DOI: 10.1093/brain/awh212 Brain (2004), 127, 1887–1898
Cortico-motoneuronal excitation of three hand
muscles determined by a novel penta-stimulation
technique
Ulf Ziemann, Tihomir V. Ilic´, Henrik Alle and Frank Meintzschel
Correspondence to: Ulf Ziemann, Motor Cortex Laboratory,
Department of Neurology, Johann Wolfgang Goethe-
University of Frankfurt, Schleusenweg 2–16, D-60528
Frankfurt am Main, Germany
E-mail: u.ziemann@em.uni-frankfurt.de
Motor Cortex Laboratory, Department of Neurology,
Johann Wolfgang Goethe-University of Frankfurt, Frankfurt
am Main, Germany
Summary
The cortico-motoneuronal system (CMS), i.e. the mono-
synaptic projection from primary motor cortex to moto-
neurons in lamina IX of the spinal cord is, among all
mammals, best developed in humans. Increasing evidence
suggests that the CMS is crucially important for skilled
individuated finger movements. Little is known about to
what extent the strength of the CMS differs between hand
muscles. Here we measured CMS excitation to the first
dorsal interosseus (FDI), abductor pollicis brevis (APB)
and abductor digiti minimi (ADM)muscles in healthy sub-
jects by using a novel penta-stimulation technique (PST)
and single motor unit (SMU) recordings. The PST is an
extension of the triple-stimulation technique. It applies two
additional supramaximal electrical stimuli at the wrist to
the ‘peripheral nerve of no interest’ (in the case of the FDI
and ADM the median nerve, in the case of the APB the
ulnar nerve) to collide with the descending volleys in that
nerve elicited by transcranial magnetic stimulation of
motor cortex and electrical stimulation of Erb’s point.
This eliminates volume conduction from neighbouring
muscles innervated by the nerve of no interest and, there-
fore, allows accurate determination of the PST response.
The PST response was significantly larger in the FDI
compared with the ADM and APB. This was validated
by the SMU recordings, which showed a higher estimated
amplitude of the mean compound excitatory postsynaptic
potential in spinal motoneurons of the FDI than in those
of the APB and ADM. Finally, as a possible functional
correlate, the maximum rate of repetitive voluntary finger
movements was higher for index finger abduction (prime
mover, FDI) than for little finger abduction (prime mover,
ADM) and thumb abduction (prime mover, APB), and
individual differences in maximum rate between the dif-
ferent movements correlated with individual differences
in the corresponding PST responses. In conclusion, PST
is a valuable novel method for accurate quantification of
CMS excitation. The findings strongly suggest that CMS
excitation differs between hand muscles and that these
differences directly link to capability differences in
individuated finger movements.
Keywords: human cortico-motoneuronal system; intrinsic hand muscles; penta-stimulation technique; transcranial magnetic
stimulation; single motor unit recording
Abbreviations: ADM = abductor digiti minimi muscle; AMT = active motor threshold; APB = abductor pollicis brevis muscle;
cEPSP = compound excitatory post-synaptic potential; CMS = cortico-motoneuronal system; EMG = electromyogram;
FDI = first dorsal interosseous muscle; ISI = inter-spike interval; M1 = primary motor cortex; MEP = motor evoked potential;
MN = motor neuron; N1 = nerve of interest; N2 = nerve of no interest; PP = primary peak; PSTH = peri-stimulus time
histogram; PST = penta-stimulation technique; RMT = resting motor threshold; SMU = single motor unit; TMS = transcranial
magnetic stimulation; TST = triple-stimulation technique.
Received January 9, 2003. Revised April 7, 2004. Accepted April 9, 2004. Advanced Access publication June 30, 2004
Brain Vol. 127 No. 8
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Introduction
H. G. J. M. Kuypers provided systematic evidence that the
cortico-motoneuronal system (CMS), i.e. the mono-synaptic
projection from the primary motor cortex (M1) to spinal
a-motoneurons (MNs) in the anterior horn (Rexed lamina
IX), does not exist in lower mammals and is best developed
in the great apes and humans (Kuypers, 1981). Early investi-
gators proposed already that the CMS is of crucial importance
for dexterous individuated finger movements (Tower, 1940;
Bernhard et al., 1953; Kuypers, 1962). This is supported by
comparative anatomical work in mammals at different phylo-
genetic levels, which shows that the presence and degree of
development of the CMS are correlated with digital dexterity
(Heffner andMasterton, 1975, 1983;Bortoff andStrick, 1993).
Further support comes from developmental studies in humans,
which demonstrate parallel maturational profiles, continuing
well into the second decade, of the myelination and axon
diameter of fibres in the CMS (Paus et al., 1999), central
motor conduction time when tested by transcranial magnetic
stimulation (TMS) (Mu¨ller et al., 1991; Mu¨ller and Ho¨mberg,
1992) anddexterity offinefinger coordination (Forssberget al.,
1991) and maximum rate of repetitive tapping movements
(Mu¨ller and Ho¨mberg, 1992). Lesion studies in monkeys
show that the most conspicuous behavioural consequence
of bilateral pyramidotomy in monkeys is a lasting loss of
independent finger movements (Lawrence and Kuypers,
1968). Finally, single-unit recordings in monkey M1 indicate
that a large fraction of cortico-spinal cells encodemotor output
parameters such as force (Cheney and Fetz, 1980), in particular
small force increments (Evarts et al., 1983) and rate of change
of force (Smith et al., 1975), andmovement velocity and accel-
eration (Ashe and Georgopoulos, 1994; Schwartz and Moran,
2000; Mehring et al., 2003).
Despite this substantial evidence for a crucial role for the
CMS in finger movements, little is known about to what extent
the strength of the CMS differs between a-MNs of different
intrinsic handmuscles. The strength of the CMSmay be estim-
ated in vivoby the sizeof thecompoundexcitatorypostsynaptic
potential (cEPSP) in single motor unit (SMU) recordings
(Maertens de Noordhout et al., 1999; Mills, 2002), and by
the amplitude of the motor evoked potential (MEP) in the
surface electromyogram (EMG). Both measures are elicited
by synchronous excitation of the CMS, for instance by TMS
applied tomotor cortex.CMSexcitation at a givenTMSintens-
ity depends on the intrinsic excitability of the activated
neural elements, and the density of CMS fibres at the site of
stimulation (Hallett et al., 1999). From the measures of cEPSP
or MEP, it is not possible to disentangle to what extent these
two effects contribute. Therefore, throughout this paper, the
term CMS excitation implicates both CMS excitability and
CMS fibre density.
Considerable differences in CMS excitation may be
expected between intrinsic hand muscles because they
participate to various extents in functionally important finger
movements, such as the pincer precision grip where the first
dorsal interosseous (FDI) muscle and the abductor pollicis
brevis (APB) muscle are agonists, while the abductor digiti
minimi (ADM) muscle is much less involved (Maier and
Hepp-Reymond, 1995). CMS excitation measured by cEPSP
amplitude in SMU recordings seems maximal for intrinsic
hand and forearm finger extensor muscles and significantly
less for forearm finger flexor and proximal arm muscles
(Palmer and Ashby, 1992; Maertens de Noordhout et al.,
1999). A systematic comparison between intrinsic hand
muscles was, however, not done. One disadvantage of SMU
recordings is that many SMUs need to be studied to obtain an
approximate picture of thewhole system.A less tediousway to
assess CMS excitation is through MEP amplitude elicited by
TMS. Accurate quantification of CMS excitation is, however,
precluded due to chronodispersion of the cortico-spinal volley,
resulting in phase cancellation and, in turn, significant reduc-
tion ofMEP amplitude. This problemwas solved by the triple-
stimulation technique (TST) (Magistris et al., 1998). TST was
described for the anatomically isolated ADM but not for other
intrinsic hand muscles, such as the FDI or APB, in which the
TST responsemay be contaminated to a considerable extent by
volume-conducted responses from neighbouring muscles. In
order to measure CMS excitation to various intrinsic hand
muscles (FDI, ADM andAPB) without the problem of volume
conduction, we introduce here, as an extension of the TST, a
novel penta-stimulation technique (PST). In addition, we per-
form SMU recordings to validate the PST data. Finally, as a
possible functional correlate of CMS excitation, we test the
maximum rate of those repetitive voluntary individuatedfinger
movements in which these muscles are prime movers (index
finger abduction for FDI, little finger abduction for ADM, and
thumb abduction for APB).
Methods
Subjects
The study was divided into three experiments. Six subjects (mean
age 32.0 6 4.9 years; five male; five right-handed) participated in
experiment I, three subjects (33.0 6 3.5 years; all male; all right-
handed) in experiment II, and 16 subjects (32.86 4.4 years; 12 male;
15 right-handed) in experiment III. All subjects gavewritten informed
consent. The study conformed to the Declaration of Helsinki and was
approved by the Ethics Committee of The Hospital of Johann
Wolfgang Goethe-University of Frankfurt am Main, Germany.
Experiment I
This experiment used PST to quantify CMS excitation to three dif-
ferent hand muscles: FDI, ADM and APB. PST is an extension of the
TST (Magistris et al., 1998). TST applies TMS to the M1 hand area,
followed by supramaximal peripheral nerve stimulation at the con-
tralateral wrist, and finally supramaximal electrical stimulation of the
brachial plexus at Erb’s point (Fig. 1). This links, through two colli-
sions along the peripheral nerve, central to peripheral conduction and
eliminates the problemof desynchronization of theMEP (Fig. 1). This
technique revealed that, in healthy subjects, all or nearly all a-MNs
can be discharged byTMS (Magistris et al., 1998). TSTwas described
1888 U. Ziemann et al.