Neuroscience Letters 557 (2013) 135–137

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Facilitation of late somatosensory evoked potentials by electrical train stimuli I. Zakharova, M.E. Kornhuber ∗ Department of Neurology, Universitätsklinikum Halle (Saale), Ernst-Grube-Straße 40, 06120 Halle (Saale), Germany

h i g h l i g h t s • • • • •

Late somatosensory evoked potentials (LSEP) reflect cerebral information processing. LSEP were facilitated by electrical train stimuli over the sensory radial nerve. Facilitation was inversely related to the within train interstimulus interval. LSEP refractoriness/habituation depended on the stimulus repetition rate. Train stimuli may contribute to characterise the cerebral synaptic plasticity.

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Article history: Received 7 August 2013 Received in revised form 9 October 2013 Accepted 17 October 2013 Keywords: Late somatosensory evoked potentials Electrical train stimuli Interstimulus interval Facilitation Habituation Synaptic plasticity

a b s t r a c t Somatosensory evoked potentials (SSEP) may reflect synaptic events and could be suitable to characterise the short-time plasticity of synaptic potentials (SP). For this purpose, the left superficial radial nerve was stimulated in 7 subjects with single or trains of 3 stimuli (C4 against Fz, time interval 500 ms, 1 Hz or 0.4 Hz). The within train interstimulus intervals (ISI) were varied from 2 ms to 10 ms. N20, N1 and N2 displayed a significant gain in amplitude following train stimuli compared with single stimuli. Short ISIs of 2–4 ms led to higher amplitudes of N20, N1 and N2 compared with longer ISIs of 7–10 ms. In general, larger amplitude values were observed with 0.4 Hz stimulus repetition compared with 1.0 Hz. This data reflects synaptic facilitation and refractoriness/habituation. Our results could be helpful to noninvasevely investigate synaptic decay dynamics by late SSEP in diseases of the central nervous system such as migraine or epilepsy. © 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Afferent sensory nerve fibres generate synaptic potentials (SP) at pyramidal cells in the sensory cortex [8,15]. These SP lead to extracellular volume currents that can be detected by surface electrodes as evoked potentials (EP). Therefore, EP may somehow reflect synaptic events. In recent years, the role of synapses and dendrites involved in neuronal information flow have been investigated in some detail [1,4,10]. However, as far as we can see no attempts have been made to gather information about SP in awake human subjects. In the present investigation, we aimed to approach this question by way of studying somatosensory EP. Train stimuli may be especially useful for this purpose as they are well known to induce temporal summation of synaptic potentials [7]. Therefore,

we made use of train stimuli here. This approach may be interesting also since action potential (AP) trains with very short within-train interstimulus intervals (ISIs) below 10 ms seem to play a role in physiological processing of sensory information in the brain [13]. Train stimuli are composed of several single stimulus components. Their within-train ISI can be altered systematically. Thereby, differences in the delay of the elicited APs arise together with according SP-intervals at target neurons. E.g. short ISIs may be associated with strong summation of synaptic potentials [7]. Therefore, we expect that the variation of the within train ISI may give information about the shape of SP involved in the formation of EP. Shorter ISI values should lead to stronger temporal summation compared to longer ISI values. Our results show that features of the short-term synaptic plasticity can be investigated by this way. 2. Material and methods

∗ Corresponding author at: Klinik und Poliklinik für Neurologie, Universitätsklinikum Halle (Saale), Ernst-Grube-Straße 40, 06120 Halle (Saale), Germany. Tel.: +49 345 557 3340; fax: +49 345 557 3335. E-mail address: [email protected] (M.E. Kornhuber). 0304-3940/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neulet.2013.10.039

Seven healthy adult subjects (4 females, 3 males; age 21–32 years) were included in the experiment after they had given their informed consent in accordance with the Helsinki declaration. The

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Fig. 1. Representative recordings of somatosensory evoked potentials, i.e. N20, N1 and N2, recorded over C4 against Fz after single and train stimuli over the left superficial radial nerve during the same session at a stimulus repetition rate of 0.4 Hz. After train stimuli, amplitude values of all SEP components were larger than after single stimuli. When the interstimulus interval (ISI) of train stimuli was stepwise spreaded from 2 ms to 10 ms, the amplitudes of all SEP components declined.

results from 2 further subjects were excluded from further analysis since the late SSEP components N1 and N2 displayed low amplitudes. Subjects were in a comfortable supine position. They were asked to keep eyes open and to fix a given point at the ceiling. First, they were made familiar with the different electrical stimuli. Supramaximum electrical 0.2 ms rectangular stimuli were delivered over the left superficial radial nerve at the wrist as either single or trains of 3 stimuli at a repetition rate of 1 Hz or 0.4 Hz. Supramaximal stimulation was achieved by monitoring the amplitude of the compound sensory action potential caudal to the lateral malleolus against a reference over the lateral malleolus. 2 mA were added to the stimulus strength when maximum amplitude responses were obtained. Supramaximal stimuli were in the range of 9–12 mA. For train stimuli, the following within train interstimulus intervals (ISI in ms) were investigated: 2, 2.5, 3, 4, 5, 6, 8, 10. Recordings were obtained by a Multiliner Economy (Natus, Höchberg, Germany) over C4 against Fz with the mastoid ipsilateral to the stimulus as the ground position. Electrode impedances were kept below 5 k. EEG-signals were sampled at 4000 Hz after band-pass filtering (0.05–50 Hz) 50 ms before and 450 ms following stimulus onset. Sixty single traces were averaged. For each experimental condition, 2 average curves were taken in order to judge reproducibility. An average curve containing a total of 120 single curves was derived from both these curves. This final average curve was used to evaluate latency values of N20, N1, N2. Furthermore, peak-to-peak amplitude values were measured on screen for N20P25, N1-P1, P1-N2. These amplitude values are referred to as N20, N1, N2, respectively. N20 was identified within 18–22 ms after the stimulus. N1 presented as a large negativity, usually peaking after 70 up to 115 ms after the stimulus. N2 was identified as the second large negativity following N1, usually between 170 and 250 ms following the stimulus. Friedman’s ANOVA was used to test for statistical significance. Post hoc analysis was done with Wilcoxon’s test. Experiments were performed in the morning from 9 to 11 o’clock. 3. Results Typical recordings are shown in Fig. 1. All the SEP components critically depended on the stimulus parameters (Fig. 2). After train

Fig. 2. Box plots displaying the results obtained the amplitudes of N20 (A), N1 (B) and N2 (C) after single and trains of 3 stimuli delivered at 1 Hz (hatched boxes) or at 0.4 Hz. Note the increase of amplitude values after train stimuli compared with single stimuli, especially when short ISI values of 2–4 ms were used (p < 0.05 stimulus repetition rate 1.0 Hz and 0.4 Hz; Wilcoxon’s test) while facilitation faded when the ISI was increased. When the stimulus repetition rate was increased from 0.4 s–1 to 1.0 s–1 , the amplitudes of all the SEP components tended to decrease. This influence reached statistical significance only in the case of N2 (C; p < 0.05).

stimuli, the amplitudes of N20, N1 and N2 were significantly larger than after single stimuli (p < 0.05 stimulus repetition rate 1.0 Hz and 0.4 Hz; Wilcoxon’s test). This gain in amplitude depended on both, the within train ISI and the stimulus repetition rate. A prominent

I. Zakharova, M.E. Kornhuber / Neuroscience Letters 557 (2013) 135–137

increase in the amplitude values of all the investigated SEP components was seen with short ISIs of 2–4 ms (p < 0.05, Wilcoxon’s test; Fig. 2), while facilitation faded when the ISI was increased. Almost no effect of train stimuli compared to single stimuli was present with ISI values of 8 and 10 ms (p > 0.05). When the stimulus repetition rate was increased from 0.4 s–1 to 1.0 s–1 , the amplitudes of all the SEP components tended to decrease. This influence reached statistical significance only in the case of N2 (p < 0.05). In contrast to amplitudes, the latency values did not display any differences depending on the stimulus conditions for any of the investigated components.

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useful to assess the influence of certain pharmacologic agents on cerebral signal processing. In summary, our data supports the idea that information on the short term SP plasticity may be extracted from EP by employing electrical train stimuli with varying within train ISI values. This could contribute to understand the pathophysiology of certain central nervous system disorders. Such knowledge might in turn be used to develop novel therapeutic strategies. Conflict of interest The authors declare no competing financial interests.

4. Discussion Acknowledgment Evoked potentials (EP) mainly result from synaptic potentials (SP) [8,15]. In the present study, train stimuli were taken to elucidate the synaptic plasticity by way of studying dynamic SSEP alterations depending on the within train ISIs. We detected a significant gain in the amplitudes of all measured SSEP components after train stimuli as compared with single stimuli. The increase in EP amplitudes was especially prominent with short ISI values of 2–4 ms and became less strong with longer ISI values of 8 or 10 ms, presumably due to weakened temporal summation of excitatory SP. N20 which is generated by primary afferent SP input to the cortex directly showed this pattern less prominently as compared to N1. It is presumably the subsequent intracerebral transsynaptic information flow that has contributed to the larger increase in N1 amplitudes by some amplification process. Thereby, also the signal-to-noise ratio was improved. Our data suggests steep decay dynamics of the SP that influence EP. This influence can best be seen in the N1 amplitudes at an SRR of 0.4 Hz (Fig. 2). A short time constant of decay in the range of several milliseconds has been reported for large neurons in the rodent brain previously [2,9,18]. Therefore, it is not far to speculate that similarly large neurons are involved in the human sensory cortex as the last part of the afferent neuronal chain in our investigation. Two stimulus repetition rates (SRR) have been studied, 0.4 Hz and 1.0 Hz. With the faster SRR, EP amplitudes declined, arguing for refractoriness and/or habituative influences. While refractoriness would lead to a drop of the EP-response from the first to the second stimulus with no further change thereafter, habituation would be associated with an ongoing decremental response [6,17]. This decremental response depending on the stimulus frequency was not in the focus of the present investigation. Therefore, the responses to subsequent stimuli have not been selectively analysed, and a distinction between refractoriness and habituation cannot be made here. The decrease in amplitude with the faster SRR was especially strong for N1 and N2. These late SEP components are known to be controlled by feedback loops [5,11,12,14,16]. Therefore, slow SRR are superior to fast SRR when short-term synaptic plasticity be studied. Train stimuli with different ISI values offer an easy way to investigate whether synaptic properties deviate from the normal situation in states of disease such as epilepsy or migraine. Indeed, abnormal decay dynamics of synaptic currents have previously been reported in a rodent epilepsy model [3]. It could be important to distinguish between different forms of e.g. epileptic disorders. Furthermore, synaptic decay properties as studied by EP may be

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Facilitation of Late Somatosensory Evoked Potentials by Electrical Train Stimuli.

Somatosensory evoked potentials (SSEP) may reflect synaptic events and could be suitable to characterise the short-time plasticity of synaptic potenti...
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