Brain activity underlying impaired continence control in older women with overactive bladder

The overactive bladder syndrome (OAB) is a prevalent problem in clinical practice, diagnosed and managed mainly by patients’ reports1. Pharmacological or conservative treatment has only moderate success, perhaps because the underlying causes or phenotypes are heterogeneous and require different therapies. The central symptom of OAB is urgency2, sometimes accompanied by urine leakage episodes (urgency urinary incontinence – UUI), believed to be associated with or caused by involuntary detrusor contractions2,3. Such contractions, observed during urodynamic examination and either spontaneous or provoked 1, are known as detrusor overactivity (DO). Although the etiology of DO and OAB is frequently unknown and although DO is not always observed in patients with OAB, it is the only unambiguous physiological sign of the lower urinary tract (LUT) dysfunction underlying OAB. Its involuntary character implies, at least in part, an abnormality in CNS function, since the CNS is essential for the regulation of voluntary micturition and continence.4, 5,6 Failure to elicit DO during urodynamics in some patients with OAB may suggest that the underlying functional disorder of continence control is different or less severe than in those with more easily elicitable DO. Recent urodynamic studies support this idea by demonstrating physiological differences at LUT level between OAB patients who exhibit DO on urodynamic study and those who do not.7,8 In a group of 144 such women7, those with urodynamically elicitable DO reported strong desire to void and urgency at smaller volumes. These findings suggested elicitability of DO as a marker of the severity of impairment of continence control within the spectrum of OAB symptoms. Elicitability may differ according to circumstances; e.g. it may be more difficult to elicit DO in the scanner than during regular urodynamics, and more difficult during urodynamics than in daily life. The underlying mechanism of elicitability remains unknown: information about brain activity during DO or during urgency preceding DO would shed light on mechanisms involving the CNS. Functional brain-imaging studies 9,10,11 have identified a group of brain regions believed to be a part of a network that regulates all phases of the micturition cycle (the ‘brain-bladder control network’) (see provisional working model, Fig. 1). Neuroanatomical and neurophysiological observations6,12 show that voiding is fundamentally regulated by a long-loop, spinobulbospinal (brainstem) reflex. During urine storage bladder afferents ascend via the sacral spinal cord to the midbrain periaqueductal gray (PAG). If they exceed a certain threshold, the reflex is triggered and a signal is sent to the micturition center in the pons (PMC). Thence an efferent signal passes to the sacral cord, where it stimulates both detrusor contraction and, via inhibitory interneurons, striated sphincter relaxation, so that voiding ensues. This voiding reflex thus switches back and forth between the storage and voiding phases 4,6. Figure 1 Provisional working model of brain/bladder control4,6,9,12,13,15. Voiding is triggered and coordinated by the voiding reflex shown in simplified form at the bottom of the diagram. Cerebral control is exercised by suppressing the reflex at the PAG during ... Normally however the reflex does not operate in isolation. During storage an ascending afferent signal is relayed from the PAG to higher regions of the brain, which assess whether voiding is safe and appropriate, generate bladder sensations, and in return provide output that promotes or suppresses voiding, probably at the PAG13,6. Thus the PAG is the pivotal region via which the reflex influences and is influenced by the cortical parts of the control network. As suggested in Fig. 1 (and elsewhere13), the primary target of the signal ascending from the PAG is the insula and nearby lateral prefrontal cortex (especially on the right), where it evokes normal bladder sensation (desire to void). Desire to void is a homeostatic emotion 14 that provides motivation as well as appropriate motor output to maintain continence (homeostasis). This appears to be a normal continence mechanism, activated when there is desire to void. Fig. 1 suggests that the insular activity is propagated to the lateral (dlPFC) and medial (mPFC) prefrontal cortex (concerned with executive decision-making and social context) and thence back to the PAG, where it suppresses the voiding reflex. The medial – particularly the ventromedial (vmPFC) – prefrontal cortex appears to be deactivated as part of this mechanism15. In UUI subjects, the signal ascending from the PAG (provoked in the scanner by further filling of a well-filled bladder) is also relayed to dorsal anterior cingulate gyrus (dACG) and nearby regions such as the supplementary motor area, SMA (Fig. 1). It evokes the abnormal sensation of ‘urgency’ 15–18, a homeostatic emotion. Activation of SMA is known to tighten the pelvic floor and urethral sphincter. This appears to be a back-up continence mechanism, used if the normal mechanism is inadequate. Finally, bladder filling provokes deactivations in parahippocampal or paralimbic areas19, subcortical changes that suggest evaluation of the safety of voiding, and may provide a third continence mechanism (Fig. 1). The presence or absence of all these activations and deactivations presumably reflects the ability or inability of the CNS to suppress DO (i.e. reduce DO elicitability) and thus prevent incontinence. To test this assumption, we here present a cohort of older women with OAB/UUI who underwent an experimental protocol set up in the brain imaging scanner, which included bladder filling coupled with simultaneous measurement of regional brain activity (via functional magnetic resonance imaging - fMRI) and urodynamic monitoring. Despite clear signs and symptoms of UUI in all subjects, only one-third of the cohort developed DO and lost continence in the scanner (the ‘DO group’). We therefore set up a secondary analysis to compare brain activity in the DO group with the group that maintained full control of the bladder in the scanner (the ‘no DO group’). These 2 groups apparently differed in DO elicitability and we postulated, a priori, that they would display different patterns of regional brain activity during urgency. Specifically, we made the postulate that the brain responses involved in maintaining continence (see Fig. 1) would be diminished in the DO group, implying: less activation in SMA/dACG (Hypothesis 1a) and less prominent deactivation in vmPFC/mPFC and parahippocampal complex (Hypothesis 1b). We also explored possible phenotypic differences by analyzing: a) differences between the groups in their response to bladder filling during standard urodynamics (e.g. sensation of filling, desire to void and urgency), and, b) differences in clinical covariates associated with urgency, UUI and continence control such as: age, extent of structural brain changes (white-matter hyperintensities - WMH), cognition, depression history and psychological burden of the disease. In addition, without making specific hypotheses, we planned to look for differences in brain activity between those with and without elicitable DO when the bladder was nearly empty and sensation relatively weak and, thus, without reported urgency.