Storing urine and emptying the bladder is a multifaceted process that requires complex and coordinated activity as well as integration of peripheral afferent and central efferent signals at different levels. The human bladder has two main functions, namely, the storage of urine until an adequate capacity of the bladder is reached and micturition when an appropriate time and place is found to empty the bladder. From a neural perspective, visceral sensory information is relayed from the bladder through the spinal cord and brainstem to higher brain areas, where levels of bladder fullness and urgency are monitored and our attention is shifted to our bladder when needed. Proper execution of these tasks is dependent on dedicated neuronal control systems at the level of the brain, brain stem and spinal cord.
One of the dedicated nuclei at the level of the brain stem is the periaqueductal gray (PAG). The PAG is proposed to function as a relay station in micturition pathways in the central nervous system and takes up a central location in the hierarchical system of lower urinary tract (LUT) control. It is proposed that the PAG is responsible for relaying afferent information from the bladder to cortical and subcortical brain areas, while simultaneously acting as a gatekeeper relaying efferent information from cortical and subcortical areas to the pons and spinal cord (1). 
Optimal functioning of these central systems enables healthy adults to accurately assess their experienced levels of bladder fullness at any given time and can reliably predict for how long they will be able to postpone micturition. The International Continence Society defines overactive bladder (OAB) as urgency, with or without urge incontinence, and often with frequency and nocturia. Over the past years, it has become more apparent that OAB is associated with altered bladder sensations. A disturbance in the neural processing of visceral sensory information might be related to LUT dysfunction. Recent neuroimaging work has reported the first indications that PAG activity reflects subjective reported bladder sensations (2). PAG activity might, therefore, offer insights into processing of visceral sensory information and could help identify alterations in interoceptive processes which might cause “false alarms” in patients with OAB.

In order to identify neural correlates of bladder sensations we need to gain a better understanding of the visceral sensory information available. Clinically used micturition diaries commonly assess patients’ perceived levels of bladder fullness and urgency, but to our knowledge it is not known how these different modalities relate to one another and to bladder volume. 

In this study, we propose that the interoceptive processing of bladder fullness and urgency are two distinct processes, and that optimal functioning of both processes are necessary for proper LUT functioning. We aim to assess differences in sensory perception of bladder fullness and urgency in healthy adults and OAB patients during a bladder filling protocol. We hypothesize that reported bladder fullness shows a linear relationship with bladder filling, while urgency sensations show a non-linear relationship.

The current study was approved by the local medical ethical committee and informed consent was obtained from participants before any study-related procedures. Upon arrival at our clinic participants were asked to void until empty in private after which a filling catheter was inserted transurethrally.
The bladder was then filled with a saline solution at body temperature at a rate of 30 ml/min using a syringe pump. During bladder filling, participants were instructed to report their experienced sensations regarding bladder fullness and urgency. Bladder fullness was measured using a visually presented VAS-scale ranging from empty to full. Participants were able to indicate their responses by moving a cursor between empty and full using a joystick. Sensations regarding experienced urgency were measured by visual presentation of the Indevus Urgency Severity Scale (IUSS). The IUSS is a four-point scale ranging from none (no urge), mild (30 minutes, awareness of urgency but able to continue usual activity), moderate (10 minutes, enough urgency to interfere with ongoing tasks), and severe (enough urgency to stop all ongoing activity). Again, the participants were able to report their urgency using a joystick. The sampling rate from the sensation data as reported by the participant using the joystick was 1 Hz. Bladder filling was stopped when the participants reported moderate urgency levels. After which they were asked to tolerate the infused volume for 10 minutes. The participants were instructed to void until empty in private.

The analysis of the sensation data was conducted using MATLAB R2017a. We utilized a custom written script to fit a line to the VAS-scale and IUSS-data and determine the extent to which the relationship between bladder filling and reported sensations (bladder fullness and urgency) is of a linear nature.

We analyzed the sensation data in three OAB patients and four healthy participants. We observed that reported bladder fullness follows a linear trend from first sensation of bladder filling to the maximal reported score (Figure 1). Visual inspection implies that the urgency levels as reported by the volunteers do not follow a linear trend. We therefore propose that the exact relationship between bladder volume and experience of urgency requires deeper investigation.

Our results indicate linear increase of reported bladder fullness sensations during bladder filling, which indicates that both OAB patients and healthy participants can accurately assess increases in bladder volume. The reported urgency sensations follow a non-linear trend for healthy participants and OAB patients. Previous research has assessed urgency sensations on a VAS-scale during a water loading protocol and has observed the increase of urgency to follow a convex or sigmoidal trend (3). We propose that the 4-point IUSS scale used in the current study does not contain enough data points to reliably visualize the progression of experienced urgency sensations.
Although we acknowledge the small sample size, we believe that the reported results are worth of further investigation. Our results provide support for the hypothesis that bladder sensations regarding fullness and urgency are two independent interoceptive processes. We expect that these independent processes will be reflected in unique CNS visceral sensory activity.
We aim to integrate these results with neuroimaging studies to create a better understanding of the interoceptive processes regarding bladder fullness and urgency. Further investigation of how CNS activity patterns relate to subjective bladder fullness and urgency sensations can lead to identification of fMRI imaging biomarkers regarding OAB. One might speculate that while awareness of urgency is disturbed in OAB patients, the assessment of bladder fullness is potentially unaffected. This would be of great value to clinics as it unravels the mechanisms of alarm falsification and could potentially lead to new, non-invasive therapies like interoceptive bladder awareness training via bio-feedback. Moreover, this research may help us understand the underlying mechanisms of current therapies, such as sacral neuromodulation.

The difference in the extent to which bladder fullness and urgency show a linear relationship with bladder filling indicates that there are two independent interoceptive processes at play. To further investigate the underlying mechanisms of interoceptive processing related to alarm thresholds, integration with neuroimaging studies is needed. Unraveling this, helps us broaden our understanding on interoceptive processing in the CNS. This enables us to streamline diagnostic and treatment strategies towards a more personalized treatment approach.

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