Prolonged peripheral nerve stimulation induces persistent changes in excitability of human motor cortex

Journal of the Neurological Sciences 208 (2003) 79 – 85 www.elsevier.com/locate/jns

Prolonged peripheral nerve stimulation induces persistent changes in excitability of human motor cortex C. Shona Charlton a, Michael C. Ridding a,b, Philip D. Thompson b, Timothy S. Miles a,* a

b

Department of Physiology, Adelaide University, Adelaide SA 5005, Australia Department of Medicine, Royal Adelaide Hospital, Adelaide SA 5000, Australia

Received 8 March 2002; received in revised form 12 September 2002; accepted 18 November 2002

Abstract This study sought to determine whether prolonged peripheral nerve stimulation was effective in inducing persistent ‘‘plastic’’ changes in the excitability of the human motor cortex. The amplitude of the electromyographic response evoked in resting intrinsic hand muscles by focal transcranial magnetic stimulation (TMS) was taken as an index of motor cortical excitability. Twelve subjects were stimulated with each of three protocols, one of which was given on each of three separate occasions. The protocols consisted of various schedules of electrical stimulation of the radial and ulnar nerves or the motor point of the first dorsal interosseous muscle (FDI), or stimulation of FDI motor point paired with low-frequency TMS. Amplitudes of TMS-elicited motor evoked potentials (MEPs) were measured before peripheral stimulation and for 2 h after stimulation. The data from one subject were unusable. In every other subject, all three protocols induced a prolonged, significant facilitation of MEPs in at least some of the three intrinsic hand muscles used. In some instances, MEPs were not enlarged and occasionally were significantly depressed. Different protocols based on peripheral afferent stimulation can induce plastic changes in the organisation of the motor cortex that persist for at least 2 h. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Motor cortex; Neuronal plasticity; Percutaneous electric nerve stimulation

1. Introduction There is now good evidence that reorganisation can be induced in adult neocortex by a number of interventions. The magnitude and duration of any such ‘‘plastic’’ changes depend on the cortical territory involved [1,2]. In the motor cortex, plastic changes have been induced by the process of acquiring or improving motor skills [3 – 6], altered sensory input [7– 9], and during recovery after central and peripheral injury and disease [10 – 12]. One manifestation of plastic changes in the motor cortex is an alteration in the boundaries of the highly ordered representational maps in the primary motor cortex [13,14]. In humans, the extent of the cortical representation of a given muscle can be assessed with transcranial magnetic stimulation (TMS) [10]. TMS activates corticospinal pathways projecting to motor neurone pools, evoking a motor

* Corresponding author. Tel.: +61-8-8303-5108 (business), +61-88272-1253 (home); fax: +61-8-8303-3356. E-mail address: [email protected] (T.S. Miles).

response which is manifested as a motor evoked potential (MEP) in the electromyograph. Increased use of specific muscle groups has induced enlargement of their cortical representations and increased excitability of these areas of motor cortex [15]. Changes in the excitability of the motor cortex measured with TMS are widely accepted as an index of motor plasticity in humans. Other experimental interventions have also been shown to alter motor cortical excitability. For example, prolonged immobilisation of a muscle induces an enduring decrease in both MEP amplitudes and the size of map area for that muscle [15]. In amputees, MEP amplitudes are enlarged in muscles above the stump [16,17]. MEP amplitudes are also rapidly but reversibly increased for muscles above an ischaemic forelimb block [7,18]. Ziemann et al. [19] have reported that pairing low-frequency TMS with ischaemic block enhances the induction of increased excitability of the cortex. Their pharmacological study suggests that a mechanism such as long-term potentiation may be responsible for the plastic changes induced by this means. In these human models of peripheral de-afferentation, the alteration in sensory input is relatively nonspecific, affecting

0022-510X/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. doi:10.1016/S0022-510X(02)00443-4

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groups of muscles rather than individual muscles. Recent studies have employed an alternative model for the induction of plastic change, namely, prolonged electrical stimulation of peripheral sensory nerves, which provides a specific, well-controlled means of increasing sensory input [9,20 –22]. The observation that plastic changes can be induced in the motor cortex by afferent stimulation is of particular interest for several reasons. Firstly, it has been suggested that an increase in muscle functionality is associated with an increase in motor excitability for that muscle [12,23]. Ridding et al. [9] have suggested that increasing motor excitability may be effective in the treatment of muscles weakened by stroke. If, for example, the motor cortical projection to the hand muscles has been damaged by stroke, it may be possible by stimulating hand afferents to induce changes in the size and excitability of the cortical hand area; that is, to cause adjacent areas of motor cortex to take over some of the function of the damaged area, thereby increasing the function of the stroke-weakened muscles. Hence, it is important to determine what stimuli can induce increases in cortical excitability. Secondly, while sensory signals must play a vital role in normal motor learning, the nature of this role is unknown. Finally, there are now preliminary observations that the return of function following traumatic brain damage is associated with reorganisation of relevant parts of the motor cortex: if so, it is highly likely that sensory signals play a significant role in this process. The present study sought to determine the relationship between different protocols of electrical stimulation of peripheral nerves with or without brain stimulation, and the nature and duration of changes that such protocols may induce in motor cortical excitability.

2. Methods Twelve neurologically healthy subjects (six males, six females) aged 21 –42 years participated in the experimental series. All subjects were word-of-mouth volunteers drawn from a sample of convenience. They gave written informed consent for the study, which was approved by the University of Adelaide Human Research Ethics Committee. Each subject was tested on four separate sessions, separated by 4 –119 days, in a temperature-controlled laboratory (22 jC). Surface EMG activity was recorded from three muscles in the right hand: first dorsal interosseous (FDI), abductor digiti minimi (ADM), and abductor pollicis brevis (APB) with disposable adhesive recording electrodes placed over each muscle. Signals were amplified and filtered (bandwidth 50 –1000 Hz), and recorded on a computerbased data acquisition system (CED 1401, CED Cambridge, UK) at 5 kHz/channel for off-line analysis. Focal stimulation was performed with a Magstim 200 magnetic stimulator (Magstim, Dyfed, UK) and a figure-of-eight coil (9 cm

external wing diameter). The coil was positioned tangentially to the scalp at an angle optimal for pre-synaptic activation of the corticospinal tract [22]. The scalp position where maximal amplitude MEPs were elicited in the right FDI was marked, and used throughout the experiment. Motor threshold was defined as the TMS intensity (% maximum output) that evoked 5 MEPs of at least 100 AV amplitude in the relaxed FDI in 10 trials. For the assessment of cortical excitability, 10 stimuli at 115% of motor threshold were given at inter-stimulus intervals of approximately 3.5 s. The amplitudes of the MEPs in the resting muscle were then averaged. Motor threshold was determined for each subject in every experimental session. Trials in which EMG activity was detected before the stimulus ( < 0.5%) were excluded from subsequent analysis. 2.1. Peripheral stimulation protocols Three stimulation protocols were used in each subject. Only one of these was used in a given experimental session, with the others being performed on separate occasions at least 4 days apart. The sequence of these sessions was pseudo-random. The electrical stimulus consisted of 500 ms trains of 10 Hz, 1 ms pulses, repeated every second (i.e., a 50% duty cycle). These stimulus parameters are comparable with those used in earlier studies in humans and animals [21,25]. The first protocol aimed to cause a sustained afferent input to the cortex from a significant area of skin and muscle in the hand. Both the superficial radial and ulnar nerves were stimulated simultaneously. One pair of stimulating electrodes was placed 1 cm apart over the right ulnar nerve (innervating FDI) at the wrist, and the other over the right superficial radial nerve (innervating the skin overlying FDI). Both pairs were connected in parallel to the electrical stimulator. The stimulus intensity was adjusted to give weak contractions in FDI and ADM muscles: adjusting the stimulus intensity to this motor criterion enabled us to ensure that population of mixed nerves stimulated did not change throughout the 2-h stimulation period. The second protocol aimed to give a more focussed stimulus to a single intrinsic hand muscle. The motor point of FDI was stimulated in order to limit the stimulus to the muscle afferents and the skin overlying the muscle. The stimulating cathode was placed over the motor point of the right FDI, and the anode over the second metacarpophalangeal joint. The duration of the stimulus was again 2 h, and the stimulus intensity was set to elicit weak contractions of FDI. The other train parameters were the same as those used for radial –ulnar nerve stimulation. The third protocol aimed to examine the effect of depolarising the cortical neurones simultaneously via two different but concurrent input pathways in a quasi-‘‘Hebbian’’ manner [23]. To achieve this, we paired a TMS stimulus with electrical stimulation of the FDI motor point. The TMS parameters were those used for excitability testing

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(above), and the motor point stimulus was a brief train of shocks (10 Hz, 1-ms duration, for 500 ms) again at a strength that elicited a weak contraction. The peripheral stimulus began 25 ms before the TMS, thereby enabling the afferent volley to reach the motor cortex at about the same time as the magnetic stimulation pulse was delivered. This paired stimulus was repeated at 10-s intervals for 30 min. A separate control experiment, in which the basic experimental procedure was identical, was conducted for each subject. The subject’s cortical excitability was tested in the same way and over the same period without nerve stimulation. In all sessions, MEP amplitudes were measured before the peripheral stimulus was applied, immediately after the end of each period of stimulation (or the control protocol), and then at 15-min intervals for 120 min. 2.2. Statistical analysis All MEP amplitudes were normalised to the mean baseline amplitude for each subject for all statistical analyses. Repeated measures analysis of variance (ANOVA) was used to compare resting motor thresholds and baseline MEP amplitudes for individual subjects across the different sessions and experimental conditions. ANOVA was also used to determine whether the MEP amplitudes of each subject were significantly altered by the various protocols of peripheral nerve stimulation, compared with the control values. Significance was accepted in all analyses at p < 0.05.

3. Results The data from one subject were discarded as he was unable to relax his target muscles completely during the MEP recording. The resting thresholds and baseline MEP amplitudes of the remaining 11 subjects did not differ significantly between the four experimental sessions or between the four testing conditions (including controls). The most common pattern of response in a given muscle following stimulation was a significant increase in the Table 1 Incidence of significant facilitation of motor cortical excitability across the two-h testing period induced by three nerve stimulation protocols in three hand muscles in 11 subjects, compared with that subject’s control experiment ( p < 0.05) Stimulus protocol

FDI

ADM

APB

Totals

Radial – ulnar FDI motor point FDI motor point plus TMS Totals

2,4,5,6,7,10 2,3,4,6,8,10,11

2,3,4,5,6,7,11 1,2,4,6,9,11

2,3,6,7,10,11 1,2,6,7,8,10,11

19/33 20/33

2,3,4,6,7,9,10,11

1,2,4,6,7,11

1,2,3,7,10,11

20/33

21/33

19/31

19/31

Each subject is identified by a number: the same number is used in Table 2.

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Table 2 Incidence of significant depression of motor cortical excitability across the two-h testing period induced by three nerve stimulation protocols in three hand muscles in 11 subjects, compared with that subject’s control experiment ( p < 0.05) Stimulus protocol

FDI

ADM

APB

Totals

Radial – ulnar FDI motor point FDI motor point plus TMS Totals

1,3,9,11 5,7,9 5

9,10 3,10 3,5,8,9,10

3,9 3,4,9 5,9

8/33 8/33 8/33

8/33

9/33

7/33

Each subject is identified by the same number used in Table 1.

amplitude of the MEP which persisted throughout the 2-h testing period. However, the responses of individual subjects and individual muscles varied widely, and in some instances, the change was either inconsistent across the testing period or the MEP amplitude was significantly less than control. The pattern of responses of individual subjects is shown in Tables 1 and 2. Table 1 shows the instances of significant facilitation by subject in each muscle with each stimulus protocol across the 2-h period following nerve stimulation. While the results varied, three conclusions can be drawn from this table. First, significant facilitation was induced in at least one hand muscle in each subject. Significant facilitation was induced in FDI in all but one subject (#1), in ADM in all but two subjects (#8, 10), and in APB in all but three subjects (#4, 5, 9). Second, each of the three stimulus protocols was equally effective in inducing significant facilitation: each induced significant facilitation in about 60% of instances across all three muscles in all subjects. Third, in all subjects tested, each muscle was about equally susceptible to facilitation, with facilitation in about 60% of instances. The time course of the facilitation induced in FDI by each of the three stimulus protocols is shown in Fig. 1. The data from each subject in whom significant facilitation was induced are combined. Radial – ulnar stimulation induced significant facilitation in FDI in 6 of the 11 subjects. The mean amplitude of the MEPs in these subjects was at least 50% greater than the controls throughout the 2-h period following the nerve stimulation. The MEP amplitudes in the five subjects in whom the FDI was not facilitated were similar to the control data for the 11 subjects. FDI stimulation resulted in a different distribution of responses. Significant facilitation was induced in seven subjects, with the mean MEP amplitude again being about 50% greater than the control values throughout the 2-h poststimulation period. However, with this stimulus protocol, significant depression was induced in three of the other four subjects: this is manifested in the middle panel of Fig. 1 as an overall depression in excitability for the ‘‘non-facilitators’’ throughout the post-stimulation period. The lowermost panel of Fig. 1 shows that paired motor point and TMS induced a similar level of facilitation in 8 of

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the 11 subjects. Of the remaining three subjects, one was significantly inhibited, and the other two were not significantly different from their control recordings. The patterns and time course of facilitation observed in ADM and APB with the different stimulus protocols were qualitatively similar to those shown in Fig. 1, with slight differences in the numbers of instances in which significant increases in MEP amplitude were seen (Table 1). The pattern of depression was variable from subject to subject and from one stimulation protocol to another. Table 2 shows that each of the three stimulation protocols used evoked significant depression in about 24% of occasions across all muscles tested and, in any given muscle, depression was about equally likely to be induced by any of the three treatments, again with an incidence of about 24%. In contrast with facilitation which could always be evoked by one or other stimulus in every subject, there were subjects in whom depression of the MEPs was never observed. For example, no significant depression was found in subjects 2 and 6 with any treatment in any muscle.

4. Discussion

Fig. 1. Pooled data from 11 subjects showing the changes induced in MEP amplitude in FDI following each of the three different stimulation protocols at 15-min intervals for 2 h after peripheral nerve stimulation (upper panel), FDI motor point stimulation (middle panel) and combined FDI motor point and TMS (lower panel). In each panel, the subjects whose responses were significantly facilitated compared with their controls have been grouped as ‘‘facilitators’’: their mean responses (SEM) are shown as filled circles. Those whose responses were not significantly facilitated are grouped as ‘‘nonfacilitators’’ shown as open circles: this group includes subjects in whom the MEP amplitude was not significantly different from control values as well as those whose MEP amplitudes were significantly depressed. The depressed responses were generally too few in number to show as a separate group. The control data for all subjects were grouped and the means are shown as filled triangles in each panel.

The primary observation in the present study is that prolonged stimulation of peripheral nerves, with or without simultaneous brain stimulation, can induce marked changes in the excitability of the human motor cortex that persist for at least 2 h after cessation of the stimulus. Significant facilitation was induced in virtually every muscle in almost every subject by one or other of the stimulus protocols. Significant facilitation was also induced in at least one muscle tested in all but 2 of 11 subjects, with an overall rate of about 60%. There is strong evidence from two recent studies that the facilitation is supraspinal. Ridding et al. [9] used transcranial electrical stimulation to activate the corticospinal pathway directly, and showed that no change occurred in the excitability of spinal motor neurons. Using this method as well as F-wave analysis, Stephan et al. [22] also found no changes in spinal excitability following induction of plastic change. It is reasonable to conclude that the prolonged increase in the amplitude of MEPs induced by peripheral nerve stimulation is the result of an increase in the excitability of the motor cortex and not in spinal circuits. Three earlier studies have employed repetitive peripheral stimulation to elicit changes in human motor cortical excitability. Bonato et al. [20] investigated the effect of muscle spindle activation on cortical excitability. Neither electrical stimulation of the median nerve nor vibration of thumb muscles for 60 s changed the post-stimulation MEP amplitude. These authors concluded that sensory feedback played no role in the modulation of motor cortical excitability. In light of the present study, however, it appears that the stimulation period used in this earlier study may have been too short.

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The lasting facilitation seen in the majority of occasions in the present study is similar to the effect induced by 10 min of high-frequency stimulation of the human pharynx [21]. This led to an enlargement in pharyngeal MEP amplitudes, which persisted for 30 min in all subjects tested. It is not known whether the higher incidence of facilitation in this earlier study is due to the apparently higher intensity of stimulation used, or to other factors. It seems unlikely that the pharyngeal cortical representation is more responsive to stimulation than the hand cortical representation. Most recently, Kaneko et al. [22] have reported facilitation induced by repeated trials in which single electrical stimuli are paired with TMS. They showed that facilitation is induced only when the TMS is given at a time corresponding approximately with the arrival of the afferent volley in the motor cortex. The magnitude and duration of the facilitation are comparable with that reported in the present study. The responses in the present study varied markedly from one subject to another, and from one stimulus protocol to another. The variation was neither subject-specific nor treatment-specific. Inconsistent responses have also been reported in a study of the effect of prolonged electrical stimulation of a cutaneous nerve on the size of receptive fields of cells in the primary somatosensory cortex of cats [24]. There are a number of possible explanations for such variability in the present study. The first is the relatively nonspecific nature of the stimulus. Although the aim was to induce a relatively consistent afferent volley across subjects, for practical reasons, the criterion used to set and maintain the stimulus intensity was based on visual observation of a motor response to peripheral nerve stimulation. Hence, it is possible that some of the variability of the response between subjects may be due to inconsistent afferent stimulation. This inconsistency was compounded when both the radial and the ulnar nerves were stimulated at intensities based on this motor criterion. It is also possible that the movements evoked in the hand muscles by the nerve stimulation influence the effectiveness of induction of plastic changes: because of the relatively uncontrolled stimulus, the twitches in the ulnar-innervated muscles doubtless varied from one subject to another. However, the pattern of plastic change induced by FDI motor point stimulation which was restricted to the muscles immediately adjacent to the stimulating electrode was not obviously different from the pattern induced by radial– ulnar stimulation, which does not support this idea. Other explanations can be suggested. For example, it is possible that preferential facilitation of one muscle could reduce the facilitation of another muscle by invading its territory in the motor cortex, thereby altering its excitability. In a study on the plasticity of monkey cortex, the pattern of afferent inputs from two digits was changed by surgically fusing the fingers so that the sensory inputs from the two digits became strongly linked [26]. Intracortical mapping then revealed that this intervention broke down the normally

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sharply-segregated representations of the digits in area 3b. Analogous changes occur at the level of single cortical neurons. Recanzone et al. [25] have shown that stimulation of peripheral nerves induces an approximately three-fold increase in the size of receptive fields of neurons in the primary sensory cortex of cats. If the motor cortex were to be modified in a similar way by afferent stimulation, it is possible that the amplitude of the MEP evoked by TMS at a single point on the scalp may increase for one muscle at the expense of that of another intrinsic hand muscle whose cortical representation is adjacent. While the pattern of facilitation of particular muscles with the various treatments varied across the 11 individuals tested, the data strongly suggest that a given strategy of stimulation produces a consistent pattern of facilitation in a given subject. Table 1 shows that if FDI motor point stimulation induces facilitation in a given individual, the probability is very high that facilitation will also be induced in this subject when this stimulus is combined with TMS. Subjects numbers 2, 6 and 11 seemed to be particularly susceptible to the induction of facilitation. With one exception for subjects #2 and #11, all treatments induced significant facilitation in all muscles in these subjects. Moreover, no instance of significant depression was found in these subjects. The depression of the MEP amplitudes in about 24% of instances following one or other of the three stimulation protocols was unexpected. There was not a clear pattern of susceptibility of individual subjects to depression. Subject #9 was the most susceptible, showing significant depression in nine instances from the three stimulus protocols and three muscles tested, and significant facilitation in only two instances. Chen et al. [27] have reported that TMS at a frequency of 0.9 Hz can induce depression of MEPs that lasts for at least 15 min. Such depression of excitability following low-frequency stimulation has also been observed in a study of long-term potentiation (LTP) and long-term depression (LTD) in the hippocampus of pentobarbitalanaesthetised adult rats [28]. In that study, prolonged electrical stimulation at 1 Hz induced long-term depression, while bursts of high-frequency stimulation (100 Hz) induced long-term potentiation. Stimulation at 10 Hz had no lasting effect. It is therefore possible that in our human model, 10-Hz stimulation lies on the cusp between the optimal stimulus frequencies for inducing LTD and LTP, respectively. Thus, in some instances, 10-Hz stimulation may have induced LTP manifest as increased amplitude MEPs, and in others, LTD manifest as depressed MEPs. It is also possible that factors that we did not control influenced the induction of facilitation or depression. For example, motor learning, which involves plastic changes, is more effective when the subject’s attention is focused on the task, and Byl et al. [29] emphasised the importance of the subject’s attention to the input for the induction of plastic changes in monkey cortex. In our protocol, therefore, it is possible that the level of the subject’s concentration on the

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sensory input influenced the induction of plastic changes in one direction or another. 4.1. Significance and implications Functional recovery from stroke is variable, and the mechanisms underlying recovery are not well understood. How much of the recovery from stroke is spontaneous and how much is due to rehabilitation techniques remains unclear. However, it has been demonstrated that during recovery from stroke, increased function in specific muscles is accompanied by enlargement of the cortical representation of those muscles measured with transcranial magnetic stimulation [12]. The present study indicates that lasting changes in the excitability of the motor cortex, measured using the same method, can be induced in the hand muscles of normal subjects by one or other peripheral nerve stimulation protocol. This is consistent with the idea that sensory afferent activation normally contributes to the change in cortical organisation following strokes, and perhaps to the partial return of motor function. It also suggests that controlled afferent stimulation has the potential to be used to in therapy, to imprint patterns of cortical reorganisation that favour the improved control of stroke-weakened muscles. The induction of depression observed in the present experiments is less well understood, but may also be relevant in the investigation and treatment of unwanted excessive muscle activity in conditions such as dystonia.

5. Conclusion It is concluded that different protocols based on prolonged peripheral afferent stimulation with or without simultaneous brain stimulation can induce plastic changes in the organisation of the motor cortex that persist for at least 2 h after cessation of the stimulus. Facilitation is the most common response, although significant depression of corticospinal excitability was also observed. These observations support an earlier suggestion that peripheral nerve stimulation may have the potential to lead to therapeutic reorganisation of the damaged cortex [9].

Acknowledgements This work was supported by a Large Grant from the Australian Research Council to TS Miles and PD Thompson. MC Ridding held a Royal Adelaide Hospital Florey Postdoctoral Research Fellowship.

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