In the past two decades, more than twenty studies addressed brain fMRI findings on urinary bladder control while simultaneous healthy females and males were barely enrolled as subjects or healthy controls in these studies [16]. In the study, the data of the healthy female group and male group were obtained and analyzed under the same scanning parameters, respectively. The differences of brain topologic property alternations evoked by the strong desire to void state may provide the understanding for the central-LUT control mechanism in healthy women and men.
4.1 Global graph metrics
In the study, the repetitive infusion and withdrawal pattern was used to activate the regions related to LUT control. Small-world network properties were observed in the empty bladder and a strong desire to void state in both groups. High Cp and low Lp are the small-world architecture's outstanding characteristics, which are optimized for information processing. Balanced functional integration and segregation were observed in the small-world architecture according to previous general assumptions. High Eglob and Eloc were detected in the small-world networks, which demonstrated higher efficiency in global and local information communication than the regular network (with low Eglob and high Eloc) and the random network (with high Eglob and low Eloc).
Although the small-world properties were detected in both states, the significantly decreased Cp and Eloc were observed in the females provoked by a strong desire to void compared with the empty bladder state, which revealed the lower capacity in local information processing and the decreased efficiency in local information transmission. The significantly decreased Lp and increased Eglob in globally connected graphs suggested the higher capacity in the information processing and higher efficiency in global information communication transmission and a better functional integration in female group.
In the male group, the decreased Eloc was observed under the strong desire to void state compared with the empty bladder state, revealing the lower efficiency in local information transmission. The results implied the decreased trendy of functional segregation in the male group. There were no statistical differences of Cp, Lp and Eglob between the both states.
4.2 Regional nodal metrics
In the female group, the significant increased Enodal under a strong desire to void state was detected in left inferior frontal gyrus and the orbital part of middle frontal gyrus, right median cingulate gyrus, middle occipital gyrus and middle temporal gyrus, and bilateral gyrus rectus, inferior parietal gyrus and supramarginal gyrus. In the male group, the increased Enodal presented in right frontal operculum and medial superior frontal gyrus, left supplementary motor area and the bilateral supramarginal gyrus. The significant decreased Enodal in female group was detected in the bilateral calcarine fissure and surrounding cortex, lingual gyrus, and fusiform gyrus. The decreased Enodal in male group presented in right inferior occipital gyrus and thalamus.
Present clinical human trials and animal experiments [17, 18, 19] have showed that there was a notable voiding reflex between the bladder and the midbrain periaqueductal gray (PAG). During the bladder storage, the afferent filling sensory signals resulted in bladder distension until the volume threshold in PAG was exceeded. The voiding reflex was provoked to relax the urethral sphincter and contract bladder detrusor, while voiding. Urinary bladder storage restarted when it was empty. In fact, the higher central mechanism works in the entire bladder filling and voiding process.
The prefrontal cortex (PFC) is crucial for the LUT control. PFC involved in human personality, decision-making, and social behavior. Significantly, the cortex has been presumed to control voluntary action, including deciding to void [20]. In a previous research [21], as the urinary bladders were passively infusion, heathy female brain responses to larger bladder volume increased in the orbitofrontal cortex. But in patients with overactivity bladder and poor bladder control had weaker responses in the region. The lateral PFC concerns cognition, especially in work memory [22]. Structural MRI has demonstrated the failure to postpone voiding due to the lateral PFC lesion in adult males and females [23]. Children with monosymptomatic nocturnal enuresis manifested abnormal resting-state connectivity in the region [24]. In the study, the regional Enodal in lateral PFC where left opercular part of inferior frontal gyrus located indeed increased compared with the empty bladder in female group. Early Positron-emission tomography (PET) and single photon emission computed tomography (SPECT) studies reported the activation in the bilateral inferior frontal gyrus, but the evidences were absent in male fMRI [9] and the increased Enodal only presented in female subjects in the study. An increased regional Enodal at medial PFC was detected in both groups. Medial PFC was an essential part of default mode network (DMN) [25]. Interoceptive and spatial representations of the body were integrated into DNM, including the bladder sensory [26]. When it came to self-awareness and self-reflection under a resting state, DNM was activated. Additionally, the region works in the cognitive process, regulating emotion, and sociability [27]. Medial prefrontal gyrus lesions were found to result in relatively short-term incontinence in adults. Nevertheless, the white-matter lesion in the medial PFC also led to long-term urinary bladder dysfunction [28]. And a fMRI research showed the region was deactivated under the full urinary bladder in patients with urgency incontinence [29]. The gyrus rectus was an essential region of the medial prefrontal network, which mediated the interaction between the visceromotor centers and the prefrontal sensory signals via the hypothalamus's descending pathway and the brainstem [30]. The ventromedial PFC was proved to connect with the limbic system and other brain regions, which determine its vital roles in LUT control.
The cingulate gyrus as a component of the limbic system was known for multiple functions such as the mediation of emotional and autonomic responses to external stimuli, and processing the information from the bladder to maintain urinary continence and impact on the urge to void [31, 32]. The cingulate gyrus was involved in visceral stimulation and the urge to void was considered as a nonpainful visceral stimulation [11]. As mentioned, the anterior or median cingulate cortex controls the heart rate via sympathetic mechanisms [33, 34]. The dorsal anterior or median cingulate cortex was speculated to control the lower urinary tract via the same mechanism, which cannot be precisely identified now. Under a strong desire to void or urgency, the activated dorsal anterior cingulate cortex would facilitate to urinary continence by urinary sphincter contraction and bladder relaxation [35] .In our study, we detected an increased Enodal in right median cingulate gyrus under the strong desire to void.
Pelvic floor muscles which are important in stress urinary incontinence cannot be isolated. In the male group, supplementary motor area (SMA),an adjacent location to dorsal anterior cingulate cortex, showed the increased Enodal under the strong desire to void. In previous researches, SMA showed the activated response during the pelvic floor muscle’s voluntary contraction [36, 37]. Yin et al. demonstrated that the middle temporal gyrus and the right inferior frontal gyrus inhibited detrusor contraction together during urinary bladder storage in healthy subjects [38]. Patients with detrusor overactivity were found weaker in the two regions [36]. Besides Cohen and coworker [39] suggested that the cingulate gyrus and premotor cortex played important roles in the regulating selective attention under task-conflict condition. During the research, these subjects who had the strong desire to void knew voiding in the scanner was inappropriate.
Visceral perception, including urinary bladder filling sensory, can be integrated with exteroceptive and interoceptive signals [14]. The frontal operculum is a region adjacent to the insula,which involves the awareness and processing of interoceptive signals[37]. The supramarginal gyrus, located in the inferior parietal lobe (IPL), showed a crucial association with proprioception. A recent study has suggested that the regions were activated under the condition of visceral perception, such as heartbeat [40]. The Multifunction of IPL has been revealed in multisensory integration, spatial attention, higher cognitive functions, and oculomotor control [41, 42]. An earlier PET and fMRI study showed the IPL also responds to urinary bladder cooling during the bladder storage using ice water [13༌43]. Meanwhile, the human fusiform gyrus is a region concerning objects recognizing and functional definition, which often interacts with the occipital lobe on visual tasks [44]. The occipital cortex change has been mentioned in previous researches, but the mechanism was not systematically discussed [45, 46].
Distinctly, regional Enodal in the male group’s thalamus was decreased under a strong desire to void state. No difference was observed between urinary bladder filling and emptying in the female group. As a relay station, the thalamus transmits the sensory signals from PAG to the insula, lateral PFC and medial PFC in terms of a frame established via several animal and human researches [9, 47]. Decreased Enodal in thalamus suggesting the lower efficiency in information transmission in regionally connected graphs. The study of Kuhtz-Buschbeck et al [35] had similar gender differences, in which thalamus in healthy males was less activated under the urge to void compared with healthy females. But the activity in other brain regions under the both urinary bladder states were not compared in detail. In our study, compared with the empty urinary bladder state, the more regions of PFC in female group showed the increased Enodal under a strong desire to void state. SMA as the motor control was significantly with the increased Enodal in the male group but not in the female group. Gehring and Knight [48] had suggested the activation in premotor cortex worked with the cingulate gyrus to monitor behavior and guiding compensatory system, the gender difference may partly result from the compensatory system. Under a strong desire to void, subjects’ brain monitored and regarded that the voiding in the scanner was inappropriate, the pelvic floor muscle contraction might be initiated as a compensatory mechanism to resist urine leakage.
No consensus has been reached in gender differences in central LUT control. Compared with female genitourinary system, the male longer urethra and prostate may impact on the brain response for the desire to void with or without the catheters. Blok and his coworkers [49] had indicated that different level of activation in the insula, hypothalamus and PAG during micturition and urine withholding between healthy female and males in his PET study. A meta-analysis of neuroimaging studies has revealed that activated clusters in brainstem (periaqueductal gray and rostral pons), thalamus, insula, and cerebellum to response the urinary bladder filling and no significant difference in brain activation between female and male subjects was detected [50]. Although only cortical and subcortical regions without pons and cerebellum were involved in our study, its results have provided the evidence for gender difference in responses to the strong desire to void under the pattern.
Finally, the sample size was small, which may be a potential limitation of the study. On the other hand, due to the AAL atlas we used to define the regions of interest, only brain activity in cortical and subcortical regions were in focus. We will consider the future studies covering the cerebellum and pons to obtain more integrated information.