cortical areas including the lateral prefrontal cortex. The authors suggested that lateral prefrontal cortex activation represented the effort needed to deal with the desire to void and remain continent, and that the observed decrease during deep brain stimulation might represent normalization of brain activity. This work supports the role of the lateral prefrontal cortex suggested in Figure 7A (LPFC), and underlines the importance (at least in Parkinson s disease) of the basal ganglia, which are included in Figure 6b but omitted from Figure 7. In a later study of Parkinson s disease patients by the same group, 37 care was taken to limit filling of the bladder so that a slight sensation of filling but not a desire to void was experienced. Correspondingly, no significant activation either of LPFC or of anterior cingulate cortex was seen, but there was still activation of PAG, thalamus and insula, entirely consistent with the pathways shown in Figure 7 and with the role of the insula in recording and processing visceral sensation. Although these activations were seen with stimulation both on and off, stimulation led to a striking difference in the correlation between neural activity in the PAG and neural activity in thalamus or insula: with stimulation on these correlations were significant and positive; with stimulation off there appeared to be no correlation at all. This observation suggests that the pathways from PAG to thalamus and insula (PAG/TH/RI in yellow in Fig. 7A) do not conduct signals properly in Parkinson s disease, and that conduction can be restored by basal ganglion activation evoked by deep brain stimulation. Stress Incontinence fmri was used to examine the effect of pelvic floor exercises in treating stress incontinence. 38 Treatment was successful in at least slightly reducing the number of incontinence episodes in all patients. fmri was performed during repetitive contraction of pelvic floor muscles. Primary brain responses to pelvic floor contraction were cortical. After treatment, responses in the primary motor and somatosensory areas became more focused, while activation in supplementary motor and premotor areas disappeared. These regions differ from those activated by bladder filling or voiding (Fig. 6), and the authors suggested that the observed changes were consistent with automatization and more skilful performance of the pelvic-floor contraction task. In addition to changes in these regions concerned with control of striated muscle, specifically the pelvic floor, brain responses were significantly smaller after treatment in dorsal anterior cingulate cortex, right insula (RI), and putamen. Anterior cingulate cortex and RI are intimately involved in emotional aspects of bladder control (Fig. 7), and so these findings may indicate reduced emotional involvement in bladder behavior after successful treatment, very much as seen after long-term treatment of urgency incontinence by sacral neural modulation (see above). FUTURE STUDIES The 24 papers cited in Table I have opened up an entirely new field of investigation, which is expected to result in an avalanche of new information about lower urinary tract

A Decade of Functional Brain Imaging 55 function and dysfunction, and in new methods of assessment and treatment. Among the numerous possibilities are: (1) Testing, correction, refinement, and expansion of the working model shown in Figure 6. (2) Further studies of connectivity between brain regions. (3) Development of analyses targeted at networks rather than individual centers. (4) Attention to white-matter connecting pathways as well as gray matter. (5) Studies of brain deactivations as well as activations. (6) Clearer definitions of urgency and other bladder sensations. (7) Studies of brain responses during detrusor overactivity. (8) Understanding of the origins of detrusor overactivity and urgency incontinence. (9) fmri studies of voiding as well as storage. (10) Understanding of the difference between voluntary detrusor contraction and (involuntary) detrusor overactivity. (11) Understanding of a broader selection of disease states, including spinal cord injury, neurological diseases beyond Parkinson s disease;fowler s syndrome (urinary retention in young women) and studies of the effects of therapy and their relation to therapeutic success. (12) Testing of the CNS effects of drugs. It is both exciting and a privilege to be able to participate in this revolution in our understanding of the lower urinary tract. ACKNOWLEDGMENTS CJF s contribution to this work was undertaken at UCL Hospital/UCL, who received a proportion of their funding from the Department of Health s NIHR Biomedical Research Centres funding scheme. DG was supported by US Public Health Service Grants R03AG25166 and R01AG020629. REFERENCES 1. Zhang H, Reitz A, Kollias S, et al. An fmri study of the role of suprapontine brain structures in the voluntary voiding control induced by pelvic floor contraction. Neuroimage 2005;24:174 80. 2. Kuhtz-Buschbeck JP, van der Horst C, Pott C, et al. 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