A model based on the topology of neurones in the enteric nervous system has been developed to understand the nature of intestinal motor activity. The model is based on identical modules of neurones and circular muscle, whose connections and projections were derived from microanatomical studies carried out on the small intestine of the guinea-pig. This neuro-topological model can demonstrate some essential properties of intestinal motor activity

Brookes, Simon Jonathan

Costa, Marcello

Nazeran, Homer

Randhawa, Sharmil

Flinders Academic Commons

Proceedings of the 20th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, Vol. 20, No 6,1998 COMPUTER SIMULATION OF INTESTINAL MOTOR ACTIVITY S. Randhawal, H. Nazeran*, S.J.H Brookes** and M. Costa** *School of Engineering and **Centre for Neuroscience The Flinders University of South Australia, GPO Box 2100, Adelaide 5001, Australia “E-mail: Sharmil.Randhawa@ flinders.edu.au Abstract A model based on the topology of neurones in the enteric nervous system has been developed to understand the nature of intestinal motor activity. The model is based on identical modules of neurones and circular muscle, whose connections and projections were derived from microanatomical studies carried out on the small intestine of the guinea-pig. This neuro-topological model can demonstrate some essential properties of intestinal motor activity. Keywords Modelling, simulation, enteric nervous system, intestinal motor activity Introduction The enteric nervous system forms the third part of the autonomic nervous system. It may be defined as the system of neurones and their supporting cells that is found within the walls of the gastrointestinal tract, including the neurones within the pancreas and gall bladder [l]. Hence the gastrointestinal tract can be considered to have its own local nervous system which contains reflexes that control functions such as the secretion of gastric acid, the contractions of smooth muscle and the transport of water and electrolyte. Enteric neurones can be classified into three main functional groups [2] : 1. Sensory neurones which are sensitive to the wall tension (distension-sensitive) or the chemical content (chemo- sensitive) of the intestine. 2. Motor neurones which activate smooth muscle in the intestine. Excitatory motor neurones cause muscle to contract and whilst inhibitory motor neurones relax them. As well as these, there are secretomotor and vasomotor neurones . 3. Interneurones or associative neurones which form information links between enteric neurones. A major motor activity observed in the intestine is peristalsis. ‘It is a form of propulsion that exists when a wave of contraction propagates from the oral to aboral end of the intestine. This behaviour is controlled by the enteric nervods system, and does not depend on inputs from the rest of the nervous system[ 11. The “law of the intestine” [3] was coined by W.M. Bayliss and E.H. Starling at the turn of the century to describe what they observed while conducting investigations of peristalsis in anaesthetised dogs. They found that inserting a bolus of cotton wool into the lumen of the intestine provoked contraction orally and relaxation anally, thus propelling the bolus in an aboral direction. Today this is known as the peristaltic reflex and is made up of an orally directed excitatory reflex which causes the circular muscle to contract, and an anally directed inhibitory reflex which produces a relaxation of circular muscle. Method Principles of Modelling The aim of this model is to represent, as simply as possible, the projections of myenteric neurons, and use this representation of polarised projections of different functional classes of neurones to explain features of motor behaviour of the intestine. Cellular or membrane properties of neurons and smooth muscle are not included and synapses have been represented as excitatory or inhibitory, but no other synaptic properties are included. The model is based on a series of assumptions outlined below regarding the anatomy and physiology of the enteric nervous system. Myenteric ganglia of the guinea pig small intestine are approximately organised into a series of rows spaced approximately 0.4 - 0.5” apart and each row appears to contain all of the functional classes of neurones [4], Thus the enteric nervous system can be represented as a series of identical modules, each of which corresponds to all of the enteric neurones within a small ring of gut. Associated with each module is a ring of circular smooth muscle. Each module contains five functional subtypes which are likely to be involved in motor activity. These are excitatory motor neurones to the circular muscle (EMNs), inhibitory motor neurones to the circular muscle (IMNs), stretch-sensitive sensory neurones (SNs), ascending (orally-directed) interneurones (AINs) and descending interneurones (DINS). Each of these classes of neurones is represented within each module by a single composite neurone. In the model, the output connections of each composite neurone were distributed along a length of intestine in a manner consistent with the combined projections of the whole class of neurones rather than the output connections of any single enteric neurone. Sensory Neurones In the model, sensory neurones (SNs) are assumed to function as in-parallel stretch receptors to the circular muscle. That is 0-7803-5164-9/98/$10.00 0 1998 IEEE 3064 they detect the state of distension of the circular muscle. For example, the more distended the circular muscle, the faster their firing rate. Conversely, if the circular muscle is in a resting or contracted state, the sensory neurone does not fire. The sensory neurone projects locally to the other four functional classes of neurones (excitatory and inhibitory motor neurones, and ascending and descending intemeurones) in that module. Excitatory & Inhibitory Motor Neurones Excitatory motor neurones (EMNs) project to circular muscle of their own module and more oral modules whereas inhibitory motor neurones (IMNs) only project to circular muscle of more aboral modules. They do not project to their own module. Excitation of EMNs causes contraction of circular muscle, whereas excitation of IMNs causes circular muscle to relax. Ascending h Descending Interneurones Interneurones form information links between other enteric neurones. Ascending interneurones (AINs) project orally, synapsing onto other AINs and EMNs of more oral modules, whereas descending interneurones (DINs) project anally, synapsing onto other DINs and IMNs of more aboral modules. Each composite neurone was configured as a generic connectionist neuron, with a linear activation function over a range of input values, with a fixed threshold and an output which could vary continuously from 0 (no firing) to 1 (maximum firing). This is illustrated in figure 1. output (activity) summed inputs Figure 1 Activation function of postsynaptic neurone The strength of connections between composite neurones at any moment in time can be determined by three factors : 1. the degree of activation of the presynaptic neurone; 2. the number of projections from the presynaptic composite neurone to the post synaptic composite neurone, which was loosely based on the quantified projections of different classes of neurones established using retrograde labelling techniques [5 ] ;  3. an assigned weight of synaptic connection between the presynaptic and postsynaptic composite neurone. Circular Muscle In this model, it is proposed that the state of the circular muscle is dependent on four main factors, namely intraluminal pressure, muscle length, wall tension and summed neuronal input (excitation and inhibition). It is well established that the tension developed by smooth muscle is approximately exponentially related to its length [6]. This length-tension curve of the model is influenced by the excitation or inhibition of the muscle, as shown in figure 2. Excitation by nerves would make the muscle less compliant, which is represented as a shift to the left of the length-tension curve, whereas inhibition is represented as a right shift. Different degrees of excitation or inhibition would be represented by an infinite series of interposed curves between the extremes of total excitation and inhibition of the muscle. The relationship of pressure to wall tension is derived from Laplace's Law (tension a intraluminal pressure x radius). Since muscle length (circumference) is proportional to radius, pressure can be represented as a straight line on the axes of length and tension with a gradient proportional to pressure. The intersection of this straight pressure line and the particular length tension curve gives the tension and length of the circular muscle at a particular level of excitation or inhibition and pressure. Tension total zero total 4 excitation net input inhibition circular muscle length Figure 2 Length-tension curves for smooth circular muscle The Enteric Neural Network The information about the projections of enteric neurones generated from physiological studies makes it possible to develop a model of the enteric circuitry involved in peristalsis, as shown in figure 3. 3065 I I MODULE N - 1  MODULE N+l I I  ORAL MODULE N Figure 3 Model of the enteric neural network ANAL Simulation of the Model The model ran as a series of iterations made up of the following steps: Stimulation of the model was simulated by either raising intraluminal pressure, by inflating a balloon (by clamping circular muscle length in a number of modules to a preset stretched value), or by electrical stimulation (setting the activity of all neurones with axons in a particular module to a predefined level for one iteration). The state of the circular muscle in each module was then used to determine the activity level of sensory neurones within that module. This was then converted to an input to other composite neurones contacted by the sensory neurone and added to inputs generated by other classes of cells in the same iteration. The output of each composite neurone was then calculated. The inhibitory and excitatory inputs to the circular muscle were then summed and used to calculate the new muscle length, using the appropriate length-tension curve, at the end of the iteration. The duration of each iteration was set by the slowest event which was taken to be the development of force by the muscle in response to neuronal input, giving an approximate iteration duration of 200-1000 ms. It is clear from biological studies that synaptic connections occur with a considerably faster time course than the duration of one iteration. Hence the use of subiterations were introduced in interneuronal pathways to represent fast interactions to be more accurately represented in each slow iteration. This was not necessary for outputs from motor neurones as they were of slow time course due to the dynamics of muscle contraction. Results Peristalsis was simulated in an intestine of 100 modules by raising intraluminal pressure above a certain threshold value, which caused a passive distension of the modelled intestine. This resulted in excitation of the oral modules and inhibition in the aboral modules of the intestine. A lumen-occlusive contraction was evoked at the oral end and this propagated to the aboral end in subsequent iterations, as seen in figure 4. The contraction, however, never fully invaded the aboral end of the intestine. oral aboral Figure 4 Simulation of intestinal peristalsis The standing (ascending and descending) reflexes were investigated in a intestine of 100 modules by inflating a balloon in the middle of the intestine. This was done by setting the circular muscle length in modules 40 to 50 to a pre-defined fixed value. Intraluminal pressure in this simulation was set to zero. Figure 5 shows a typical example of a balloon inflation. This stimulus evoked contraction oral 3066 to the balloon and inhibition aboral to the balloon. Both diminished with increasing distance from the balloon. The muscle in the region of the balloon was found to be under a net inhibition. These polarised responses developed rapidly and neither spread nor decayed for the duration of the stimulus. It was found that increasing the balloon diameter evoked increasing graded responses in the muscle oral and aboral to the simulated balloon. oral aboral Figure 5 Simulation of standing reflexes In the case of electrical stimulation, this was simulated by activating transiently all neurones with processes or cell bodies in a module in the middle of a 100 moduled intestine. Again the intraluminal pressure was set to zero. Figure 6 shows the typical response from such a simulation. The stimulus evoked excitation of the circular muscle well oral to the stimulus point and inhibition extending for many modules aboral to the stimulus point. Both of these declined with distance. It was also found that there existed a net inhibition for several modules oral to the site of stimulus. stimulation point 4 oral aboral Figure 6 Simulation of electrical stimulation Discussion A model of the small intestine was developed based on the known topological projections of enteric neurones. It was designed to explore the relationship of enteric neurones and smooth circular muscle in order to account for motor activity observed in the intestine. The model did not take into account the neuronal, muscular and synaptic properties of the intestine, however its simplistic approach has demonstrated that the propulsive behaviour of the intestine can be related to the polarised projections of inhibitory and excitatory motor neurones. This was clearly observed in the simulations of the standing reflexes and electrical stimulation. The model showed that the known polarized projections of enteric neuronal pathways which underlie the ascending excitatory and descending inhibitory reflexes in the small intestine, can account for peristaltic motion which begins at the oral end of the distended piece of intestine. The model also accounted for the aboral propagation of the contraction and the failure of the contraction to invade the most aboral segment of the intestine. These are all characteristics of peristalsis as recorded in vitro[7]. It should be noted that the model failed to replicate the all-or-nothing phenomena of peristalsis as documented by Tonini et a1[8]. In all simulations, peristalsis began in a graded fashion, whereas in biological preparations, it starts at one point in an all-or-nothing manner when preparations are gradually distended. However despite the omission of some complex properties of smooth muscle and neurones, this simple model can simulate the essential features of peristalsis successfully. Conclusion A neuro-topological model of the enteric nervous system has been developed to simulate some of the fundamental properties of motion as observed in the intestine. Using the known projections of enteric neurones, this model can predict the initiation of peristalsis at the oral end of a segment of intestine, and its propagation to the aboral end. Further features need to be incorporated into this model, in particular a more realistic representation of smooth muscle contractility and nerve activity. References [l]  J.B. Furness & M. Costa - The Enteric Nervous System, Churchill Livingstone, Edinburgh, 1987. [2] S.A. Waterman - The neuronal basis of intestinal peristalsis, PhD. dissertation, The Flinders University of South Australia, 1994. [3] W.M. Bayliss. & E.H. Starling - The movements and innervation of the small intestine, Journal of Physiology, [4] M. Costa, S.J.H. Brookes, P.A. Steele, I.J. Gibbons, E. Burcher and K.J. Kandian - Neurochemical classijication of myenteric neurons in the guinea-pig small intestine, Neuroscience, vol. 75, pp 949-967, 1996. [5] S.J.H. Brookes, P.A. Steele & M. Costa - Zdent$cation and immunohistochemistry of cholinergic and non- cholinergic circular muscle motor neurons in the guinea-pig small intestine, Neuroscience, vol 42(3), pp [6] W.A. Weems - Am J Physiol, vol 243, pp G177-G188, 1992. [7] S.A. Waterman, M. Costa and M. Tonini - Accommodation mediated by enteric inhibitory reflexes in the isolated guinea-pig small intestine, J Physiol Lond, vol. 474, pp 539-46, 1994. [8] M. Tonini, M. Costa, S.J.H. Brookes and C.M.S. Humphreys - Dissociation of the ascending excitatory reflex from peristalsis in the guinea-pig small intestine, Neuroscience in press, 1996. V O ~ .  24, pp 99-143, 1899. 863-878, 1991. 3067 

Computer simulation of intestinal motor activity

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Computer simulation of intestinal motor activity

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