Abstract

Previous studies have shown that paired associative stimulation (PAS) protocol, in which peripheral nerve stimuli are followed by transcranial magnetic stimulation (TMS) of the motor cortex at intervals that produce an approximately synchronous activation of cortical networks, enhances the amplitude of motor evoked potentials (MEPs) evoked by cortical stimulation. Indirect data support the hypothesis that the enhancement of MEPs produced by PAS involves long-term potentiation like changes in cortical synapses. The aim of present paper was to investigate the central nervous system level at which PAS produces its effects. We recorded corticospinal descending volleys evoked by single pulse TMS of the motor cortex before and after PAS in 4 conscious subjects who had an electrode implanted in the cervical epidural space for the control of pain. The descending volleys evoked by TMS represent postsynaptic activity of corticospinal neurones that can provide indirect information about the effectiveness of synaptic inputs to these neurones. PAS significantly enhanced the amplitude of later descending waves, whereas the earliest descending wave was not significantly modified by PAS. The present results show that PAS may increase the amplitude of later corticospinal volleys, consistent with a cortical origin of the effect of PAS.

Introduction

The phenomenon of activity-dependent strengthening of synaptic transmission, known as long-term potentiation (LTP) is an important mechanism of learning and memory as well as many other forms of experience-dependent plasticity in the mammalian brain (Malenka and Bear 2004). Several LTP protocols have been developed in animal studies and in many of these studies it has been found that if an excitatory synaptic input repeatedly arrives at a neuron shortly before the neuron will then fire an action potential, then the strength of the synapse is increased (Bi and Poo 1998). These protocols of repetitive stimulation are known as associative LTP. Protocols of repetitive transcranial magnetic stimulation (rTMS) of the human brain that resemble models of associative stimulation similar to those developed in animal studies have been recently introduced (Cooke and Bliss 2006; Hallett 2007). A rTMS based approach for producing LTP-like changes in the human brain is the so called paired associative stimulation (PAS) (Stefan et al. 2000). This method is based on the Hebbian concept of spike-timing–dependent plasticity: 2 inputs, the first arising from electrical peripheral nerve stimulation and the second delivered over the motor cortex using TMS, are paired to activate brain networks approximately synchronously. If the TMS pulse is applied at an interstimulus interval (ISI) slightly longer than the time needed for the afferent inputs, generated by median nerve stimulation, to reach the cerebral cortex and if a sufficient number of pairs of stimuli are delivered, then the excitability of the sensorimotor cortex increases. Pharmacological studies have shown that PAS effects are influenced by drugs that act at the NMDA receptor, supporting the hypothesis that the after effects of PAS involve LTP-like changes in cortical synapses (Stefan et al. 2002). However, the PAS-induced change in the excitability of central motor circuits, were revealed indirectly by measuring peripheral responses at the muscle level after single pulse TMS. Moreover, a recent study evaluating the effects of PAS on the H reflex, an electrophysiological test that explores the excitability of the spinal motoneurons (Coombs et al. 1955), showed that PAS can produce changes in the amplitude of the H reflex thus suggesting that the development of spinal plasticity may contribute to the increase in the amplitude of muscles responses evoked by TMS after PAS (Meunier et al. 2007). For these reasons the nature and the site of the changes produced by PAS in the central nervous system are still not completely clarified. The present experiment attempted to characterize more precisely the role of cortical mechanisms in the facilitation of muscle responses evoked by transcranial stimulation produced by PAS. To this end, we recorded directly the corticospinal activity evoked by single pulse TMS of the motor cortex before and after PAS in 4 conscious subjects who had cervical spinal electrodes implanted chronically for the control of medically refractory pain. The ability to record descending corticospinal activity evoked by TMS in conscious humans provides a very useful insight into the after effects of PAS because the synchronous neural volleys provide an indirect measure of the effectiveness of synaptic input to corticospinal neurones (Di Lazzaro et al. 2004). The corticospinal volleys represent a high frequency (∼600 Hz) repetitive discharge of corticospinal cells produced by a complex mechanism involving a combination of intrinsic neuronal properties (oscillatory activity) and interactions between chains of inhibitory and excitatory interneurons of the motor cortex (Di Lazzaro, Ziemann, and Lemon 2008). Effectively, these corticospinal volleys can provide information about postsynaptic activity that is reasonably comparable to that recorded in experimental studies of LTP performed in hippocampal slice preparations.

Subject and Methods

As described in previous publications (Di Lazzaro et al. 2004), we recorded descending corticospinal activity evoked by TMS of the motor cortex directly from the high cervical epidural space of 4 conscious patients (aged 56, 61, 30, and 74 years) who had electrodes inserted for control of intractable dorso-lumbar pain. Because pain was resistant to medical therapy, the implantation of epidural electrodes for spinal cord stimulation, a minimally invasive and effective option for treatment of chronic pain (Lanner and Spendel 2007), was performed in these patients. The patients were taking no centrally acting medication at the time of the experiments. This is because the trial screening period of epidural stimulation, before permanent implantation, is arranged to occur after a period of wash out of any drugs used for pain relief and as well as any other central nervous system acting drug. This is well tolerated by the patients because epidural stimulation is considered only in patients resistant to medical treatment and the interruption of medical treatment for a few days does not usually produce any discomfort. It is necessary to do this so that the efficacy of the epidural stimulation on the symptoms of pain can be evaluated before permanent implantation.

Three subjects (subjects 1, 2, and 3) had no abnormality of central nervous system, whereas subject 4 had early-stage Parkinson's disease (PD) with symptoms completely controlled by dopaminergic treatment (L-DOPA).

All patients gave their written informed consent. The study was performed according to the Declaration of Helsinki and approved by the ethics committee of the Medical Faculty of the Catholic University of Rome.

Recordings were made simultaneously from the epidural electrode and from the relaxed first dorsal interosseous muscle (FDI) of the left hand.

Magnetic stimulation was performed with a high power Magstim 200 (Magstim Co., Whitland, Dyfed, UK). A figure-of-8 coil with external loop diameters of 9 cm, was held over the right motor cortex at the optimum scalp position to elicit motor responses in the contralateral FDI. Intensities were expressed as a percentage of the maximum output of the stimulator. Resting motor threshold (RMT) was defined according to the recommendations of the IFCN Committee (Chen et al. 2008) as the minimum stimulus intensity that produced a liminal motor evoked potentials (MEP) (>50 μV in 50% of 10 trials) with the tested muscle at rest. Two different orientations of the stimulating coil over the motor strip were used, with the induced current flowing either in a latero-medial (LM) or in a posterior–anterior (PA) direction. RMT was determined separately for LM and PA stimulation. LM magnetic stimulation was used to identify the latency of the earliest (D-wave) descending volley (Di Lazzaro et al. 2004). The responses to 20 stimuli at an intensity of 150% RMT were averaged at rest.

Epidural recordings were made between the most proximal and distal of the 4 electrode contacts on the epidural electrode. These had a surface area of 2.54 mm2 and were 30 mm apart. The distal contact was connected to the reference input of the amplifier.

MEPs and epidural activity were band pass filtered (bandwidth 3 Hz–3 kHz) (Digitimer D360 amplifiers) and each single trial was recorded on computer for later analysis using a CED 1401 A/D converter (Cambridge Electronic Design, Cambridge, UK) and associated software. Amplitude of the volleys was measured from onset to peak, where onset was defined either as the immediately preceding trough, or as the initial deflection from baseline.

Paired Associative Stimulation

We used a high power Magstim 200 (Magstim Co.) connected to a figure-of-8 coil, with external loop diameters of 9 cm held over the right motor cortex at the optimum scalp position to elicit MEPs in the contralateral FDI. The induced monophasic current in the brain flowed in a posterior-to-anterior direction. The intervention consisted of single electrical stimuli delivered to the left ulnar nerve at the wrist at 300% of the perceptual threshold, followed by TMS at an intensity sufficient to produce an unconditioned response amplitude of approximately 1 mV in the resting FDI. Ninety pairs were delivered at 0.05 Hz over 30 min at an ISI of 25 ms. An ISI of 25 ms was used because this interval had been shown in previous experiments to be effective in increasing cortical excitability (Stefan et al. 2000).

We compared the corticospinal volleys, evoked by single pulse PA TMS immediately before and immediately after the end of PAS, and again thirty minutes after the end of PAS. The responses to 20 stimuli obtained at rest at an intensity of 150% RMT were averaged. Because the mechanism of the I1 wave is different from that of the later I-waves as suggested by the differential behavior of the I1 and later I-waves in several single, paired pulse (Di Lazzaro et al. 2004), and repetitive (Di Lazzaro et al. 2008a, 2008b) TMS paradigms, the effects of PAS on the amplitude of the I1 and of the later I-waves (the sum of the amplitude of all the individual waves after the I1 wave) were analyzed separately.

Statistics

Because previous studies have reported PAS abnormalities in PD (Bagnato et al. 2006; Morgante et al. 2006), the effects of PAS in the patient with PD were analyzed separately.

The aim of this study was to evaluate the effects on epidural volley induced by PAS. Volleys were assessed at 3 time points: one before and 2 after the PAS. For subjects with no central nervous system abnormality, we entered MEPs and epidural volleys (I1 waves and Later waves) into 2 separate repeated measures ANOVAs. For MEPs we evaluated a repeated measures ANOVA with TIME (baseline, post-PAS and 30 min after PAS) as within-subject factor. For epidural volleys, a repeated measures ANOVA with COMPONENT (2 levels: I1 wave amplitude and later I-wave amplitudes) and TIME (baseline, post-PAS and 30 min after PAS) as within-subject factors was performed. Repeated measure ANOVA incorporated, where necessary, a Greenhouse–Geisser correction for nonsphericity. In case of significant main effect or interaction, post hoc analyses with paired t-test were applied using Bonferroni correction for multiple comparisons. We normalized the data by subtracting each value from the average value of the amplitudes at the 3 time points and dividing it by the standard deviation.

Results

Epidural Volleys

LM magnetic stimulation evoked the earliest negative potential in all subjects. It had a latency of 2.9 ms in subject one, 2.3 ms in subject 2, 3.0 ms in subject 3, and 2.7 ms in subject 4. The short latency of this wave is consistent with direct activation of corticospinal axons. We have therefore termed this volley D-wave (Di Lazzaro et al. 2004). PA magnetic stimulation evoked a series of descending waves, the largest of these waves had a latency which was 1.1–1.5 ms longer than the earlier volley recruited by LM magnetic stimulation. Because the earliest volley elicited by LM magnetic stimulation is probably a D-wave we have termed the later volleys recruited by PA magnetic stimulation as I-waves, numbered in order of their appearance.

Paired Associative Stimulation

Subjects with No Central Nervous System Abnormality

Figure 1 shows the effect of PAS on the amplitudes of the I1, of later I-waves (the sum of the amplitudes of all the waves following the I1 wave) and of MEPs in subject 1. Figure 2 shows the effect of PAS on the mean amplitudes of MEPs, of the I1 wave and of later I-waves (the sum of the amplitudes of all the waves following the I1 wave) in the 3 subjects. Mean MEP amplitude was increased by about 45% immediately after PAS (baseline 1.15 ± 0.08 mV vs. 1.67 ± 0.11 mV after stimulation) and by about 30% 30 min after PAS (1.5 ± 0.09 mV 30 min after stimulation). In this small group of subjects, this increase did not reach statistical significance (TIME: F2,4 = 3.639, P = 0.126).

Figure 1.

Epidural volleys evoked by single pulse TMS in baseline and at different intervals after the end of PAS. TMS evokes 3 descending waves (I-waves), the earlier I wave (I1) is indicated by the vertical dotted line. After PAS, 2 further I-waves are recruited (I4 and I5), the size of the I2 and I3 waves is slightly increased, the amplitude of the I1 wave is unchanged. The amplitude of MEP is also increased after PAS. A less pronounced facilitation of later I-waves and of MEPs is evident 30 min after PAS.

Figure 1.

Epidural volleys evoked by single pulse TMS in baseline and at different intervals after the end of PAS. TMS evokes 3 descending waves (I-waves), the earlier I wave (I1) is indicated by the vertical dotted line. After PAS, 2 further I-waves are recruited (I4 and I5), the size of the I2 and I3 waves is slightly increased, the amplitude of the I1 wave is unchanged. The amplitude of MEP is also increased after PAS. A less pronounced facilitation of later I-waves and of MEPs is evident 30 min after PAS.

Figure 2.

Effects of PAS on the mean amplitude of the I1 wave, later I-waves and MEPs in the 3 subjects with no central nervous system abnormalities. Error bars indicate standard deviations. MEPs are increased by about 45% immediately after PAS and by about 30% 30 min after PAS. Mean amplitude of later volleys is increased by about 51% after PAS (*P = 0.0001; paired t-test) and by about 15% 30 min after PAS. The mean amplitude of the I1 wave is unchanged after PAS.

Figure 2.

Effects of PAS on the mean amplitude of the I1 wave, later I-waves and MEPs in the 3 subjects with no central nervous system abnormalities. Error bars indicate standard deviations. MEPs are increased by about 45% immediately after PAS and by about 30% 30 min after PAS. Mean amplitude of later volleys is increased by about 51% after PAS (*P = 0.0001; paired t-test) and by about 15% 30 min after PAS. The mean amplitude of the I1 wave is unchanged after PAS.

Mean later volley amplitude increased by about 51% after PAS (baseline 8.1 ± 2 μV vs. 12.2 ± 3.3 μV after stimulation) and by about 15% 30 min after PAS (9.4 ± 6.8 μV 30 min after stimulation). Mean amplitude of I1 wave remained unchanged after PAS (baseline 3 ± 1.4 μV, 2.8 ± 1.2 μV after stimulation and 2.9 ± 1.1 μV 30 min after stimulation).

A repeated measures ANOVA with COMPONENT (2 levels: I1 wave amplitude and later I-waves) and TIME as main factors showed a significant effect of the interaction component x time (F2,4 = 7.495, P = 0.044). Post hoc analysis showed that the mean of later wave amplitudes was significantly increased immediately after PAS (paired t-test: P = 0.0005) and was not significantly increased 30 min later (paired t-test: P = 0.74).

The analysis of the effects of PAS on different later I-waves showed that there was a substantial variation in the size of the effects produced by PAS on individual later I-waves: after PAS an I5 wave appeared in subjects 1 and 3. A clear increase was observed in I3 (+38 ± 18%), and in I4 (+88 ± 52%), whereas only moderate effects were observed in I2 (+5 ± 8%).

Patient with PD

This subject showed no substantial change either of MEP amplitude (+11%) or of later I-wave amplitude (+4%) after PAS.

Discussion

The knowledge of LTP in humans is limited and based on indirect data (Cooke and Bliss 2006). Experiments comparable with those conducted in animal models have been performed in hippocampal tissue removed from the brain of patients undergoing surgery for epilepsy (Chen et al. 1996). The noninvasive TMS technique appears to be able to emulate some of the experimental paradigms inducing LTP and has offered the opportunity to investigate this phenomenon in the intact human brain (Cooke and Bliss 2006; Thickbroom 2007; Ziemann 2004), however the data obtained in previous studies are indirect in that they rely on the evaluation of peripheral muscle responses evoked by cortical stimulation. The recording of corticospinal activity evoked by motor cortex TMS (Di Lazzaro et al. 2004) enabled us to investigate the effects of PAS protocol on excitability in the intact human brain more directly. The present results demonstrate that rTMS given as PAS leads to a pronounced increase in the excitability of cortical circuits generating the later I-waves, whilst the earliest I-wave is unaffected. I-waves represent synchronous activity of corticospinal axons originating from trans-synaptic activation of corticospinal cells. Although their origin is still unclear, there is a good deal of evidence to suggest that the early and late I-waves are generated by independent cortical mechanisms (Di Lazzaro et al. 2004; Ziemann and Rothwell 2000). The I1 wave is believed to be produced by a monosynaptic input to corticospinal neurones, whereas later I-waves are believed to be produced by activation of more complex chains of interneurons projecting upon the corticospinal cells (Ziemann and Rothwell 2000; Di Lazzaro et al. 2004; Di Lazzaro, Ziemann, and Lemon 2008). Thus, our results suggest that PAS produces its effect by influencing the cortico-cortical connections of the motor cortex that generates later I-waves. The increase in synaptic cortical activity revealed by the increase in corticospinal activity in our patients is consistent with the idea that PAS may induce LTP-like changes at synaptic connections in human motor cortex (Stefan et al. 2000). The main facilitatory effect was observed on the latest I3, I4, and I5 volleys, this is in agreement with previous observations based on MEP recording after PAS. Kujirai et al. (2006) used PAS to examine further which cortical elements might be responsible for the PAS-induced excitability changes. They used different TMS approaches in order to maximize the chances of activating either preferentially the I1-wave or the I3-wave. At near-threshold intensities, reversing the direction of the induced current in the brain from the conventional PA direction to an anterior–posterior direction has previously been shown to elicit a comparatively larger and relatively isolated I3-waves (Sakai et al. 1997; Di Lazzaro et al. 2001). Kujirai et al. (2006) showed that, MEPs were facilitated more readily if PAS was applied with the direction of the induced current in anterior–posterior direction. Thus, the hypothesis derived from these indirect observations is that specific cortical elements, namely those involved in generating later I-waves, are preferentially facilitated by PAS. Support for involvement of late, rather than early, TMS-induced cortical events in PAS-induced plasticity is also derived from 2 other arguments: PAS has been shown to lead to enhanced corticospinal excitability even when using ISI shorter than the estimated arrival time of the afferent signal in the primary motor cortex (Wolters et al. 2003; Ziemann et al. 2004; Morgante et al. 2006; Weise et al. 2006). With these short intervals (ISI ∼20–21.5 ms), a pre (afferent signal) → post (TMS-signal) sequence of events would be achieved only, if the interaction between the afferent-stimulation induced events were with late TMS-induced events. As noted above, such late events are likely to correspond to late I-waves and are believed to originate in upper cortical layers II/III. This conclusion gains further support by studies applying PAS with the magnetic coil centered over the primary somatosensory cortex (S1) (Wolters et al. 2005; Litvak et al. 2007). PAS-induced cortical excitability changes in S1, which were probed by median nerve somatosensory-evoked potentials (MN-SSEP), resembled those induced in the primary motor cortex in several aspects. Similar to PAS targeting M1, bidirectional changes were induced and PAS efficacy depended on near-synchronicity between the median nerve pulse and the TMS pulse. PAS increased exclusively the amplitude of the P25 component of the MN-SSEP, which is probably generated in superficial cortical layers of area 3b. Indeed, changes of synaptic efficacy in superficially traveling horizontal cortical pathways are believed to underlie much of the experience-dependent plasticity in neocortex (Diamond et al. 1993; Rioult-Pedotti et al. 2000).

The effect of the PAS on the later I-waves is similar to that induced by intermittent theta burst stimulation (iTBS) protocol as introduced by Huang et al. (2005). iTBS produces a similar enhancement of later I-waves (Di Lazzaro et al. 2008a). However, the effect of PAS contrasts with that of a recently introduced protocol of rTMS based on repetitive paired-pulse TMS at I-wave periodicity because paired-pulse rTMS increases MEPs but leaves the I-waves virtually unchanged (Di Lazzaro et al. 2007). Thus, these 2 facilitatory protocols might modulate different circuits of the motor cortex. It has been proposed that TMS evokes the highly synchronized I-waves, by activating horizontal fibers arranged isotropically in the cortical layers (Silva et al. 2008), and it might be that PAS increases the excitability of these fibers whereas paired-pulse rTMS increases the excitability of a different population of axons not isotropically distributed. The epidural volleys may not represent all the descending activity evoked by TMS and there might be additional activity that is more dispersed and not evident in the records (Di Lazzaro et al. 2007). If the excitability of the networks producing the dispersed activity is selectively increased by paired-pulse rTMS, then the MEP would be larger even though the increase in the I-wave activity is rather limited. Another possibility is that PAS and paired-pulse rTMS, modulate the same circuits but at different sites with a more dispersed descending activity after paired-pulse rTMS. In any case, it seems that there is a less closely coupling between the facilitated networks and those generating later I-waves in the case of paired-pulse rTMS.

The patient with early-stage PD (patient 4) showed no facilitation after PAS. Interestingly, it has been shown that PD patients OFF their normal therapy have an abnormal response to PAS (Bagnato et al. 2006; Morgante et al. 2006). Thus, the lack of effect of PAS in patient 4 might be explained by PD related abnormal plasticity. However, it should be considered that our patient had only mild symptoms and was studied after taking her normal anti-parkinsonian medication when she was completely asymptomatic and it has been shown that PAS is normalized by treatment with L-DOPA (Bagnato et al. 2006; Morgante et al. 2006). Therefore, it is also conceivable that the lack of effect of PAS is related to the considerable interindividual variability of this protocol that has been demonstrated by several previous studies reporting the lack of response to PAS in some twenty percent of subjects (Fratello et al. 2006; Florian et al. 2008). Other factors, such as attention (Stefan et al. 2004) may have contributed as well. It should also be considered that the PD patient was the oldest subject, thus the lack of facilitation after PAS in this patient could be explained by aging and/or hormonal factors, in agreement with the findings of 2 recent papers reporting an age related decrease in PAS effects (Muller-Dahlhaus et al. 2008; Tecchio et al. 2008). The most pronounced reduction in PAS effects was found in older women and it was attributed to postmenopause reduction in sexual hormone levels (Tecchio et al. 2008). Finally, it should be considered that, in analogy with our previous studies in which we evaluated the effects of rTMS protocols on epidural activity, the coil position was optimized to stimulate the first dorsal interosseus muscle and this muscle is outside of the cutaneous region supplied by the ulnar nerve. Because previous studies have demonstrated that the efficacy of PAS is optimal when the position of the coil is congruent with the cutaneous region of the conditioning nerve (Stefan et al. 2000), it might be that the fact that we have not used the most efficacious stimulation may have contributed to the failure to induce enhancement of late I-waves in the patient with PD.

In conclusion, we found that PAS leads to an increase in the excitability of cortical mechanisms that generate later I-waves in response to single TMS pulses. This appears to be the most direct demonstration of motor cortical associative plasticity in the intact human brain. The knowledge of the mechanisms of PAS may be of importance because of its therapeutic potential in rehabilitation of patients with several neurological disorders (Ridding and Rothwell 2007).

Table 1

Demographic and clinical characteristics and RMT of patients

Patient Age Sex Diagnosis RMT (% maximal stimulator output) 
56 Intractable dorso-lumbar pain 40 
61 Intractable dorso-lumbar pain 63 
30 Intractable dorso-lumbar pain 50 
74 Intractable dorso-lumbar pain/Early PD 56 
Patient Age Sex Diagnosis RMT (% maximal stimulator output) 
56 Intractable dorso-lumbar pain 40 
61 Intractable dorso-lumbar pain 63 
30 Intractable dorso-lumbar pain 50 
74 Intractable dorso-lumbar pain/Early PD 56 

Conflict of Interest: None declared.

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