JCJC SVSE 1 - JCJC - SVSE 1 - Physiologie, physiopathologie, santé publique

Effect of sacral nerve stimulation on central and enteric nervous system – SacralNeurostim

Submission summary

Fecal incontinence is a distressing condition defined as the involuntary discharge of liquid or solid stools. Fecal incontinence is a worldwide public health burden with a prevalence of 2-15% in adult patients, resulting in a cost of more than $400 million per year in United States. The first step of fecal incontinence management is represented by conservative therapies aiming either to improve anal contraction by behavioral therapy, or to delay colorectal transit with anti-diarrheal medication. However, approximately 50% of patients fail to respond to medical treatment.
In the past few years, sacral nerve stimulation (SNS) has provided a new and alternative surgical treatment of medically refractory patients. In fact, SNS has been used for more than 10 years for the treatment of incontinence due to urinary bladder hyperactivity. SNS is performed by stimulating one sacral nerve root (usually S3 or S4) using a bipolar electrode implanted in the sacral foramen. A recent French multicenter controlled study has confirmed the clinical efficacy and cost effectiveness of SNS with a success rate in the region of 70-80%. Although the indications for SNS are constantly widening, mechanisms of action of this treatment remains to date poorly understood.
Previous reports demonstrated that symptomatic improvement observed after SNS was not related to increased striated anal sphincter contraction. Recent evidence suggests SNS has an effect on lower gut afferent nerves that may in turn impact on the on the autonomic nervous system activity. We recently showed in a cat model that SNS inhibited colonic phasic activity while increasing anal internal sphincter tone through the increased sympathetic outflow. Ultimately, this could explain symptomatic improvements observed in patients during SNS, with a decrease in bowel movement frequency, and stool hardening. In addition, these results strongly suggest that SNS recruits long-loop reflexes acting on brain centres. Beside central nervous system (CNS), colorectal motility is also under the control of the enteric nervous system (ENS) organized into myenteric and submucosal plexi. The goal of this project is to decipher the central and peripheral mechanisms involved during SNS and their modulation of lower gut afferents which lead to decrease colorectal motility and hence improvement in fecal incontinence.
The primary objective of the present project is to demonstrate that SNS affects brain centres that process visceral sensitivity and govern colonic motility. To achieve this aim, we will use an anesthetized then a conscious rat model with SNS and carry out neuroanatomical studies within the brain to identify SNS-activated nuclei.
The second aim of this project is to assess if SNS modulates visceral sensitivity directly. This will be achieved by performing colorectal distension in an anesthetized then a conscious rat model with SNS, and monitor the pseudoaffective reflex as a pain response
The final aim of this study is to determine whether SNS can decrease colorectal motility and modulate the ENS both in rats and patients. In rats, the effect of SNS on colonic motility will be investigated in anesthetized then conscious models by miniaturized manometry. The effect of SNS on neuronal activation will be studied in colonic myenteric and submucosal plexi in rats and in patients, before and after treatment with SNS. Additionally, ENS phenotyping might reveal differences or changes correlated either with patient basal evaluation or patient response to SNS.
Identification of mechanisms of action of SNS will be useful in determining objective and molecular markers which may predict the effect of SNS. This is invaluable in the better selection of patients for SNS implantation. In addition, results from this study may bring preclinical data which may extend the role of SNS to areas such as irritable bowel syndrome, a condition characterized by altered colorectal sensitivity and motility.

Project coordination

Guillaume GOURCEROL (Université)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

Help of the ANR 297,442 euros
Beginning and duration of the scientific project: January 2012 - 48 Months

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