Overactive bladder (OAB) is a symptom syndrome with urgency as an essential symptom, and its causes range from the central nervous system, including the brain and spinal cord, to the peripheral nerves. However, the essential pathogenesis of OAB has not been fully elucidated and existing treatments are symptomatic and ignore the pathophysiology of individual patients. Therefore, a treatment strategy that is appropriate to the pathophysiology of the disease is required.
Vesical adaptation response of diuresis (VARD) is the homeostatic system that constantly changes bladder volume to adapt to diuresis. Previous study has shown that patients with male lower urinary tract symptoms (LUTS) perform an absence of VARD comorbidity and absence of VARD is strongly implicated as one of the causes of OAB. But the mechanism of VARD and how its impairment contributes to OAB remains unresolved.
Recent advances in functional brain imaging have revealed regions of central nervous activity associated with urinary storage. In particular, the brain regions involved in the urinary reflex center may cause overactive bladder associated with VARD.

Study 1: Adult male Sprague-Dawley rats (14 weeks old) were divided into three groups (sham group, low-rate group and high-rate group; n = 4 for each group). All groups had a vesicostomy; the sham group did not the received saline infusion; low-rate group received saline infusion at a rate of 1 ml/h for 60 minutes through the vesicostomy; the high-rate group received saline infusion at a rate of 10 ml/h for 60 minutes through the vesicostomy. After injection, the brain was immediately perfusion-fixed and removed; the degree of activation in the brain regions was assessed using c-Fos, which is a marker of neural activity to detect regional brain activation related saline infusion rate.
Study 2: The brain activation region of the rats, which was detected in the Study 1, were broken by injecting the neurotoxin ibotenic acid (IBO). Three weeks after injection, the rats were performed metabolic cage studies and cystometrogram. VARD was defined as a positive correlation (γ > 0.4) between urine output rate and voided volume at each void. In cystometry, room-temperature saline was instilled into the bladder at rate of 2.4 ml/h or 4.8 ml/h for 3 hours (n = 5-6 for each group).

Study 1: In both periaqueductal gray (PAG) and prefrontal cortex (PFC), the number of c-Fos positive cell increased significantly as the injection rate increased (PFC: sham group 11.5 ± 6.5 count/region, low-rate group 12.0 ± 9.1 count/region, high-rate group 67.3 ± 5.8 count/region, low-rate group vs high-rate group, p < 0.01, PAG: sham group 43.0 ± 20.0 count/region, low-rate group 13.0 ± 3.3 count/region, high-rate group 51.8 ± 4.7 count/region, low-rate group vs high-rate group, p < 0.01).
Study 2: In the metabolic cage study, single voided volume was significantly lower in the rats with PAG broken (PAG broken group) than in that without PAG broken (PAG non-broken group) (1.2 ± 0.6 mL vs 0.9 ± 0.7 mL, p = 0.04). Micturition frequency increased significantly more in PAG broken group than in PAG non-broken group (10.5 ± 3.6 count/24-h vs 12.8 ± 4.0 count/day, p = 0.03). In addition, PAG broken group had developed a lack of VARD (γ = 0.14). On the other hands, the VARD was maintained in the rats with PFC broken (PFC broken group) (γ = 0.70). In the cystometry, micturition interval was significantly shorter in PAG broken group than PAG non-broken group (p = 0.02). Mean voided volume was significantly lower in PAG broken group than PAG non-broken group (p < 0.05). Lack of VARD had developed in PAG broken group (γ = 0.17). On the other hands, micturition interval was significantly shorter in PFC broken group than PFC non-broken group (p < 0.01). Mean voided volume was significantly lower in PFC broken group than PFC non-broken group (p < 0.05). Lack of VARD had developed in PAG broken group. VARD was maintained in the rats with PFC broken group (γ = 0.70).

PAG is known as one of the urinary reflex centers and is thought to be the area responsible for processing urine storage information. This study revealed that PAG was the region responsible for OAB associated with VARD, suggesting that the dysfunction of PAG may have resulted in VARD due to the inability to process information about urine storage. 
PFC is known as a region that suppresses the urinary reflex. In this study, the dysfunction of PFC resulted in OAB, but VARD was maintained. The results might suggest that lack of VARD might not be caused by an increased urinary reflex related with PFC dysfunction.

This study suggested that PAG was responsible for VARD. Dysfunction of PAG might involve OAB due to lack of VARD.

Continence 12S (2024) 101428
DOI: 10.1016/j.cont.2024.101428