Does Spike-Time Dependant Plasticity Occurs in Dorsal Horn Neurons

Does spike-time dependent plasticity occur in dorsal horn neurons? An approach to chronic pain modeling

Aydin Farajidavar1, Shahriar Gharibzadeh1, Farzad Towhidkhah2, Parisa Hasanain3, Mohsen Parviz4

1 Neuromuscular Systems Laboratory, Faculty of Biomedical Engineering, Amirkabir University of Technology (Tehran Polytechnic ); 2 Biological Systems Modeling Laboratory, Faculty of Biomedical Engineering, Amirkabir University of Technology (Tehran Polytechnic); 3Biology department, Basic sciences college, BuAli Sina University, Hamadan, Iran; Department of Physiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran..

Keywords: wind-up; Aβ fiber; C fiber; depression; pain relief; STDP; TENS

Summary

Activity-dependent synaptic modification is critical for the development and functioning of the nervous system. Recent experimental discoveries suggest that both the extent and the direction of modification may depend on the precise timing of pre- and postsynaptic action potentials (spikes). This phenomenon, termed spike timing-dependent plasticity (STDP), provides a new, quantitative interpretation of Hebb’s rule and raises intriguing questions regarding the fundamental processes of cellular signaling. In this regard, STDPof dorsal horn neurons in spinal cord has gained little attention and no obvious interpretation is discussed about it. In this regard, STDP of dorsal horn neurons has gained little attention. On the other hand, there are two phenomena in hyperalgesic state pain, Aβ wind up and pain depression following Aβ fiber electrical stimulation (PDFESTENS), that we think are a form of STDP in spinal cord. Aβ wind up is a form kind of potentiation and Aβ pain depression PDFES TENS is a form kind of depression and both occurs with the electrical stimulation of Aβ fibers under different frequencies. Our new hypothesis tries to describes the STDP synaptic timing relation characterisitics of these phenomena. ModelSimulatiing wind-up potentiation and TENS pain depression with ourthis hypothesis by means of and with the use of ANN that has dynamic synapses models would properly lead to modeling chronic pain modeling. Furthermore, it seems that our results can be used to we can optimize transcutaneous electrical nerve stimulation (TENS) stimulation frequency for better pain relief. Surely, It is worth noting that fFfuture clinical studies are needed to validate these predictions.

INTRODUCTION

Rational treatment of chronic pain depends on understanding of the pathophysiological mechanisms underlying the various characteristics of chronic pain, among which central sensitization has received great attention in recent years. The experimental models used to explore mechanisms of central sensitization include the study of wind-up in animals and temporal summation of pain in humans. Temporal summation of repeated painful stimuli has been regarded as a psychophysical correlate of wind-up in humans [4]. Wind-up is described traditionally as a frequency dependent increase in the excitability of spinal cord neurons, evoked by electrical stimulation of afferent C-fibers. Although it has been studied over the past thirty years, there are still uncertainties about its physiological meaning [5]. It is worth noting that different kinds of wind-up have been proposed by researchers. The wind-up of dorsal horn neurons is usually evoked by C-fiber and occasionally by Aδ- fiber stimulation [9]. A novel type of wind-up has been evoked by the stimulation of Aβ fibers in hyperalgesic states induced by peripheral injury or inflammation [14, sprouting]. A new hypothesis of Aβ wind-up claims that, after nerve injury or inflammation for at least 20 h, Aβ fibers sprout to more superficial lamina where they may contact nociceptive neurons [7]. ]. Aβ wind up was observed with trains of stimuli applied at 1 Hz, but not at 0.3 or 0.1 Hz, indicating that the Aβ wind up has the same frequency dependence as C-fiber evoked wind up [5]. In addition, Several authors have reviewed the electrophysiological and behavioral data indicating a significant role of NMDA (N-methyl-D-aspartate) (NMDA) receptor in wind-up [3,16].Therefore, Wind-up is a lastinglong-lasting phenomenon that resemblesresembles a potentiation in dorsal horn. Several authors have reviewed the electrophysiological and behavioral data indicating a significant role of NMDA (N- methyl-D-aspartate) receptor in wind-up [3,16]. Furthermore, the introduction of the gate control theory of pain by Melzack and Wall in 1965 provided a convincing theory about the nature of pain and offered a theoretical basis for the effectiveness of transcutaneous electrical nerve stimulation (TENS) in the treatment of pain relief. The theory suggests that stimulating large myelinated primary afferent fibers will inhibit input from nociceptive primary afferent fibers through neurons located in the spinal cord dorsal horn. TENS at the parameters used clinically is expected to activate large afferent fibers. Inflammation or tissue injury produces increased input from small diameter fibers to the spinal cord. Therefore, it would follow that the use of TENS would inhibit pain perception by stimulating the large sensory nerve fibers, thereby inhibiting the spinal cord events of small nociceptive nerve fibers. TENS stimulation frequency is about 4 Hz (low frequency) or 100 Hz (high frequency), which is different withfrom the Aβ wind up frequency [Ellen]. Altogether, this stimulation ( TENS) would cause depression in dorsal horn and NMDA receptors are responsible for this depression. [R? sandkuhler].

Synaptic plasticity consists of any changes in the synaptic connections between neurons, including strengthening and weakening of synapses, changes in the distribution of receptor proteins and postsynaptic signal transduction mechanisms, and even changes in the number and distribution of synapses formed between pairs of neurons. One kind of synaptic plasticity, Spike timing-dependent plasticity (STDP), is characterized by synaptic weight changes that depend on the precise timing of spikes fired by pre- and post-synaptic cells. Figure 1 illustrates a pairing experiment with cultured hippocampal neurons where the (f) presynaptic neuron (j) and the postsynaptic neuron (i) are forced to fire spikes at time tj (f) and ti , respectively (Bi and Poo, 1998). The resulting change in the synaptic efficacy Δwij after several repetitions of the experiment, turns out to be a function of the spike (f) (f) time differences tj -ti (`spike-time dependent synaptic plasticity').. The amplitude and even the direction of the change depend on the relative timing of presynaptic spike arrival and postsynaptic triggering of action potentials [].Most notably, the direction of the change depends critically, i.e., on a millisecond time-scale, on the relative timing of pre- and postsynaptic spikes. The synapse is strengthened if the presynaptic spike occurs shortly before the postsynaptic neuron fires, but the synapse is weakened if the sequence of spikes is reversed.

As noted in Section 3.1, LTP can be induced by pairing PSPs in specific synapses with generation of an AP in the postsynaptic neuron. To be effective, this pairing must occur within a narrow time window, with the AP occurring within 20 ms after the PSP. If, on the other hand, the AP occurs less than 20 ms before the PSP, LTD is induced instead (Magee and Johnston, 1997; Markram et al., 1997; Sjostrom and Nelson, 2002). This phenomenon, referred to as spike-timing-dependent plasticity (STDP) is consistent with the idea of a Hebbian synapse in that a PSP is only likely to contribute to generation of an AP when it occurs immediately before the AP (Bi and Poo, 2001). Occurrence of a PSP milliseconds after an AP instead indicates that the presynaptic neuron is not effectively synchronized with the circuits which are effective in triggering an AP in the postsynaptic neuron.

On the other hand, there are many researches, which discuss different aspects of Spike- Time Dependent Plasticity (STDP) in different kinds of neurons especially in cortex. STDP notifies that synaptic efficacy is driven by temporal correlations between presynaptic spike arrival and postsynaptic firing. The amplitude and even the direction of the change depend on the relative timing of presynaptic spike arrival and postsynaptic triggering of action potentials []. In this paper, we consider both Aβ wind-up potentiation and TENS PDFES and try to depression to explain why different frequencies of electrical sitmulation nerve afferents mechanisms (presynaptic spikes) and postsynaptic action potentialsinduces this synaptic plasticity of the dorsal horn neuron. We intend to show on dorsal horn neurons, which cause a that more or less a form of STDP exists in dorsal hornthe spinal cord.

The HYPOTHESIS

In this theory we assume a C fiber as j neuron (presynaptic) and dorsal horn neuron as i (postsynaptic). In the case of wind-up, presynaptic spikes from Aβ fibers cause a fast depolarization on dorsal horn neuron, this depolarization cannot lead to any postsynaptic spike firing and action potential of the dorsal horn, but it up-regulates the NMDA receptors which are located on dorsal horn. Then a spike from C fiber fires, this spike plays the role of the presynaptic firing. Occurrence of this spike in the presynaptic space with the help of up- regulated NMDAR would trigger a postsynaptic action potential. If we name the C fiber as j (like above) and dorsal horn neuron as i, we observe that the similar things happen and cause potentiation. This is absolutely compatible with the potentiation process of STDP and cause the potentiation in the synapse between C fibers and the dorsal horn neuron. Therefore, painful stimuli from C fibers would strengthen and wind-up happens. Then the second messenger which is the presynaptic spikes from C fibers causes In the case of TENS depressionPDFES presynaptic Spikes from Aβ fibers cause triggering of action potential in dorsal horn neuron hence the post synaptic fires. This firing down regulates the NMDA receptors, so when the spikes from C fibers receive to the synapses between C fibers and dorsal horn (presynaptic spikes) this synapse would depress. Thus, painful stimuli from C fibers weaken and pain relief happens. As it is apparent, stimulations with different frequencies to the same fibers lead to different phenomena. We think this is because of different spike timing which occurs on the synapse of dorsal horn neuron. The HYPOTHESIS

For the purpose of simplicity, we call the afferent C fiber as "j" neuron and the dorsal horn neuron as "i". In the case of wind-up, presynaptic spikes from Aβ fibers cause a fast depolarization in the dorsal horn neurons. This depolarization cannot lead to any postsynaptic action potential in the dorsal horn, but up-regulates the NMDA receptors, which are located on the dorsal horn. Then, spikes from C fiber excite the dorsal horn neuron. In other words, it plays the role of presynaptic firing. The occurrence of this spike in the presynaptic space with the help of up-regulated NMDA receptors would trigger a postsynaptic action potential. If we name the C fiber as j (like above) and dorsal horn neuron as i, we observe that similar events, compatible with a classic STDP happens in wind up. Therefore, painful stimuli from C fibers would strengthen and induce wind-up. In the case of TENS, depression presynaptic Spikes from Aβ fibers cause triggering of action potential in dorsal horn neuron hence the post synaptic fires. This firing down regulates the NMDA receptors, so when the spikes from C fibers receive to the synapses between C fibers and dorsal horn (presynaptic spikes) this synapse would depress. As it is apparent, stimulations with different frequencies to the same fibers lead to different phenomena. We think this is because of different spike timing which occurs on the synapse of dorsal horn neuron. Consequences of hypothesis Recently, there has been a substantial advance in the neurophysiological studies on synaptic plasticity, mainly exploring a function of the relative timing between the pre and post-synaptic spikes (reviewed in [1,8]). Consequently, research in computational modelling has build upon that and derived synaptic plasticity rules capable of tuning neurons to respond to specific spatio-temporal input patterns [2–6]. Temporal relationships between neuronal firing and plasticity have received significant attention in recent decades. Neurophysiological studies have shown the phenomenon of spike-timing-dependent plasticity (STDP). Various models were suggested to implement an STDP-like learning rule in artificial networks based on spiking neuronal representations.

Modeling wind-up with the STDP hypothesis can ensue to the modeling of chronic pain with artficial neural networks that are dynamics and use dynamic weights. In this regard the weights of the artificial neural network (ANN) should be a function of input neuron and output neuron and weights do not fix even after training. On the other hand using STDP models for TENS can lead to manage better frequencies for TENS. With this modeling you can tune TENS frequency with regards to timing of potentiation and depression. References [3] Dickenson A. Mechanisms of central hypersensitivity: excitatory amino acid mechanisms and their control. In: Dickenson A, Besson JM, editors. The pharmacology of pain. Berlin: Springer-Verlag; 1997. p. 167–210. [4] Eide PK. Wind-up and the NMDA receptor complex from a clinical perspective. Eur J Pain 2000;4:5–17. []Ellen W. King and Kathleen A. Sluka The Effect of Varying Frequency and Intensity of Transcutaneous Electrical Nerve Stimulation on Secondary Mechanical Hyperalgesia in an Animal Model of Inflammation The Journal of Pain, 2001

[5] Herrero JF, Laird JM, Lopez-Garcia JA. Wind-up of spinal cord neurons and pain sensation: much ado about something? Prog Neurobiol 2000;61(2):169–203. []Macefield, G, Burke, D (1991) Long-lasting depression of central synaptic transmission following prolonged highfrequency stimulation of cutaneous afferents: a mechanism for post-vibratory hypaesthesia. Electroencephalography and Clinical Neurophysiology 78: 150–158. []Nilsson HJ, Psouni E, Schouenborg J. Long term depression of human nociceptive skin senses induced by thin fibre stimulation Eur J Pain 2003;7(3):225-33. [9] Price DD, Hull CD, Buchwald NA. Intracellular responses of dorsal horn cells to cutaneous and sural nerve A and C fiber stimuli. Exp Neurol 1971;33:291–309. []Sandkühler, J (2000) Long-lasting analgesia following TENS and acupuncture: Spinal mechanisms beyond gate control. In: Devor, M, Rowbotham, MC, Wiesenfeld-Mallin, Z (eds) 9th World Congress on Pain: Progress in Pain Research and Management, vol. 16. IASP, Austria, pp 359–369. []Sandkühler, J, Chen, JG, Cheng, G, Randic, M (1997) Lowfrequency stimulation of afferent Aδ-fibers induces longterm depression at primary afferent synapses with substantia gelatinosa neurons in the rat. Journal of Neuroscience 17: 6483–6491. [14] Thompson SWN, Dray A, Urban L. Injury-induced plasticity of spinal reflex activity: NK1 neurokinin receptor activation and enhanced A- and C-fiber mediated responses in rat spinal cord in vitro. J Neurosci 1994;14:3672–87. [16] Willis WD, Sluka KA, Rees H, Westlund KN. Cooperative mechanisms of neurotransmitter action in central nervous sensitization. Prog Brain Res 1996;110:151– 66. []Wulfram Gerstner and Werner M. Kistler Spiking Neuron Models Single Neurons, Populations, Plasticity Cambridge University Press, 2002

The most famous rule of synaptic modification was proposed by Donald Hebb [1]: ‘‘When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A’s efficiency, as one of the cells firing B, is increased.’’ This ‘‘neurophysiological postulate’’ has since become a