Functional connectivity is the correlation between brain regions that share functional properties. MRI is widely used to study the structure and function of the brain. Task-based fMRI connectivity can reveal the degree to which various brain regions work together towards achieving specific functions. Resting state fMRI connectivity is used to evaluate brain’s intrinsic regional interactions that occur when a subject is not performing an explicit task. Studying brain connectivity in neuropathic patients during the bladder cycle can help to reveal an important level of brain organization regarding the execution and maintenance of bladder functions. The use of 7T ultra-high field MRI provides more than doubled signal-to-noise ratios, higher tissue contrast, increased spatial resolution, and increased susceptibility compared to conventional lower field MRI such as 3T. In this study, we evaluated the functional sub-networks within the bladder related brain regions at three urodynamic phases [‘strong desire to void’, ‘(attempt at) voiding initiation’ and ‘(continued attempt of) voiding’] during urodynamic testing and compared them with the resting state connectivity in female patients with multiple sclerosis (MS) using fMRI data. We found that these three phases activated different sub-networks in the brain and the voiding network closely resembled the bladder related resting state intrinsic network.

Subjects/Urodynamic testing: Ten ambulatory female patients diagnosed with stable MS and voiding dysfunction between the ages of 35 to 77 participated in this study. Prior to scanning, an MRI compatible lumen catheter was inserted into the patients’ bladder. During fMRI scanning, the patients’ bladder was filled and permission to void was given 30 sec after cessation of filling when patient signaled strong desire to void. Residual of urine was manually aspirated. Patients communicated their progress using a response grid indicating ‘strong desire to void’, ‘(attempt at) voiding initiation’, or ‘(continued attempt of) voiding’. This urodynamic testing was repeated at least 3 times for each patient.  

Data acquisition: Eight subjects’ MR images were acquired on a 7T scanner (Siemens MAGNETOM Terra) with a 32-channel head coil. Each session included the following scans: 
1) 3D T1-weighed anatomical scan (spatial resolution = 0.35 x 0.35 x 0.70 mm3); 
2) T2*-weighted blood oxygen level-dependent (BOLD) fMRI scan in a resting state (TR=2500ms, TE=24ms, isotropic spatial resolution=1.4mm3, 8 min); 
3) Simultaneous T2*-weighted BOLD fMRI during urodynamic testing. Acquisition parameters were identical to the resting state scan, however, scan times were varied due to the voiding process being different in each individual subject. 
Due to MR safety regarding the body implants, two subjects’ MR images were acquired on a 3T scanner (Siemens MAGNETOM Vida) with a 20-channel head coil. Each session included the following scans:
1) 3D T1-weighed anatomical scan (spatial resolution = 0.86 x 0.86 x 1.00 mm3); 
2) T2*-weighted BOLD fMRI scan in resting states (TR=2000ms, TE=30ms, isotropic spatial resolution=2.98mm3, 7 min); 
3) Simultaneous T2*-weighted BOLD fMRI during urodynamic testing as described above. 

Data analysis: Preprocessing of fMRI was accomplished using AFNI. The protocol included slice timing, motion correction, and spatial smoothing using a 5mm full-width-at-half-maximum Gaussian kernel. The resting state fMRI time series were then temporally bandpass filtered between 0.01 to 0.1 Hz. 13 regions-of-interests (ROIs) in the bladder related network were analyzed [1-3] including bilateral caudal/rostral anterior cingulate cortex (ACC), bilateral supplementary motor area (SMA), right inferior/superior frontal gyrus, right insula, right parahippocampal, right precuneus, and right inferior/superior parietal gyrus. Individual subject’s brain segmentation was completed using FreeSurfer. Average fMRI time series were computed across each region and functional connectivity (Pearson’s correlation coefficient) between region pairs was computed at resting states and three urodynamic phases: ‘strong desire to void’, ‘(attempt at) voiding initiation’, and ‘(continued attempt of) voiding’. The similarity between connectivity matrices was measured using 2D correlation coefficient.

Data from ten individuals were acquired for this study, but only nine were used for analysis due to one patient having a significant loss of brain tissue. As shown in figure 1, when subjects have a strong desire to void, their inferior frontal gyrus (IFG)/insula and inferiorparietal/superiorparietal sub-networks are more connected (>0.45) than other regions within the bladder related regions. When subjects attempt at voiding initiation, the SMA/superiorfrontal and inferiorparietal /superiorparietal sub-networks are more connected (>0.50) than other regions. Both during (continued attempt of) voiding and resting states, all bladder related regions were highly correlated (>0.55) with each other. In addition, as seen in figure 2, only the (continued attempt of) voiding network closely resembles the resting state intrinsic bladder related network and voiding is consistently achieved through similar regions independent from the regions required to ‘strong desire to void’ or ‘(attempted at) voiding initiation’.

When subjects have a strong desire to void, their connectivity pattern is in agreement with brain regions involved in the registration of bladder filling and fullness sensations [2]. When subjects attempt at voiding initiation, the activation of the SMA/superiorfrontal and inferiorparietal /superiorparietal sub-networks may be because when afferent signals from the bladder to the insula and ACC reach a certain limit, signals are sent to the frontal gyrus which subsequently lifts its inhibitory influence on the pontine micturition center (PMC) in the brainstem. The frontal gyrus then works together with SMA to initiate motor output [3]. We hypothesize when the voiding reflex starts, the voiding continues with minimal activity changes and thus the brain connectivity becomes similar to its resting states.

Different functional sub-networks within the bladder related brain regions are activated at different urodynamic phases such as the sensation associated with bladder fullness and preparation for motor output. All bladder related brain regions are highly correlated during (continued attempt of) voiding and resting states. Additionally, the functional connectivity derived from a task-based urodynamic testing closely resembles the resting state intrinsic connectivity only during (continued attempt of) voiding. Identifying brain sub-networks corresponding to specific bladder functions in neuropathic population is of importance for interventions such as brain modulation with the goal to restore function in patients with debilitation disorders.

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