Benign prostatic hyperplasia (BPH) affects the entire micturition cycle including filling and storage phases, often creating bothersome lower urinary tract symptoms (LUTS). Among the most bothersome symptoms to patients' quality of life are daytime frequency and nocturia, both of which hover around 20% incidence. Men with BPH and bladder outlet obstruction (BOO) leading to LUTS often require transurethral procedures to address the BOO. However, it has been found that up to 33% of patients will have ongoing bothersome symptoms despite surgical removal of the obstruction. Persistent BOO is known to remodel the bladder’s smooth muscle, connective tissue and local neural network; however, the extent to which it alters the central nervous system (CNS) in BPH patients is unknown [1]. The goal of this study is twofold: compare brain activation pattern findings on functional MRI (fMRI) in men with BPH and BOO to known regions of interest in healthy adults from the literature, while also utilizing diffusion tensor imaging to explore the relationship of LUTS and BPH in the same cohort.

Men ≥ 45 years old who have failed conservative BPH therapy planning to undergo BOO procedures were recruited. Men with international prostate symptoms score ≥ 12, max urinary flow rate ≤ 15 cc/s were selected. Men with neurogenic bladder, urethral stricture, previous BOO procedure, and catheter dependance at baseline were excluded. Eligible men underwent concurrent fMRI-urodynamics (UDS) examination, during which the bladder was gradually filled with sterile water until subjects signaled a strong desire to void [2]. Subjects were then instructed to hold for 30 seconds, after which they were given permission to void while supine. UDS was performed concurrently to monitor the entire filling/voiding cycle. After voiding/attempt to void was completed, the bladder was drained and the cycle was repeated up to four times. Functional images were obtained via T-1 weighted 3 Tesla MRI images. Significant activated voxels (p<0.05) were identified at strong desire to void, voiding initiation, and during voiding using student t-test using SPSS statistical software for analysis. White matter tractography was acquired by diffusion tensor imaging (DTI) modality to investigate the structural connectivity of the brain. Two DTI measures—fractional anisotropy (FA) and mean diffusivity (MD)—for each white matter tract were extracted and aligned onto the ICBM DTI-81 atlas. Each white matter tract was evaluated by correlation study between its DTI measures and the participant’s baseline clinical/uroflow parameters.

After exclusion, seven men mean age 61 were evaluated. Baseline demographics are represented in table 1. At strong desire to void, there was neural activation in the right inferior frontal gyrus (IFG) (p<0.05), figure 1a. Deactivation was seen in the thalamus bilaterally, bilateral middle frontal gyrus, left middle and superior temporal gyrus, bilateral insula, and bilateral parahippocampal gyrus (p<0.05). At voiding initiation, activation was observed in the left angular gyrus and left superior temporal gyrus, with notable deactivation in the IFG, figure 1b.  Of note, only four of seven patients were able to void supine during the initial fMRI scan. DTI analysis, based on the FA and MD, revealed eight tracts (p<0.05) associated with uroflow parameters: Qmax, Qmean, and PVR, as illustrated in figure 2. Amongst these white matter tracts, there were six positively correlated tracts and two negatively correlated ones. For example, there were two tracts that showed significant association with the maximum urinary flow rate (Qmax); the FA values of the middle cerebellar peduncle were increased, and the MD values of the left medial lemniscus were reduced with elevated Qmax demonstrating a positive (r=0.930) and a negative (r=-0.909) correlation, respectively. In addition, there was one tract—left posterior corona radiata—with a significant association with PVR which exhibited a positive (r=0.921) correlation. Multiple tracts significantly correlated with subjective symptom scores. A few examples are the FA values of the right superior cerebellar peduncle with a negative (r=-0.863) correlation against IPSS-Q1 (incomplete emptying) and the MD values of the left anterior limb of internal capsule with a positive (r=0.899) correlation against IPSS-Q5 (weak stream).

It has long been known that BOO causes physical changes to the bladder itself, including smooth muscle hypertrophy, hyperplasia and increased collagen deposition; however it was not until a seminal work looking at neural changes in animal models arrived that a better understanding of afferent neuroplasticity in the micturition cycle was achieved [1]. In addition to an overall increase in bladder mass, there was significant sacral afferent neuronal hypertrophy of 40% in areas of somatic and dendritic projection to the lateral border of the dorsal horn, an area known to communicate with the pontine micturition center (PMC) and regulate the spinal micturition reflex [3]. Our preliminary analysis demonstrated a significant activation of the IFG at strong desire to void, consistent with prior data showing its significance during the voiding phase. However, there were important deactivations including the bilateral thalamus, insula, and the IFG during initiation and voiding attempts previously shown to be important regions in normal micturition [3]. In addition, DTI analysis unveiled significant associations between baseline white matter integrity and voiding function in men with BPH and chronic BOO. Each significant white matter tract could indicate either a preserved uniaxial flow of protons in a healthy tract, or a compensatory response in a damaged neural pathway; in this notion, each data point may represent the degree of deterioration or compensatory strengthening exhibited by the specific white matter tract. Though there may not be a causal relationship between the DTI measures and the uroflow/clinical parameters, the strong correlations (regardless of the polarity of the correlation coefficient) may reflect changes in the structural connectivity of the white matter due to LUTS. Furthermore, significant DTI findings of the white matter with respect to subjective questionnaire scores—especially regarding symptoms such as incomplete emptying and weak stream—further support the contribution of white matter to LUTS in men with BPH and BOO. Taken together, these findings suggest that the central nervous system can undergo physiologic changes in its functional and structural connectivity in response to chronic BOO beyond its mechanically obstructive nature consistent with earlier results from animal models with BOO [1].

This represents the first study evaluating functional and structural connectivity of the brain in men with BPH and LUTS. Our study reports significant changes in cortical areas generally known to be important to supraspinal micturition by evaluating functional connectivity patterns of this cohort, which could represent neurophysiologic responses and plasticity to persistent BOO. Additionally, evaluation of the white matter integrity from DTI analyses revealed tracts in the white matter associated with LUTS. Further studies should evaluate whether these patterns of cortical activation/deactivation and structural connectivity changes reflect the inability to void of multiple subjects and the neuroplasticity of supraspinal micturition control in response to chronic outlet obstruction in men with BPH. These valuable findings may serve as baseline predictors of successful response to BOO procedures and/or as foundation for novel therapeutic technologies that are aimed to improve functional and structural connectivity of the brain for this patient population.

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