With advances in neuroimaging over the last two decades, such as functional magnetic resonance imaging (fMRI), the evaluation of supraspinal control over the lower urinary tract has become feasible. However, imaging of significant structures in the brainstem has been met with challenges due to relative size, physiological noise from nearby arteries, and the limited resolution of 1.5 and 3 Tesla MRIs. Measuring activity in the brainstem has become a critical component in understanding the fundamental mechanisms of bladder function as the periaqueductal gray (PAG) and pontine micturition center (PMC) known to be involved in the voiding reflex are housed in this area. As imaging techniques and protocol designs have improved in just the last couple of decades, Blood Oxygen Level-Dependent (BOLD) studies of the brain and more specifically the brainstem have become a pragmatic reality. In this study, we evaluated brain and brainstem activation during initiation of voiding in healthy men and women utilizing a 7 Tesla MRI scanner and a non-invasive brain-bladder paradigm.

Twenty healthy adult volunteer men and women with no history of urinary symptoms or neurological diseases were invited to participate. Uroflow was obtained, and those who failed to meet all inclusion and exclusion criteria were removed from the study. Volunteers were instructed to practice voiding and holding 4 times for a day prior to the day of the MRI scan. For the brain-bladder protocol, each volunteer was asked to consume 500mL to 750mL of water and empty their bladder prior to entering the scanner. Post-void residual (PVR) volume was measured. Next, volunteers were placed within the 7T MRI. An anatomical scan and diffusion tensor imaging (DTI) image were obtained. Volunteers then remained in the scanner until they felt the urge to void, prompting a functional scan during the full bladder phase. Once completed, another function scan began where volunteers began five cycles, consisting of fifteen seconds of attempting to void, followed by thirty seconds of rest. The first 7.5 seconds of each void cycle identified as “initiation of voiding” were analyzed. Activation of regions of interest (ROIs) including brainstem structures were obtained for all men and women enrolled in the study. ROIs with a t-value greater than 2.1 were statistically significant and BOLD maps of the brain and brainstem were generated.

The average age of each participant was 27.45 years with males averaging 26 and a females averaging 28.9 years of age. Five distinct regions of interest within the PAG and PMC yielded statistically significant activation according to BOLD analysis of initiation of voiding. These included 3 distinct PAG regions and 2 distinct PMC regions (Table 1). Additionally, there were several other Talairach regions in the brain (consistent with prior neuroimaging literature) beyond our scope that showed statistically significant activation (Figure 2a). Interestingly, when comparing BOLD activation in men and women, women had overall lower BOLD activation compared to men with the exception of the caudate (Figure 2b).

We again see significant BOLD activation in specific brainstem structures that have been shown to play an active role in the voiding cycle, including the PAG and PMC [1]. Beyond our ROIs, many of the significantly activated Talairach regions fit nicely within Griffiths et al’s Working Model of Lower Urinary Tract Control. Specifically, the left and right superior frontal gyrus contribute to Circuit 1, the left and right anterior cingulate gyrus contribute to Circuit 2, and the left and right parahippocampal gyrus contribute to Circuit 3 [1]. Next, activation of certain regions such as the left and right thalamus seem appropriate, as the thalamus is the ‘relay center’ for all sensory information. Others, such as the caudate and putamen are part of the basal ganglia, which is critical for coordinating voluntary movements and making postural adjustments. As this is the first study using a 7-Tesla to evaluate voiding and micturition in both men and women, subsequent studies are needed to clarify how previously unidentified Talairach areas may fit into the current working model of higher neural control of bladder. Interestingly, the results with respect to lower BOLD activation in women as compared to men is particularly notable; prompting further investigation in both the cause of this difference in activation, as well as other differences that may exist between genders and its impact on initiation of voiding.

To our knowledge, we have conducted the first study of its kind to implement a non-invasive fMRI protocol to evaluate brainstem involvement during initiation of voiding in real-time in both men and women utilizing a 7-Tesla MRI . Our findings support the critical role of the PAG and PMC in the initiation of voiding, previously studied in animals, incorporating the complex social, emotional, and mechanical criteria needed for voiding in humans.

Griffiths D. Neural control of micturition in humans: a working model. Nat Rev Urol. 2015;12(12):695-705. doi:10.1038/nrurol.2015.266

Continence 2S2 (2022) 100295
DOI: 10.1016/j.cont.2022.100295