Protocol for a prospective magnetic resonance imaging study on supraspinal lower urinary tract control in healthy subjects and spinal cord injury patients undergoing intradetrusor onabotulinumtoxinA injections for treating neurogenic detrusor overactivity

Spinal cord injury (SCI) is a devastating event with far-reaching consequences for the individual’s health and the economic and social future. In the past, renal failure due to neurogenic lower urinary tract dysfunction (NLUTD) was a leading cause of death after SCI [1]. Furthermore, NLUTD has a highly negative impact on patients’ quality of life (QoL). Acute SCI initially causes “spinal shock”, characterised by an acontractile/hypocontractile detrusor and urinary retention, which in case of a suprasacral lesion (today the vast majority of SCI) is followed by development of detrusor overactivity mostly combined with detrusor sphincter dyssynergia [2]. Antimuscarinics are the pharmacological first-line treatment for detrusor overactivity although the effectiveness is limited [3]. In addition, many patients discontinue antimuscarinics due to bothersome side-effects [4]. Thus, intradetrusor onabotulinumtoxinA injections have become an established, highly effective, minimally invasive, and generally well-tolerated therapy for refractory detrusor overactivity [5] to improve patients’ health and QoL [6]. Despite the popularity of intradetrusor onabotulinumtoxinA injections, the exact mechanisms of action remain to be elucidated. Nevertheless, it seems highly probable that, in addition to a direct efferent effect by blocking the presynaptic release of acetylcholine from the parasympathetic innervation resulting in temporary chemodenervation of the detrusor, onabotulinumtoxinA also modulates afferent pathways [7]. It is, however, not known whether this treatment can normalise alterations in supraspinal areas and whether supraspinal modulation correlates with clinical improvements.

The control of the lower urinary tract (LUT) is a complex, multilevel process that involves both the peripheral and central nervous system but the exact mechanisms involved in humans are still incompletely understood [8]. Neuroimaging studies over the last decade have consistently pointed to a complex supraspinal network that controls LUT function [9]. These studies tremendously increased our understanding of how human LUT function is coordinated and how it can be affected by neurological disorders. Recent neuroimaging studies demonstrated reorganisation of supraspinal activity in response to LUT stimulation tasks in patients with disorders such as Parkinson’s disease [10‐12] and SCI [13] as compared to healthy controls, which might represent the neural correlate of their NLUTD.

Cortical and sub-cortical (for example, brainstem) brain regions are essential for voluntary LUT control [9, 14, 15]. Investigation of the supraspinal regions with high-resolution imaging techniques, for example, structural magnetic resonance imaging (MRI) and functional MRI (fMRI), can significantly increase our knowledge on the effects of supraspinal lesions and alterations related to NLUTD [9, 16]. Although diffusion tensor imaging (DTI) [17] is popular in other fields in neuroscience, it has only been applied in the context of supraspinal LUT control in one prospective study [18] in patients with non-neurogenic LUT symptoms.

In this study, we will first identify supraspinal areas associated with LUT control in SCI patients with neurogenic detrusor overactivity and healthy controls. Subsequently, we will investigate the effects of intradetrusor onabotulinumtoxinA injections on supraspinal areas. Task-related blood oxygen level-dependent (BOLD) fMRI will be used along structural MRI (T1-weighted and DTI). Moreover, we will examine volumetric parameters (for example, grey and white matter concentration) by voxel- (VBM) [19] and tensor-based morphometry (TBM) [20], structural integrity and connectivity of white matter tracts (DTI) as well as structural (SC) and functional connectivity (FC).

This unique and detailed multimodal imaging and clinical approach will distinguish the different structural and functional processing units involved during supraspinal LUT control and will identify dysfunctional neuronal components in SCI patients responsible for neurogenic detrusor overactivity.

For a test-retest validation, we will additionally investigate the reliability [21] of BOLD signals in task-related fMRI in healthy controls by the intra-class correlation coefficient (ICC) for absolute or consistent agreement of participants activations over two visits.

This study will investigate structural and functional abnormalities and specific alterations in the brain networks of supraspinal LUT control in SCI patients with neurogenic detrusor overactivity compared to healthy controls using a multimodal imaging protocol. Importantly, effects on the supraspinal LUT control after treatment for neurogenic detrusor overactivity with intradetrusor onabotulinumtoxinA injections in SCI patients will be explored.

The findings will help to verify, amend, or adjust neuronal circuitry models established from findings in healthy controls, now in the context of SCI patients with neurogenic detrusor overactivity. Furthermore it will show whether neurogenic detrusor overactivity specific treatment such as intradetrusor onabotulinumtoxinA injections induce structural or functional reorganisation in supraspinal areas related to LUT control and in how far such changes correlate with improvements of clinical outcome parameters. These investigations will help us to understand how onabotulinumtoxinA modulates afferent pathways.

Advanced neuroimaging and evaluation techniques have the potential to serve as quantifiable outcome measures for therapy success and for improving our treatment strategies in this patient population.