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Most of the time the bladder is locked in storage mode, switching to voiding only when it is judged safe and/or socially appropriate to urinate. Here we show, in humans and rodents, that deep brain stimulation in the periaqueductal gray matter can rapidly and reversibly manipulate switching within the micturition control circuitry, to defer voiding and maintain urinary continence, even when the bladder is full. Manipulation of neural continence pathways by deep brain stimulation may offer new avenues for the treatment of urinary incontinence of central origin. Ann Neurol 2012;72:144–147

Non-technical summary Even when the bladder is full, emptying can be deferred voluntarily until individuals find themselves in a socially appropriate environment. This indicates that the brain is important in the control of bladder function. This study used drugs that either mimic or block the effects of the neurotransmitter chemicals involved in communication between nerve cells to investigate the brain nerve circuits that govern the control of the bladder. A small region in the midbrain was shown to be critical for normal bladder emptying to occur. Normally the excitability of the nerve circuits in this region was controlled by the action of an inhibitory neurotransmitter chemical called GABA. However, if GABA's effect was removed, bladder emptying became abnormally frequent. These results advance our understanding of the normal control of bladder function, and have implications for the development of new treatments for some forms of incontinence. Abstract In urethane-anaesthetised rats continuous infusion of saline into the bladder (6 ml h−1) evoked periodic sharp rises in intravesicular pressure accompanied by rhythmic bursting of external urethral sphincter (EUS) EMG and expulsion of urine from the urethral meatus. Microinjection of the GABA agonist muscimol (250 pmol) into the caudal ventrolateral periaqueductal grey (PAG), but not at other sites in the PAG, either depressed reflex voiding frequency (−60%, n= 7) and tonic EUS EMG activity (−38%, n= 6) or completely inhibited voiding (four sites). Microinjection of the GABA antagonist bicuculline (BIC; 1 nmol) into the same region, to reduce ongoing GABA tone, increased reflex voiding frequency (+467%, n= 16) and tonic activity in the EUS (+56%, n= 7) whilst bursting activity in the EUS became desynchronised. Although muscimol failed to change reflex micturition when microinjected into the dorsal caudal PAG, microinjection of BIC at these sites evoked pronounced autonomic arousal and increased reflex voiding frequency (+237%, n= 34). The results demonstrate that the functional integrity of synapses in the caudal ventrolateral PAG is essential to permit micturition. Transmission through the region is normally regulated by a tonic GABAergic inhibitory influence. In contrast, the functional integrity of the dorsal caudal PAG is not essential for reflex micturition. However, micturition may be initiated from this region via projections to the caudal ventrolateral PAG, as part of the behavioural response to psychological threat or other stressful stimuli.

Aim To understand how deep brain stimulation of the midbrain influences control of the urinary bladder. Methods In urethane-anaesthetized male rats, saline was infused continuously into the bladder to evoke cycles of filling and voiding. The effect of electrical (0.1–2.0 ms pulses, 5–180 Hz, 0.5–2.5 V) compared to chemical stimulation (microinjection of D,L-homocysteic acid, 50 nL 0.1 m solution) at the same midbrain sites was tested. Results Electrical stimulation of the periaqueductal grey matter and surrounding midbrain disrupted normal coordinated voiding activity in detrusor and sphincters muscles and suppressed urine output. The effect occurred within seconds was reversible and not secondary to cardiorespiratory changes. Bladder compliance remained unchanged. Chemical stimulation over the same area using microinjection of D,L-homocysteic acid (DLH) to preferentially activate somatodendritic receptors decreased the frequency of micturition but did not disrupt the coordinated pattern of voiding. In contrast, chemical stimulation within the caudal ventrolateral periaqueductal grey, in the area where critical synapses in the micturition reflex pathway are located, increased the frequency of micturition. Conclusion Electrical deep brain stimulation within the midbrain can inhibit reflex micturition. We suggest that the applied stimulus entrained activity in the neural circuitry locally, thereby imposing an unphysiological pattern of activity. In a way similar to the use of electrical signals to ‘jam’ radio transmission, this may prevent a synchronized pattern of efferent activity being transmitted to the spinal outflows to orchestrate a coordinated voiding response. Further experiments to record neuronal firing in the midbrain during the deep brain stimulation will be necessary to test this hypothesis.