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S. M. Danner, F. Rattay, U. Hofstötter, W. Mayr, K. Minassian:
"Modelling locomotor pattern generating networks of the human lumbar spinal cord";
Talk: International Symposium on Spasticity and Neural Control of Movement with the 30th Dr. Janez Faganel Memorial Lecture, Ljubljana, Slovenia (invited); 2014-09-04 - 2014-09-06; in: "International Symposium on Spasticity and Neural Control of Movement with the 30th Dr. Janez Faganel Memorial Lecture: Program and Proceedings", J. Zidar (ed.); Section for Clinical Neurophysiology of the Slovenian Medical Association, Ljubljana, Slovenia (2014), ISBN: 978-961-6956-04-8; 60 - 61.

The existence of locomotor pattern generating neural networks in the human lumbar spina lcord is meanwhile well accepted. Yet, little is known about their organization. Epidural stimulation of the lumbar spinal cord can produce rhythmic activities in the paralyzed lower limbs (1), consisting of amplitude-modulated trains of single stimulus-triggered responses, the posterior root-muscle reflexes (2). Their phase-dependent modulation gives insight into the operation of the neural circuits involved in generating rhythmicity. Here we present a computer model incorporating characteristic features of rhythmic activity in response to epidural stimulation.

The model was designed with following constraints and goals: i) motor outputs consist of stimulus triggered responses and are driven by pulsed spinal cord stimulation, ii) repetitive afferent inputs via spinal cord stimulation within certain frequency ranges induce characteristic motor outputs, i.e., 20 to 50 Hz induces rhythmicity, 5 to 15 Hz sustained extension, tonic activity, and < 5 Hz does not activate the interneurons in a way that modulates responses, iii) investigation of sub-threshold influence of the interneuron pools as a potential cause for rhythmic modulation of reflex responses, iv) de-selection of alternative pathways as a cause for increased reflex latencies (2), v) investigation of the role of presynaptic inhibition, vi) investigation of persistent sodium currents (INaP) as a possible source for rhythm generation in the human and vii) conformance with contemporary views on rhythm and pattern generating circuits in the mammalian spinal cord (3, 4).

The modeled network consists of various classes of neurons with Hodgkin-Huxley-like membrane dynamics, including a pattern generating half-center model, Ia inhibitory interneurons and Renshaw cells as well as motoneurons (5). Furthermore, presynaptic inhibition of the afferents synapsing on the motoneurons and disinhibition of an additional central pathway
on the flexor half-center as well as conduction delays were incorporated.

Pulsed stimulation can activate pattern-generating centers. Their frequency dependent activation matches electrophysiological recordings (cf. 1, 2). Rhythmic activity can be produced by bursting and non-bursting neurons. Stimulus-coupled responses can be explained by the high synchronicity and relatively high efficacy of the influence of the afferent
excitatory postsynaptic potential volleys. In the extension half-center, direct afferent connections play a dominant role in exciting motorneurons as suggested by constant response latencies. The existence of a mono- and a separate oligosynaptic pathway with presynaptic inhibition of the afferent fibers of the flexor half-center synapsing on the motoneurons explains the substitution of the short latency responses by prolonged ones. Hypothetical INaP sufficiently reproduced the observed data.

The pulsed nature of the stimulation, providing a causal relation between input and output, along with the computer simulation of the processing network revealed components of the organization of the locomotor pattern generating networks in humans.

References
1. Dimitrijevic MR, Gerasimenko Y, Pinter MM. Evidence for a spinal central pattern generator in humans. Ann NY Acad Sci 1998; 860: 360-76.
2. Minassian K, Persy I, Rattay F, Pinter MM, Kern H, Dimitrijevic MR. Human lumbar cord circuitries can be activated by extrinsic tonic input to generate locomotor-like activity. Hum Mov Sci 2007; 26: 275-95.
3. Zhong G, Shevtsova NA, Rybak IA, Harris-Warrick RM. Neuronal activity in the isolated mouse spinal cord during spontaneous deletions in fictive locomotion: insights into locomotor central pattern generator organization. J Physiol 2012; 590 (19): 4735-59.
4. Hägglund M, Dougherty KJ, Borgius L, Itohara S, Iwasato T, Kiehn O. Optogenetic dissection reveals multiple rhythmogenic modules underlying locomotion. PNAS 2013; 110 (28): 11589-94.
5. Rybak IA, Shevtsova NA, Lafreniere-Roula M, McCrea DA. Modelling spinal circuitry involved in locomotor pattern generation: insights from deletions during fictive locomotion. J Physiol 2006; 577 (2): 617-39.

http://www2.kclj.si/ikn/DEJA/FAGA/Zborniki/Zbornik2014.pdf

Project Head Frank Rattay:
Life Sciences - Linking Research and Patients' Needs Augmentation of residual neural control by non-invasive spinal cord stimulation to modify spasticity in spinal cord injured people