Short- and long-term modulation of upper limb motor-evoked potentials induced by acupuncture
Short- and long-term modulation of upper limb motor-evoked
potentials induced by acupuncture
Claudio Maioli, Luca Falciati, Mattia Marangon,1 Sergio Perini 2 and Antonio Losio 2
1Department of Biomedical Sciences and Biotechnologies, University of Brescia, Viale Europa 11, 25123 Brescia, Italy
2U.M.A.B. – Unione Medici Agopuntori Bresciani, Brescia, Italy
“European Journal of Science” Vol 23,pp1931-1938,2006
Keywords: human, long-loop reflex, long-term plasticity, motor cortex, transcranial magnetic stimulation
The aim of this study was to investigate in humans the effects of acupuncture upon upper-limb motor-evoked potentials (MEPs),
elicited by transcranial magnetic stimulation of the primary motor cortex. It is known that peripheral sensory stimulation can be used
to induce short- and long-term changes in motor cortex excitability.
Data show that the simple insertion of the needle is an adequate
somatosensory stimulus to induce a significant modulation of MEP amplitude, the sign of which (facilitation or inhibition) is specific to
the investigated muscle and to the point of needle insertion.
Moreover, MEP changes in upper-limb muscles are also observed
following needling of lower-limb sites, revealing the presence of long-distance effects of acupuncture.
Finally, the modulation in
muscle excitability considerably outlasts the time period of needle application, demonstrating the induction of long-term plastic
changes in the central nervous system. In addition, results have shown that the effects on muscle excitability are not restricted to the
stimulation of well-coded acupoints, as described in traditional Chinese medicine, but they can also be induced by needling of
nonacupoints, normally not used for therapeutic purposes.
The possible neuronal mechanisms underlying the observed effects of
acupuncture are discussed in relation to the available neurophysiological data regarding the interlimb reflexes and the changes in the
representational cortical maps induced in humans by a prolonged somatosensory stimulation.
Introduction
Acupuncture is a 1000-year-old therapeutic technique of traditional
oriental medicine. In western countries it has gained increasing
popularity in health care over the past few decades. Although
mechanisms of its action remain elusive, the National Institute of
Health Consensus Conference (NIH Consensus Conference, 1998)
concluded that acupuncture is an efficacious alternative therapy in
postoperative and chemotherapy-induced nausea and vomiting, as well
as in postoperative dental pain, and that it may be helpful in treating
many other medical conditions.
According to traditional Chinese medicine, functional organic
systems are connected through a network of channels, called
‘meridians’.
The insertion of acupuncture needles in specific acupoints
along the meridians would have a therapeutic benefit on nearby or
distant organs, by regulating energetic imbalances within the organism.
However, recent neuropharmacological and neuroimaging data
have shown that many of the effects of acupuncture might be mediated
by the activation of disease-related areas within the central nervous
system.
For example, stimulation of analgesic acupoints induces the
release of different kinds of opioid neuropeptides (Han & Terenius,
1982; Han, 2003) and the activation of many areas of the
limbic ⁄ paralimbic systems involved in pain mediation (Hui et al.,
2000; Biella et al., 2001; Hsieh et al., 2001).
Furthermore, stimulation
of eye-related (Cho et al., 1998; Siedentopf et al., 2002; Li et al.,
2003a) and language-related acupoints (Cho et al., 2000; Li et al.,
2003b) has been shown to activate cortical areas implicated in vision
and auditory ⁄ language processing, respectively.
An interesting tool for investigating acupuncture effects on activity
of the central nervous system is the study of motor cortex excitability.
This approach arises from the consideration that if multiple brain areas
are activated by acupuncture, this must be the consequence of the
stimulation of somatosensory afferent fibres, produced by needle
insertion. It is well known that peripheral sensory stimulation induces
short- and long-term changes in motor cortex excitability.
In fact, the stimulation of skin or muscle nociceptive fibres in the distal upper
limb has an inhibitory effect on motor-evoked potentials (MEPs),
induced by transcranial magnetic stimulation (TMS) of the primary
motor cortex (Kofler et al., 1998, 2001; Valeriani et al., 1999; Farina
et al., 2001; La Pera et al., 2001; Svensson et al., 2003).
This
inhibition is specific to the muscles adjacent to the painful area, given
that it is not present or becomes excitation in more proximal muscles.
Conversely, a prolonged nonpainful stimulation of peripheral nerves
induces a long-term increase in excitability in the motor cortex
representation of the corresponding muscles (Mariorenzi et al., 1991;
Hamdy et al., 1998; Ridding et al., 2000, 2001; Kaelin-Lang et al.,
2002; Charlton et al., 2003). These effects are also very specific and
are accompanied by topographic changes in the related representational
cortical maps.
The aim of this study was to ascertain whether insertion of an
acupuncture needle constitutes an adequate stimulus of somatosensory
afferents, in order to induce changes in the excitability of cortical
and ⁄ or spinal motor areas.
This issue has been investigated by
studying the acupuncture-induced modulation of MEPs in various
muscles of the upper limb, after TMS of the contralateral primary
motor cortex. How the sensory fibre stimulation or the changes in
motor excitability, induced as a result of needle insertion, relate to the
therapeutic effects of acupuncture is far beyond the scope of the
present paper and cannot be addressed by the experimental approach
utilized here. Instead, we were particularly interested to ascertain
whether acupuncture is able to induce long-lasting plastic changes in
cortical ⁄ spinal excitability, as with those reported to occur after the
prolonged stimulation of somatosensory afferent fibres, by verifying
the persistence of changes in MEP amplitude after needle extraction.
In addition, the specificity of acupoint effects has also been addressed
by comparing the responses induced by needle insertion in well-coded
analgesic points of traditional acupuncture with those induced by
stimulation of nonacupoints, normally not used for therapeutic
purposes.
Finally, because in oriental medicine acupoints are believed
to exert effects on body parts located at a considerable distance, we
investigated whether MEP amplitude of hand and wrist muscles is also
affected by acupuncture applied to distant cutaneous areas of the lower
extremities.
Materials and methods
Subjects
Fifteen healthy adult volunteers (eight female and seven male, ages
19–46 years, mean age 28.9 years), with no history of head trauma or
neurological disease, participated in the study, and all gave written
informed consent. All procedures were conducted in accordance with
the ethical guidelines set forth by the Helsinki declaration. All subjects
were Europeans and right-handed, as measured by the Edinburgh
handedness inventory. They were all naı¨ve to acupuncture stimulation,
except three participants who had previous experience and cultural
exposure to acupuncture.
Stimulation and recording
Subjects lay comfortably in a supine position, with their head
immobilized by a polystyrene-bead vacuum splint, moulded on the
neck and rear part of the head. Acupuncture needling was performed
by experienced acupuncturists under aseptic conditions. Disposable
sterilized Hawato needles (Suzhou Medical Appliance Factory, China)
were used, measuring Ø 0.30 · 25 mm for hand acupuncture and
Ø 0.26 · 40 mm for lower limb acupuncture. Two distinct sites for
acupuncture were chosen on both upper and lower limb: a well-known
classical acupoint, as described in traditional Chinese medicine, and a
nonacupoint. On the upper limb, acupoint LI4 (Hegu) at the region of
the first dorsal interosseous space of the left hand was used (Fig. 1A).
This is one of the most frequently exploited points in Chinese
acupuncture, of prominent analgesic efficacy. As a hand nonacupoint
(hereafter HNA), we chose a site in the proximal third of the thenar
eminence on the left side, at a distance of 2 cm from the radio-carpal
joint. Experiments with upper-limb acupuncture were conducted on
ten subjects. For lower-limb acupunture, we used acupoint ST38
(Tiaokou) situated laterally to the anterior crest of the tibia, about
midway along the course of the tibialis anterior muscle (Fig. 1B). This
is another classical analgesic acupoint, which is often utilized to treat
shoulder pain. As a lower-limb nonacupoint, we chose a site on the
lateral aspect of the thigh (TNA), placed between the vastus lateralis
and the biceps femori, midway between the transverse popliteal crease
and the highest point of the great trochanter. Eight subjects
participated in the experiments with lower-limb acupuncture, which
was performed either to the left or to the right side in equal numbers
(two subjects were tested on both sides). Three subjects were involved
in both upper- and lower-limb experiments. In both upper- and lowerlimb
groups, all subjects underwent needling of both acupoints and
nonacupoints in different experimental sessions, in a randomized
order. The depth of needle insertion in the tissue was _1 cm at LI4
and HNA, and _2 cm at ST38 and TNA.
Surface electromyograms (EMG) were simultaneously recorded
from abductor digiti minimi (ADM), first dorsal interosseous (FDI)
and flexor carpi radialis (FCR) muscles, ipsilaterally to the acupuncture
sites, by means of silver ⁄ silver chloride electrodes in bipolar
configuration (interdetection spacing of about 2 cm). FDI muscle was
not recorded when acupuncture was applied to the LI4 acupoint,
because of its proximity to the needling site. Signals were amplified
1000· in the bandwidth 0.2 Hz to 1 kHz. EMG was digitally
converted (PCI-MIO-16E-4, National Instruments, Austin, TX, USA)
and sampled at 4 kHz on a personal computer. MEP waveforms were
logged and analysed off-line by means of custom-written Labview
software (National Instruments).
TMS was applied to the motor cortex, contralaterally to the EMG
recorded muscles, with a Magstim Super Rapid magnetic stimulator
(Mag-1450-00, Magstim Co. Ltd, Whitland, UK), using a figure-ofeight
double coil (Ø 70 mm). The coil was orientated at 45_ oblique to
the sagittal plane, so that the induced current flowed perpendicular to
the estimated alignment of the central sulcus. The scalp site at which
MEPs were elicited in ADM muscle at the lowest stimulus strength
was determined. Once the optimal scalp site was found, the coil was
securely fixed in place by means of an appropriate mechanical device.
The response threshold was defined as the stimulus intensity at which
5 ⁄ 10 consecutive single stimuli at the optimal site evoked an MEP of
at least 100 lVamplitude in the relaxed muscle (Rossini et al., 1994).
Stimulus intensity during the entire stimulation paradigm was set at
1.2 times the ADM motor threshold. This stimulation intensity at the
optimal scalp site for ADM also evoked MEPs in FDI and FCR
muscles in all experimental sessions. However, to ensure that
acupuncture effects could be measured against a reliable baseline,
FDI and FCR data were included in the analysis only if their MEPs
had an amplitude greater than 100 lV in 10⁄ 12 stimuli delivered
during the control phase of the experimental protocol, before
acupuncture needle insertion. This acceptance criterion was always
fulfilled by FDI recordings; by contrast, FCR data were rejected in
6 ⁄ 40 experimental sessions. All data from one experiment with LI4
acupuncture had to be discarded for technical reasons. Furthermore,
attention was paid that all TMS sequences were performed with
subjects keeping their muscles completely relaxed, in the absence of
any detectable EMG activity.
MEP amplitude was defined as the peak-to-peak amplitude of the
mean response obtained by averaging 12 consecutive TMS trials,
delivered with an interstimulus interval of 5 s. This sequence of test
stimuli had an overall duration of 1 min and was employed as our
standard procedure to measure cortical ⁄ spinal excitability to TMS in
resting conditions and following acupuncture.
Stimulation protocol
The experimental protocol was designed in order to differentiate the
effects induced by the simple needle insertion from those induced by a
prolonged needle manipulation, similar to that applied for therapeutic
purposes in traditional Chinese medicine. Furthermore, we also
wanted to ascertain the existence of long-term changes in cortical
⁄ spinal excitability, persisting after needle removal. To this end, we
divided the experimental session into four phases (Fig. 1C). In the
‘control phase’, MEP amplitude in resting conditions was measured by
three sequences of test stimuli applied at 3-min intervals. Following a
resting period of 3 min, the ‘needle insertion phase’ began by simply
inserting the acupuncture needle in the selected site, without applying
any kind of manipulation. Changes in muscle excitability to TMS
were assessed by means of four sequences of test stimuli delivered at
3-min intervals, starting 1 min after needle insertion. A needle
manipulation was then undertaken by the acupuncturist for 15 s, by
using the lifting and thrusting technique with no needle rotation. This
procedure was repeated after a resting time interval of 15 s, for a total
duration of 2 min of alternating manipulation and resting periods. The
‘postmanipulation phase’ followed in which, after a further 2 min of
rest, TMS stimulation was applied again by delivering three sequences
of test stimuli at 3-min intervals. One minute after the last sequence
the needle was removed, marking the beginning of the final
‘postacupuncture phase’. Here, the presence of long-term changes in
muscle excitability to TMS was ascertained by measuring the changes
in MEP amplitude by four sequences of test stimuli applied at 3-min
intervals, starting 2 min after needle removal. The entire stimulation
protocol therefore had a total duration of 55 min.
Results
Needling sensation
Subjects well tolerated the acupuncture procedure in all 40 experimental
sessions. Needling was experienced as a mild (29 trials) to
moderate (seven trials), short-lasting pain sensation (pricking), for all
four sites of acupuncture. No sensation at needle insertion was
reported in the remaining four cases.
In traditional Chinese medicine, De Qi is a unique sensation of
numbness, soreness, heaviness or tingling that develops at the site of
acupuncture, often spreading towards nearby cutaneous areas. When
Fig. 1. Schematic drawings of the right hand (A) and leg (B), showing the location of acupoints LI4 (Hegu) and ST38 (Tiaokou), where acupuncture was
performed. (C) The experimental paradigm, divided into control, needle insertion, postmanipulation and postacupuncture phases. Arrows indicate the exact occurrence of needle insertion (IN) and extraction (OUT), and the time period in which the needle was manipulated by using the lifting and thrusting technique. The rectangles labelled STS represent the 1-min sequences of test stimuli, in which 12 consecutive TMS trials were delivered with an interstimulus interval of 5 s. acupuncture was performed along classical meridians (both at LI4 on the hand and at ST38 on the leg) De Qi sensation was reported
following needle manipulation in 90% of the experimental sessions.
Subjects never described needle manipulation at LI4 or ST38
acupoints as painful.
By contrast, De Qi was never reported during needle manipulation
at the two nonacupoints HNA and TNA. Pooling together hand and
thigh data, needle manipulation yielded no sensation in four sessions
and a moderate but bearable painful sensation in seven sessions. In all
other cases, subjects reported a tactile or nonpainful pricking
sensation, strictly localized at the needle insertion point.
Effects of hand acupuncture on MEP amplitude
Needling of both LI4 and HNA significantly influenced MEP
amplitude of both hand and forearm muscles. However, the direction
of change and its time course markedly differed depending on the
acupuncture site.
Figure 2A shows, as an example, the effects of LI4 acupuncture on
the average MEP recordings from the ADM muscle in one representative
subject. Each column contains all MEP measurements obtained
in the corresponding phase of the experimental protocol. Note the
steadiness of the waveform amplitudes during the control phase, as
well as within the subsequent phases following needle insertion. A
clear decrease in MEP amplitude can readily be observed after needle
manipulation, which is maintained also after needle removal.
Figure 3 shows the modulation of mean MEP amplitude across
subjects in ADM, FCR and FDI muscles during the different phases
of our acupuncture protocol, with separate graphs for the two
stimulation sites. Each point represents the group average value, after
an intrasubject normalization by the mean MEP amplitude of the
three control values recorded before needle insertion. For each phase
of the protocol, MEP amplitude was compared with the control
values by a two-way anova for repeated measurements (phase and
timing-within-phase as factors). No significant principal effects for
the timing-within-phase of stimulation or interaction between the two
factors were found in all comparisons. The phases for which the test
yielded a statistically significant difference (P < 0.05) with respect to
the control are indicated in Fig. 3 by filled symbols. For LI4
acupuncture, neither needle insertion nor its manipulation produced
changes in MEP amplitude. However, a highly significant decrease
in MEP amplitude was observed after needle extraction in ADM
(P < 0.001). No modulation of MEP amplitude was observed in
FCR muscle.
By contrast, a completely different response pattern was observed
following HNA acupuncture. Simple needle insertion induced an MEP
Fig. 2. Average EMG recordings from ADM muscle of two representative subjects, showing the effects of acupuncture at the LI4 and ST38 acupoints on the amplitude of MEPs, evoked by TMS of the contralateral motor cortex. Each trace is the average of 12 responses; trace onsets correspond to the time of delivery of the TMS pulse. For each phase of the experimental protocol, all repetitions of MEP measurements are shown, ordered according to their time sequence from top to bottom. (A) MEP recordings from one subject in an experimental session in which acupuncture was performed at the LI4 acupoint (hand). (B) MEP recordings in
a different subject following acupuncture at the ST38 acupoint (leg).
Fig. 3. Amplitude modulation of MEPs in ADM, FCR and FDI muscles
following hand acupuncture, during the different phases of the experimental
protocol. The upper panel shows the average values across subjects for the
experiments in which needling was performed at the LI4 acupoint, while the
lower panel refers to the data recorded after needling of the hand nonacupoint
(HNA). Filled symbols indicate a statistically significant difference with respect
to the control (P < 0.05), for the set of measurements obtained within the
corresponding protocol phase. Arrows labelled ‘in’ and ‘out’ show the timing
of occurrence of needle insertion and extraction, respectively. The three arrows
at the centre of the graph (labelled ‘man.’) correspond to the time interval of
needle manipulation. amplitude increase in ADM (P < 0.05) and a reduction in FDI
(P < 0.001). However, these changes were not maintained in the last
two protocol phases, i.e. after needle manipulation and extraction.
Again, no significant modulation of MEP amplitude occurred in FCR
muscle.
Effects of lower-limb acupuncture on MEP amplitude
Because acupuncture proved to be very effective in modulating MEP
amplitude when applied near the recorded muscle, irrespective of
whether that the site was or was not a classical acupoint, we
investigated whether distant points in the lower limb could also
similarly affect hand muscle excitability following TMS. Needling
was applied to the anterior surface of the leg on ST38, a commonly
used distal acupoint to treat shoulder pain, and to TNA, which was
located on the thigh along the long head of the biceps femoris muscle,
outside any classical meridian.
As an example, Fig. 2B shows the effects of ST38 acupuncture on
the average MEP recordings from the ADM muscle in one representative
subject. It can be seen that the simple needle insertion induces a
slow build-up in MEP amplitude. This increase in muscle excitability
is then maintained also in the postmanipulation phase and following
needle extraction.
We performed two experimental series that differed with respect to
the side on which lower-limb acupuncture (and muscle recording) was
executed. Three-way anova (side, phase and timing-within-phase as
factors) yielded no significant left–right difference in MEP amplitude
of ADM (P > 0.5), FCR (P > 0.5) and FDI (P > 0.1) muscles, for
both ST38 and TNA acupuncture. Therefore, left- and right-side data
were pooled together for further analysis.
Figure 4 shows the modulation of mean MEP amplitude across
subjects, in the three studied muscles during the different phases of our
acupuncture protocol, when needling was performed in the two lowerlimb
sites. As in Fig. 3, filled symbols indicate a statistically significant
difference (P < 0.05) in MEP amplitude with respect to the control, as
revealed by a two-way anova test for repeated measurements. Again
modulations in MEP amplitude were induced by acupuncture at both
ST38 and TNA. In general, an increase in MEP amplitude was observed
in all three phases (after needle insertion, manipulation and extraction).
However, the amplitude increase observed in FCR never reached
statistical significance, in both ST38 andTNAexperiments. By contrast,
there was a very large MEP facilitation after needle manipulation in
ADM (P < 0.005) and FDI (P < 0.0005) muscles, which was maintained
even over the entire last phase after needle extraction.
Discussion
Effects of acupuncture on excitability of upper-limb muscles to
motor cortex TMS
We investigated the effects of acupuncture upon upper-limb MEPs,
elicited by TMS of the primary motor cortex. Our study yields a number
of remarkable findings. First, the data demonstrate that simple insertion
of the acupuncture needle, which produces only a very mild, localized
and short-lasting somatosensory stimulation, is sufficient to induce a
significant modulation of excitability of the motor pathways that depart
from the primary motor cortex. Secondly, changes in MEP amplitude of
upper-limb muscles also occur following acupuncture of lower-limb
sites, the central afferent projections of which are primarily directed
towards areas of the spinal cord and motor cortex, which are located far
from the areas that exert a motor control of the affected muscles. Lastly,
the observed modulation of muscle excitability can considerably outlast
the time period of needle application, demonstrating that acupuncture is
able to induce long-term plastic changes in the central nervous system.
Acupuncture effects can hardly be ascribed to nonspecific changes
in whole-system excitability, e.g. due to the level of arousal, given that
they appear to depend very specifically on the recorded muscle and on
the needling point. For example, acupuncture of the lower limb
induces a generalized increase in MEP amplitude, which progressively
builds up after needle insertion. This MEP facilitation is then steadily
maintained after needle manipulation and needle removal. Conversely,
changes in MEP amplitude following acupuncture of the hand strongly
depend on the stimulation point and on the investigated muscle. Thus,
simple needle insertion at HNA induces an MEP facilitation in ADM
muscle, but an MEP inhibition in FDI, with no change in FCR. These
effects are not maintained after manipulation or extraction of the
needle. By contrast, a marked decrease in ADM muscle excitability
builds up after needle manipulation at the LI4 acupoint, which is
steadily maintained after needle extraction. It should be pointed out
that these markedly different MEP modulations occur in spite of the
fact that both the LI4 and the HNA cutaneous sites lie on the C6
dermatome and both ADM and FDI motor innervations come
primarily from C8–T1 spinal segments.
This observed decrease in ADM muscle response is in agreement
with the conclusions of Lo & Cui (2003), the only study in the
literature on the short-term modulation of muscular MEPs induced by
acupuncture. These authors also found an MEP decrease in ADM,
occurring 2 min following needle manipulation at the LI4 acupoint.
However, they did not investigate the long-term effects following
needle removal and restricted the analysis to only one muscle.
Acupoint vs. nonacupoint responses
We also attempted here to address the issue of the specificity of
acupuncture effects, by comparing the responses induced by stimulating
well-coded analgesic acupoints, as described in traditional
Fig. 4. Amplitude modulation of MEPs in ADM, FCR and FDI muscles
following lower-limb acupuncture, during the different phases of the experimental protocol. The upper panel shows the average values across subjects for the experiments in which needling was performed at the ST38 acupoint, while nonacupoint (TNA). See Fig. 2 for details.
Acupuncture and motor cortex TMS 1935
Chinese medicine, with the responses elicited by acupuncture at points
located outside classical meridians, i.e. points that are normally not
used for therapeutic purposes. Our data clearly demonstrate that both
classical acupoints and nonacupoints are similarly effective in
modulating MEP responses to motor cortex TMS. Nevertheless, it
should be noted that the elicited responses strongly depend on the
needling point, as far as it concerns the affected muscles, direction of
excitability changes and time course of the effects.
Finding a reliable ‘sham point’ to use in comparison with classical
acupoints is a well-known difficulty in all studies on the efficacy of
acupuncture treatments. An ideal ‘sham point’ would be an area of
skin located at some distance from any known acupoint. However,
over 400 points have been described on meridians in traditional
Chinese medicine, so that it is hard to identify a site that is not in the
immediate proximity of an acupoint or influences it. Accordingly, it is
known that points other than those indicated on acupuncture charts can
have therapeutic effects and that needling at ‘sham points’ is effective
in inducing analgesia in about 33–50% of patients with chronic pain
(Richardson & Vincent, 1986).
In this respect, it is interesting to note that functional neuroimaging
studies have demonstrated a remarkable overlapping between the brain
areas activated by needling at acupoints and nonacupoints (Wu et al.,
2002; Yoo et al., 2004), including a number of areas of the pain
neuromatrix such as the insula and the anterior cingulate cortex.
Furthermore, auditory and visual cortices are activated not only
following acupuncture of eye-related and ear-related acupoints, but
also after needling of acupoints not implicated in the treatment of eye
or language diseases, as well as following acupuncture of nonmeridian
points, normally not used in classical acupuncture (Wu et al., 2002;
Yoo et al., 2004).
It should also pointed out that in our study modulation of MEP
amplitude was not found to be related to the occurrence of a De Qi
sensation, as De Qi was commonly reported by the subjects after
acupuncture at the LI4 and ST38 acupoints, but was never experienced
after needling at nonacupoints.
Acupuncture-mediated interlimb effects
Our results have shown that acupuncture in the lower limb induces a
marked facilitation of MEP amplitude in upper-limb distal muscles.
MEP amplitude of the more proximal FCR muscle is also somewhat
increased with respect to control, especially following ST38 needling,
but the difference does not reach statistical significance, probably
because of the large sample variability. This is an intriguing finding as
it shows that a mild and tonic stimulation of somatosensory afferents
to the lumbar spinal cord induces a slow build up of excitability in
muscles which are innervated by the cervical segments. Moreover,
these changes in muscular excitability are plastic, as they are steadily
maintained for more than 15 min after needle removal. Whether this
increase in MEP amplitude is due to an augmented excitability of the
motoneuronal pool in the spinal cord, or reflects changes occurring at
the level of the motor cortex, is an issue that cannot be addressed on
the basis of our results. However, data from the literature can suggest a
possible neuronal substrate to our finding.
There is a growing body of recent experimental evidence that in
humans, similarly to quadrupedal animals, cervical and lumbar spinal
cord segments are extensively interconnected. Several studies have
investigated reflexes from lower-limb sensory afferents onto
motoneurons of upper-limb muscles (and vice versa). In particular,
large excitatory and ⁄ or inhibitory reflexes in upper-limb flexor and
extensor muscles of intact subjects have been described after ankle
displacement or cutaneous stimulation of the foot (Kearney & Chan,
1979, 1981), and after electrical stimulation of cutaneous nerves from
the distal lower limb (Dietz et al., 2001; Zehr et al., 2001). Similarly,
lower-limb reflexes are also evoked following stimulation of upperlimb
afferents (Sarica & Ertekin, 1985; Zehr et al., 2001; Kagamihara
et al., 2003).
Uncertainty exists about the pathways mediating these reflexes. On
the basis of the shortest response latencies, Zehr et al. (2001)
suggested that cutaneous reflexes interconnect the four limbs through
a propriospinal pathway. However, only a minority of the interlimb
response latencies fall below 70 ms (Dietz et al., 2001; Zehr et al.,
2001), which has been proposed as the shortest possible latency for a
transcortical loop (Nielsen et al., 1997). Obviously, the assumption
that interlimb reflexes and the increase in upper-limb muscle
excitability, induced by lower-limb acupuncture, are mediated by the
same neuronal pathways should be taken very cautiously. Furthermore,
it should be noted that interlimb reflexes have been primarily
described in proximal muscles including FCR (Dietz et al., 2001; Zehr
et al., 2001; Kagamihara et al., 2003). By contrast, in our study FCR
excitability is only mildly affected by lower-limb acupuncture, the
largest effects being recorded in the distalmost muscles, FDI and
ADM.
Nevertheless, the existence of spinal and supraspinal interconnections
between lumbar and cervical segments, as revealed by the studies
on interlimb reflexes, provides a suitable anatomical and neurophysiological
substrate to account for the described long-distance effects of
acupuncture.
Long-term effects induced by acupuncture
A remarkable finding of this study is the demonstration of an
acupuncture-induced neurophysiological effect that outlasts the period
of needle insertion. In particular, acupuncture at LI4 induces a
statistically highly significant MEP reduction in ADM muscle, which
is still present 15 min after needle removal and does not show any sign
of adaptation in four consecutive assessments of MEP amplitude. This
MEP inhibition, observed in the mean response of nine different
subjects, must therefore be considered to be the result of a long-term
reorganization of motor cortex and ⁄ or spinal circuitry. Interestingly, a
long-term modulation of MEP amplitude in hand muscles was
observed also after acupuncture of the lower limb. In fact, a significant
MEP facilitation in ADM and FDI muscles persists after needle
extraction following stimulation of both ST38 and TNA. This result
clearly demonstrates that the mild and tonic somatosensory stimulation
produced by acupuncture has the property of inducing long-term
plastic changes in the excitability of very distant nervous structures,
which exert a motor control upon remote muscles.
Prolonged stimulation of peripheral somatosensory afferents is
known to induce in humans a long-term reorganization of the motor
cortex (Hamdy et al., 1998; Farina et al., 2001; Ridding et al., 2001;
Kaelin-Lang et al., 2002; Charlton et al., 2003; Svensson et al., 2003).
In particular, a painful stimulation of upper extremities induces a longlasting
depression of MEPs elicited by motor cortex TMS in upperlimb
distal muscles (Svensson et al., 2003) and a short-lasting
facilitation in the ipsilateral biceps brachii (Kofler et al., 1998, 2001).
Conversely, a facilitation of MEPs has been described following a
nonpainful stimulation of peripheral afferents in both pharyngeal
muscles (Hamdy et al., 1998) and hand muscles (Ridding et al., 2000,
2001; Kaelin-Lang et al., 2002; Charlton et al., 2003). Furthermore,
extended plastic changes in the cortical maps, which persist for hours
(Stefan et al., 2000) or days (McKay et al., 2002) after the end of the
1936 C. Maioli et al.
ª The Authors (2006). Journal Compilation ª Federation of European Neuroscience Societies and Blackwell Publishing Ltd
European Journal of Neuroscience, 23, 1931–1938
stimulation sessions, have been described to occur following a
prolonged combined stimulation of the peripheral nerve and the motor
cortex with TMS.
Our results on the long-lasting effects of acupuncture can be
cautiously interpreted in this conceptual framework. The site of
occurrence of the neuronal reorganization cannot be ascertained on the
basis of our data, as the amplitude of MEPs depends on the excitability
of both the motor cortex and the spinal cord at the time the TMS pulse
is applied. The exact type of afferent fibres that are activated by our
procedure is also unknown. Measurements of H-reflex, in order to test
changes in spinal cord excitability, are difficult to obtain reliably in
upper-limb muscles, except in FCR. Unfortunately, modulations of
MEP amplitude in FCR muscle are not statistically significant with our
acupuncture protocol, so that this technique to probe spinal cord
excitability cannot be usefully applied to our study. Future experiments
with F-wave recordings or with measurements of intracortical
inhibition with paired-pulse TMS (Kujirai et al., 1993) will be
undertaken in order to investigate the level of plastic changes induced
by acupuncture.
It should also be mentioned that recent work has demonstrated that
subjects must pay attention to the site to which a sustained somatosensory
stimulus is applied, in order to induce a sensorimotor reorganization
of the motor cortex (Rosenkranz & Rothwell, 2004, 2005). In fact, only
in this case was a specific pattern of reorganization produced, in which
nearby and distant muscles showed an increase or a decrease of MEP
amplitude, respectively. In our study, subjects, although lying relaxed in
a supine position, cannot avoid paying attention to the acupuncture site,
at least during insertion and manipulation of the needle. In our case,
however, long-lasting changes in MEP amplitudes appear to be far more
diversified depending on the acupuncture site. For example, a marked
MEP increase in hand muscles is induced after needling of very distant
sites in the lower limb.
Regardless of the location of the neural reorganization, we are faced
with persisting changes in motor excitability induced by a somatosensory
stimulation, consisting either in the simple insertion of the
needle, as in the case of lower-limb acupuncture, or in a repeated
needle manipulation. Unlike findings from previous neurophysiological
studies, the plastic changes are here produced by a very localized
stimulation of somatosensory afferents and, moreover, can involve
muscles that are located far from the site of stimulation. Furthermore,
both facilitatory and inhibitory effects can be elicited in the different
muscles, depending on the acupuncture site. Although the functional
significance of these responses is still far from clear, this study
provides further evidence in favour of the capacity of acupuncture to
affect nervous functions in a profound and diversified manner.
Abbreviations
ADM, abductor digiti minimi; EMG, electromyogram; FCR, flexor carpi
radialis; FDI, first dorsal interosseous; HNA, hand nonacupoint; MEP, motorevoked
potential; TMS, transcranial magnetic stimulation; TNA, thigh
nonacupoint.
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