Clinical Neurophysiology 119 (2008) 744–762

www.elsevier.com/locate/clinph

Invited review

Neurophysiology of unimanual motor control and mirror movements

a,* b
M. Cincotta , U. Ziemann
a
Unità Operativa di Neurologia, Azienda Sanitaria di Firenze, Ospedale Piero Palagi, Viale Michelangiolo, 41, 50125 Firenze, Italy
b
Neurologische Klinik, J.W. Goethe-Universität, Frankfurt/Main, Germany

Accepted 23 November 2007

Available online 9 January 2008

Abstract

In humans, execution of unimanual motor tasks requires a neural network that is capable of restricting neuronal motor output activity
to the primary motor cortex (M1) contralateral to the voluntary movement by counteracting the default propensity to produce mirror-
symmetrical bimanual movements. The motor command is transmitted from the M1 to the contralateral spinal motoneurons by a largely
crossed system of fast-conducting corticospinal neurons. Alteration or even transient dysfunction of the neural circuits underlying move-
ment lateralization may result in involuntary mirror movements (MM). Different models exist, which have attributed MM to unintended
motor output from the M1 ipsilateral to the voluntary movement, functionally active uncrossed corticospinal projections, or on a com-
bination of both. Over the last two decades, transcranial magnetic stimulation (TMS) proved as a valuable, non-invasive neurophysio-
logical tool to investigate motor control in healthy volunteers and neurological patients. The contribution of TMS and other non-
invasive electrophysiological techniques to characterize the neural network responsible for the so-called ‘non-mirror transformation’
of motor programs and the various mechanisms underlying ‘physiological’ mirroring, and congenital or acquired pathological MM
are the focus of this review.
Ó 2007 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Keywords: Mirror movements; Motor control; Motor overflow; Parkinson’s disease; Surface EMG; Transcranial magnetic stimulation

1. Introduction of homologous muscles occurs in alternation (parallel move-

Human beings have a highly specialized largely crossed
system of fast-conducting axons providing monosynaptic
connections between the primary motor cortex (M1) and
the contralateral spinal motoneurons to support digital dex-
terity or individuated finger movements (Porter and Lemon,
1993). The execution of strictly unilateral motor tasks
requires restriction of motor output activity in the M1 con-
tralateral to the voluntary movement (Carson, 2005). Since
the seminal kinematic data of Kelso et al. (1979), several
studies showed that patterns of bimanual coordination in
which the symmetrical contraction of homologous muscle
groups occurs simultaneously (voluntary mirror move-
ments) are more stable than those in which the engagement
*
Corresponding author. Tel.: +39 055 6577476; fax: +39 055 6577693.
E-mail address: cincotta@unifi.it (M. Cincotta).
ments) and identified a number of spatial and temporal con-
straints that limit the execution of asymmetrical bimanual
tasks (for review, see Swinnen, 2002; Swinnen and Wende-
roth, 2004). Hence, motor programs responsible for mir-
ror-symmetrical bimanual voluntary movements represent
a basic coordinative behavior of the central nervous system,
whereas asymmetrical bimanual movements require more
complex patterns of neural activity. Likewise, unimanual
voluntary movements are thought to require the activity of
a neural network that is capable of operating the so-called
‘non-mirror transformation’ of default ‘symmetrical’ motor
programs (Chan and Ross, 1988). This view is supported by
scalp and subdural movement-related cortical potential
(MRCP) recordings (for review, see Shibasaki and Hallett,
2006). Both unimanual and bimanual self-paced voluntary
tasks are preceded by an initial, diffusely distributed slow
negativity (Bereitschaftspotential) starting about 2 s before
the movement onset, which is generated by activation of

1388-2457/$34.00 Ó 2007 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.clinph.2007.11.047
 M. Cincotta, U. Ziemann / Clinical Neurophysiology 119 (2008) 744–762
bilateral supplementary motor area (SMA) and dorsal pre-
motor cortex (dPMC). In contrast, the subsequent steeper
negative slope (NS 0 ) starting about 400 ms before the move-
ment onset is focused on the M1 and dPMC contralateral to
the intended unilateral movement, suggesting that processes
acting to transform bilateral to lateralized neural activity
occur relatively late during preparation of self-initiated uni-
lateral hand movements. There is growing evidence that the
neural network underlying this voluntary movement lateral-
ization involves different cortical areas and interhemispheric
mechanisms.
Alteration or even transient functional deficiency of
motor programs and neural circuits responsible for unilat-
eral voluntary movements may result in motor overflow
across the midline (Hoy et al., 2004a). This unintended pro-
cess may produce movements which are mirror reversals of
the contralateral voluntary ones (mirror movements, MM)
(Schott and Wyke, 1981; Carson, 2005). Although, to our
knowledge, the term MM was first used by Bauman in
1932, the phenomenon had been already described in the
late nineteenth century (Drinkwater, 1914). MM mainly
involve the distal upper limb muscles (Schott and Wyke,
1981), although leg and foot MM have also been reported
(Tubbs et al., 2004; Espay et al., 2005). Overt MM can be
seen in healthy children up to 10 years of age, likely due to
immaturity of the motor system, but their intensity
decreases with age (Lazarus and Todor, 1987; Armatas
et al., 1994; Reitz and Müller, 1998; Mayston et al.,
1999). In adulthood, the persistence or the reappearance
of MM is considered abnormal, although a tendency for
the movements of the upper extremities to be drawn
towards one another is suggested by the subtle mirroring
that can be present also in healthy adults during intended
unilateral tasks (Cernacek, 1961; Armatas et al., 1994; Bod-
well et al., 2003; Baliz et al., 2005).
The aetiology of pathological MM is diverse. Persistent
congenital MM can be observed in different clinical condi-
tions, ranging from the absence of other neurological
abnormalities to severe congenital hemispheric lesions
(Schott and Wyke, 1981; Rasmussen, 1993; Carr et al.,
1993). Congenital MM not associated with other relevant
motor abnormalities may be sporadic or familial (Schott
and Wyke, 1981; Cohen et al., 1991a; Cincotta et al.,
2002) and can occur in otherwise normal subjects or are
associated with diseases such as Klippel-Feil syndrome
(Bauman, 1932; Gunderson and Solitare, 1968; Gardner,
1979; Schott and Wyke, 1981; Farmer et al., 1990), Kall-
mann’s syndrome (Kallmann et al., 1944; Conrad et al.,
1978; Schwankhaus et al., 1989; Danek et al., 1992; Lein-
singer et al., 1997; Mayston et al., 1997), and cervical
meningocele (Odabasi et al., 1998). When familial congen-
ital MM occur in otherwise healthy subjects, the pattern of
inheritance is usually autosomal dominant (Guttmann
et al., 1939; Haerer and Currier, 1966; Regli et al., 1967;
Cincotta et al., 1996). Acquired MM and contralateral
motor overflow have also been reported in patients with
several conditions, such as Parkinson’s disease (PD) (Gutt-
745
mann et al., 1939; Nassetti et al., 1999; van den Berg et al.,
2000; Vidal et al., 2003; Espay et al., 2005; Cincotta et al.,
2006a,b; Ottaviani et al., 2007, corticobasal degeneration
(Fisher, 2000), Huntington’s disease (Hashimoto et al.,
2001; Georgiou-Karistianis et al., 2004), Friedreich’s ataxia
(Regli et al., 1967), stroke (Hopf et al., 1974; Weiller et al.,
1993; Netz et al., 1997; Nelles et al., 1998), focal lesions
involving the SMA (Chan and Ross, 1988), amyotrophic
lateral sclerosis (ALS) (Krampfl et al., 2004; Wittstock
et al., 2007), and schizophrenia (Levin, 1954; Hoy et al.,
2004b, 2007).
As to pathophysiological mechanisms responsible for
MM, two main hypotheses have been put forward. First,
MM may depend on motor output from the voluntarily
active M1 via functionally active corticofugal projections
to the ipsilateral spinal motoneurons. The neural substrate
of this projection could be either branching of crossed cor-
ticospinal fibers or a separate ipsilateral corticospinal pro-
jection. Second, MM may rely on motor output from the
other M1 that is not voluntarily active (mirror M1). These
hypotheses are not mutually exclusive. According to the
aetiological diversity of MM, the pathophysiology of this
phenomenon may vary across different pathological condi-
tions (Cincotta et al., 2003a). Non-invasive clinical neuro-
physiology and, above all, the availability of transcranial
electrical and magnetic stimulation techniques provided
valuable means of investigating this issue in the last two
decades. In particular, transcranial magnetic stimulation
(TMS) allows a detailed evaluation of several aspects of
motor control in MM. First, focal TMS allows studying
separately the corticospinal projections from either M1 in
intact humans (Cohen et al., 1991b; Ziemann et al.,
1999). Second, TMS provides a non-invasive technique to
assess distinct excitatory and inhibitory neural circuits
within the M1 (Ziemann et al., 1996; Rossini and Rossi,
1998; Chen, 2000; Hallett, 2000). Third, TMS can test
whether (and when) a cortical area is necessary for a given
task, with a high temporal resolution and a good spatial
resolution (Pascual-Leone et al., 2000; Hallett, 2000). In
the present paper, we review various ways how TMS and
other non-invasive electrophysiological techniques have
been used to investigate the neural mechanisms underlying
normal and altered voluntary movement lateralization. In
the first section, we will provide a synopsis on the available
data regarding the neural network responsible for volun-
tary movement lateralization and the mechanisms underly-
ing ‘physiological’ mirroring in healthy humans. In the
second section, we will review the current knowledge on
the pathophysiology of persistent congenital MM. Finally,
in the last section, we will discuss the mechanisms underly-
ing acquired MM in PD and other neurological and neuro-
psychiatric disorders.
2. Voluntary movement lateralization in healthy humans
An efficient lateralization of voluntary movements
requires a mature motor system, as suggested by the pres-
746 M. Cincotta, U. Ziemann / Clinical Neurophysiology 119 (2008) 744–762
ence of MM during intended unimanual tasks in healthy
children (Lazarus and Todor, 1987; Reitz and Müller,
1998; Mayston et al., 1999). In contrast, normal adults
are usually able to perform unilateral movements in daily
life (Schott and Wyke, 1981), although a slight, involuntary
mirroring can often be observed (Cernacek, 1961; Armatas
et al., 1994; Bodwell et al., 2003; Baliz et al., 2005). This
unintended mirror activity has been mainly reported using
EMG (Cernacek, 1961; Hopf et al., 1974; Mayston et al.,
1999; Leocani et al., 2000; Zijdewind and Kernell, 2001;
Aranyi and Rösler, 2002; Bodwell et al., 2003; Cincotta
et al., 2006b; Vardy et al., 2007) or force transduction
(Armatas et al., 1994, 1996; Armatas and Summers, 2001;
Zijdewind and Kernell, 2001; Baliz et al., 2005; Uttner
et al., 2007) techniques. In healthy adults, the amount of
mirror EMG activity increases with more demanding
motor tasks, fatigue, cognitive distraction, decrease in
attentional capacity, and age (Hopf et al., 1974; Zijdewind
and Kernell, 2001; Aranyi and Rösler, 2002; Bodwell et al.,
2003; Baliz et al., 2005; Uttner et al., 2005; Addamo et al.,
2007). However, in a large unselected series of elderly
healthy volunteers, clinically detectable slight MM have
been frequently observed even during relatively simple uni-
manual tasks, if subjects were not asked explicitly to sup-
press unintended motor activity (Ottaviani et al., 2007).
Most studies that explored asymmetry of ‘physiological’
mirroring reported stronger mirror activity during volun-
tary movement of the non-dominant hand, in particular
in right-handers (Liederman and Foley, 1987; Armatas
et al., 1994, 1996; Uttner et al., 2007), although the reverse
pattern (Cernacek, 1961) or no difference between the
hands (Armatas and Summers, 2001) has also been found.
It has been hypothesized that the asymmetry of MM
depends on the type of task (Parlow, 1990; Armatas
et al., 1996; Armatas and Summers, 2001). In addition,
healthy left-handers tend to exhibit more mirror activity
than right-handers (Armatas et al., 1996; Armatas and
Summers, 2001).‘Physiological’ mirroring appears to be
influenced by the preceding motor activity, as involuntary
mirror EMG activity is enhanced following in-phase sym-
metric bimanual movements or, in other words, voluntary
MM (Vardy et al., 2007). Mayston et al. (1999) showed
that time of onset of mirror compared to voluntary
EMG activity is variable, but typically mirror and volun-
tary EMG activity starts at about the same time (range
14 to 14 ms in normal adults).
A number of neurophysiological data suggests that
‘physiological’ mirroring depends on activation of the
crossed corticospinal tract originating from the M1 ipsilat-
eral to the voluntary movement (mirror M1). When
healthy subjects perform an unilateral strong isometric
contraction of a hand muscle, amplitudes of the TMS-
induced motor evoked potentials (MEP) in the mirror hand
reveal an increased excitability of the crossed corticospinal
system originating from the mirror M1 even when no overt
MM occur (Hess et al., 1986; Rossini et al., 1987, 1994;
Zwarts, 1992; Stedman et al., 1998; Muellbacher et al.,
2000; Liepert et al., 2001; Ziemann and Hallett, 2001; Cin-
cotta et al., 2004). While concurrent facilitation of spinal
alpha-motoneurons suggests that part of this facilitation
may occur at the spinal level, reduced paired-pulse short-
interval intracortical inhibition (SICI) (Kujirai et al.,
1993) in the mirror M1 during an isometric muscle contrac-
tion of the ipsilateral hand suggests a motor cortical
involvement (Muellbacher et al., 2000). However, studies
which addressed the effects of phasic hand movements on
the excitability of corticospinal neurons in the ipsilateral
M1 reported complex and somewhat conflicting results:
Tinazzi and Zanette (1998) and Ziemann and Hallett
(2001) found enhanced MEP elicited from the mirror M1
during self-paced, unimanual phasic motor tasks, in partic-
ular during complex finger sequences. In right-handed sub-
jects, this facilitation of the mirror M1 was significantly less
pronounced when the dominant hand rather than the non-
dominant hand performed the task (Ziemann and Hallett,
2001). In contrast, other authors reported a decrease of
MEP amplitude elicited from the mirror M1 during self-
paced phasic movements of the ipsilateral hand (Liepert
et al., 2001; Sohn et al., 2003), and either before (Leocani
et al., 2000; Weiss et al., 2003; Duque et al., 2005), during
(Weiss et al., 2003), or after (Leocani et al., 2000) an exter-
nally triggered reaction of the ipsilateral hand. In right-
handers performing RT paradigms, this inhibition of the
mirror M1 was significantly more pronounced when volun-
tary movements were performed with the dominant rather
than non-dominant hand (Leocani et al., 2000). These find-
ings indicate that activation of the mirror M1 can be coun-
teracted by inhibitory processes (see below). One possibility
to explain why results on excitability of the corticomoto-
neuronal system in the mirror M1 during hand movements
partly differ from those before movement onset is that dur-
ing the motor task, the ipsilateral M1 could be influenced
by proprioceptive afferences, whereas this does not happen
during movement preparation. Two findings indirectly sup-
port this notion. First, the excitability of the M1, as tested
by TMS, is modulated by contralateral passive movement
at the wrist (Lewis et al., 2001) or at the metacarpophalan-
geal joint (Edwards et al., 2002). Second, symmetrical bilat-
eral passive movements enhance this modulation with
respect to contralateral passive movements alone, suggest-
ing a role of the proprioceptive input from the ipsilateral
upper limb to the stimulated M1 (Stinear and Byblow,
2002). However, facilitation and inhibition of corticospinal
neurons in the mirror M1 seems to be modulated by many
additional factors, such as the force exerted in the volun-
tary motor task (Liepert et al., 2001; Weiss et al., 2003),
overtraining (Tinazzi and Zanette, 1998), and movement
kinematics (Duque et al., 2005). Further studies are needed
to improve our understanding of this complex interaction
between the voluntary active and mirror M1.
There is more evidence in favor of an activation of the
mirror M1 during intended unimanual movement of the
ipsilateral hand: the amplitude of the E2 component of
the cutaneomuscular reflex recorded in a hand muscle after
 M. Cincotta, U. Ziemann / Clinical Neurophysiology 119 (2008) 744–762
electrical finger stimulation increases if the homologous
muscle of the contralateral hand performs phasic contrac-
tions, compared with the rest condition (Mayston et al.,
1999). As in the hand muscles, this long-latency reflex
EMG response is thought to be mainly mediated via a
transcortical circuit (Jenner and Stephens, 1982; Farmer
et al., 1990), its enhancement likely reflects increased excit-
ability of the corticospinal neurons in the mirror M1 (May-
ston et al., 1999). Recently, Zijdewind et al. (2006) used
focal TMS to disrupt the motor output from either M1
in healthy adults according to a paradigm first applied by
Cincotta et al. (1996) in congenital MM (see also the par-
agraph ‘‘Persistent congenital MM’’). Briefly, when a nor-
mal subject performs an isometric contraction of an upper
limb muscle, TMS of the contralateral M1 produces a long-
lasting disruption of the voluntary cortical motor output
resulting in an absolute cortical silent period (SP) of up
to a few hundred milliseconds in the ongoing EMG (for
review, see Hallett, 1995). In contrast, stimulation of the
M1 ipsilateral to the contracting target muscle produces
only a short-lasting disruption of the motor output result-
ing in a relative SP in the order of tens of milliseconds,
which likely reflects an interhemispheric inhibitory transfer
to the voluntarily active M1 of the opposite hemisphere
(Ferbert et al., 1992; Meyer et al., 1995). Zijdewind et al.
(2006) found that strong unilateral tonic contraction of
one biceps muscle produces unintended contraction of
the biceps muscle of the other side and that, no matter
whether activation in this target biceps muscle was volun-
tary or mirror, focal TMS of the contralateral M1 always
produced a long-lasting SP, as expected if the unintended
motor output was entirely generated in the stimulated
hemisphere. On the contrary, focal TMS of the ipsilateral
M1 always produced a by far shorter SP, as expected if
the motor output responsible for mirroring was solely gen-
erated in the non-stimulated hemisphere and TMS dis-
rupted it via interhemispheric inhibitory influences. It is
well known that, in normal adults, focal TMS of one M1
fails to elicit ipsilateral MEP of the same short latency as
contralateral MEP (Ziemann et al., 1999). This finding is
a robust argument against the existence of ipsilateral fast-
conducting corticomotoneuronal fibers that could account
for ‘physiological’ mirroring. However, when healthy
adults perform a strong contraction of the target upper
limb muscle, high-intensity focal TMS of the ipsilateral
M1 elicits low-amplitude MEP. The latency of this ipsilat-
eral MEP exceeds the latency of a size-matched MEP in the
contracting homologous contralateral muscle by 5–7 ms
(Wassermann et al., 1994; Ziemann et al., 1999). Dissocia-
tion of ipsilateral and contralateral MEP by differences in
cortical map location, preferred stimulating current direc-
tion, and effects of head rotation, as well as the presence
of ipsilateral MEP in a patient with agenesis of the corpus
callosum suggested that the ipsilateral MEP is mediated by
an ipsilateral oligosynaptic pathway such as the corticoret-
iculospinal or corticopropriospinal projection (Ziemann
et al., 1999). However, the above mentioned pattern of
747
motor output disruption produced by focal TMS of the
voluntarily active and the mirror M1 (Zijdewind et al.,
2006) renders it rather unlikely that this weak ipsilateral
oligosynaptic pathway contributes significantly to MM.
Otherwise, one would expect that focal TMS of the contra-
lateral (voluntarily non-active) M1 to result in an only
short-lasting disruption of mirror activity via interhemi-
spheric pathways. One limitation of data addressing
TMS-induced disruption of unintended motor output in
healthy humans is that they refer to biceps rather than to
hand muscles (Zijdewind et al., 2006). However, with
respect to the monosynaptic corticospinal fibers, the pro-
portion of motor commands mediated through oligosynap-
tic projections, such as the corticopropriospinal pathways,
is by far greater in proximal than in distal upper limb mus-
cles (Pierrot-Deseilligny, 1996; Ziemann et al., 1999).
Hence, if the ipsilateral oligosynaptic corticofugal pathway
does not play a relevant role in mediating ‘physiological’
mirroring in biceps muscles, as suggested by the work of
Zijdewind et al. (2006), then this is even less likely in hand
muscles.
The ability of healthy subjects to restrict partially or
completely production of motor output in the hemisphere
contralateral to the voluntary movement depends on a dis-
tributed cortical network, whose functional organization is
still partly unknown. Data from lesioned monkeys (Brink-
man, 1984) and human patients (Chan and Ross, 1988)
suggest that the SMA and the cingulate gyrus are involved
in voluntary movement lateralization. TMS induced inter-
ference with the function of the SMA or the dPMC caused
a transition from out-of-phase to in-phase bilateral hand
movements but not vice versa (Meyer-Lindenberg et al.,
2002). In addition, PET data demonstrated that activation
of the right dPMC is more prominent during out-of-phase
than in-phase finger movements of the two hands (Sadato
et al., 1997). These findings pointed to a role also of the
dPMC in this process. Recently, this hypothesis has been
tested more specifically using repetitive TMS (rTMS) (Cin-
cotta et al., 2004; Giovannelli et al., 2006). In a group of
eleven healthy adults, whilst performing an unilateral iso-
metric contraction of a left hand muscle, on-line disruption
of the right dPMC by 20 Hz rTMS increased the excitabil-
ity of the left (mirror) M1, as probed by MEP amplitude to
the homologous right hand muscle (Cincotta et al., 2004).
This effect was not seen with sham rTMS, and it was topo-
graphically specific because it was not observed with rTMS
of the right M1 (Cincotta et al., 2004). In addition, rTMS
of the right dPMC increased the excitability of the corti-
comotoneuronal system in the left M1 only if the right
M1 was engaged in voluntary contraction of the left hand
muscle but not if at rest (Cincotta et al., 2004). This task
dependence led to the conclusion that rTMS of the right
dPMC disrupted activity of a cortical network that is cru-
cial to focus production of motor output in the right M1
during intended unilateral contraction of the left hand.
Although disruption of the right dPMC should then poten-
tially facilitate MM in the right hand, no overt mirroring
748 M. Cincotta, U. Ziemann / Clinical Neurophysiology 119 (2008) 744–762
was observed. Hence, in a subsequent experiment, an easily
reproducible motor task that generally induces mirror
EMG activity even in normal adults was used to test
whether off-line disruption of the dPMC produced behav-
ioral effects in addition to the previously observed electro-
physiological effects (Giovannelli et al., 2006). Involuntary
mirror EMG activity occurs if the subject maintains a
slight background isometric muscle contraction in the mir-
ror hand, whilst performing an intended unilateral brief
phasic contraction with the homologous muscle of the
other hand (Mayston et al., 1999) (Fig. 1). In a group of
twelve healthy volunteers, this ‘physiological’ mirror
EMG activity in the right hand increased after 15 min
suprathreshold 1 Hz rTMS (Chen et al., 1997) delivered
to the right dPMC when compared to the baseline (Gio-
vannelli et al., 2006). In contrast, no significant increase
of mirror EMG activity in the right hand occurred with
sham rTMS of the right dPMC, real rTMS of the right
M1, or real rTMS of the left dPMC (Giovannelli et al.,
2006). Although the motor task employed in this study rep-
resents an asymmetrical bimanual voluntary movement
and not an unimanual voluntary task sensu strictu, these
findings further support the view that, during a phasic con-
0.8
0.6
0.4
APBMIRROR
0.2
0 Ziemann, 2006). Finally, during a simple reaction time
mV
2 their dominant hand, IHI from the mirror M1 to the volun-
1
APBVOL
0 active M1, it remains to be elucidated how exactly and to
50 ms
Fig. 1. Measurement of the mirror EMG activity in a representative
healthy subject performing a phasic abduction of the left thumb (APBvol),
while sustaining a tonic contraction of the right abductor pollicis brevis
muscle (APBmirror) at the minimum strength level that he could steadily
maintain against resistance. Striped area between the two vertical bars
represents the EMG activity in the APBMIRROR during 50 ms following
the onset of the phasic EMG burst in the APBvol. Each trace is the average
of 20 rectified trials. Mean EMG amplitude in this time interval was
expressed as a percentage of the mean background EMG level in the
APBmirror in the time window of 1 s before APBvol burst onset. Reprinted
from Giovannelli et al. (2006) with kind permission of Springer Science
and Business Media.
tralateral voluntary movement, the right dPMC is involved
in the ‘non-mirror transformation’ of motor programs.
The notion that the neural processes responsible for
movement lateralization mainly occur upstream the M1
(in order to restrict motor output to the M1 contralateral
to the voluntary movement) does not exclude the possibil-
ity that an active inhibition of the motor output in the mir-
ror M1 also plays a role in this process. Several TMS
studies support the existence of such a last-stage inhibition
of unwanted motor activity in healthy individuals. Inter-
hemispheric inhibition (IHI), as tested by a paired-pulse
focal TMS protocol with the conditioning pulse delivered
to one M1 and the test pulse delivered 10 ms later to the
opposite M1, slightly increases during an unilateral muscle
contraction in the hand contralateral to the conditioning
stimulus compared to the rest condition (Ferbert et al.,
1992). Similarly, the ipsilateral SP, which also reflects inter-
hemispheric inhibitory influences from the stimulated to
the non-stimulated M1 (Ferbert et al., 1992; Meyer et al.,
1995), is enhanced by real and imagined motor tasks of
the hand contralateral to the stimulated M1 (Cincotta
et al., 2006c). In addition, the ipsilateral SP (Heinen
et al., 1998) and the IHI (Mayston et al., 1999) are absent
in children. This could explain why ‘physiological’ mirror-
ing in children is by far greater than in adults, although it
should be noted that the TMS findings could merely reflect
immaturity of callosal fibers, which may not be accessible
by TMS due to a high threshold (Mayston et al., 1999).
Focal 1 Hz rTMS of one M1 in healthy adults changed
IHI from this M1 to the other non-stimulated M1, and
the magnitude of this change correlated inversely with a
concomitant change in ‘physiological’ mirror EMG activity
in the hand contralateral to the stimulated M1 (Hübers and
(RT) that was performed by right-handed volunteers with
tarily active M1 reversed to facilitation close to reaction
onset, whereas the influence from the voluntarily active
M1 to the mirror M1 remained inhibitory (Duque et al.,
2007). In contrast, this switch to interhemispheric facilita-
tion from the mirror M1 to the voluntarily active M1
was not observed prior to onset of movements of the
non-dominant hand. As this imbalance refers to interhemi-
spheric interaction from the mirror M1 to the voluntarily
what extent the neural mechanisms underlying IHI influ-
ence the excitability of the crossed corticomotoneuronal
system in the mirror M1 and act to suppress unintended
MM in healthy humans.
3. Persistent congenital MM
3.1. Congenital MM not associated with other relevant
motor abnormalities
In adults with abnormally persistent congenital MM not
associated with other motor abnormalities, the onset of
 M. Cincotta, U. Ziemann / Clinical Neurophysiology 119 (2008) 744–762
MM is nearly simultaneous to that of voluntary move-
ments, as shown by surface EMG recordings during
intended unilateral phasic movements (Conrad et al.,
1978; Forget et al., 1986; Cohen et al., 1991a; Cincotta
et al., 1994).
The neurophysiological hallmark of persistent congeni-
tal MM is the presence of fast-conducting corticospinal
pathways connecting abnormally the hand area of either
M1 with both sides of the spinal cord. This was demon-
strated more than fifteen years ago by transcranial electri-
cal stimulation (Farmer et al., 1990; Cohen et al., 1991a)
and consistently confirmed by a large number of TMS
studies, showing that focal stimulation of either the left
or right M1 elicits bilateral MEP of normal and symmetri-
cal latency in the resting hand muscles (Capaday et al.,
1991; van der Linden and Bruggeman, 1991; Danek
et al., 1992; Cincotta et al., 1994, 2002; Fellows et al.,
1996; Kanouchi et al., 1997; Mayston et al., 1997; Odabasi
et al., 1998; Reitz and Müller, 1998; Balbi et al., 2000; Fol-
tys et al., 2001; Maegaki et al., 2002; Ueki et al., 2005; Ver-
stynen et al., 2007) (Fig. 2), although the amplitude of the
ipsilateral MEP with respect to homologous contralateral
ones may vary across different upper extremity muscles
(Verstynen et al., 2007). The pathophysiological relevance
of fast-conducting projections connecting abnormally M1
to the ipsilateral spinal motoneurons is supported by a
cross-correlation analysis of the EMG spikes recorded
from bilaterally contracting homologous hand muscles.
The cross-correlation analysis measures the distribution
right APB left APB
patient 1
right M1
stimulation
left M1
stimulation
patient 2
right M1
stimulation
left M1
stimulation
2 mV
20 ms
Fig. 2. Three consecutive MEP recordings from the resting right and left
abductor pollicis brevis (APB) after focal TMS of either M1 at the optimal
position in a 15-year-old girl (Patient 1) and in a 40-year-old woman
(Patient 2) with persistent congenital MM not associated with other motor
abnormalities. TMS was delivered at 70% of the maximum stimulator
output. In both patients, bilateral MEP of normal latency were elicited.
Note that in Patient 1 the MEP recorded in the ipsilateral abductor pollicis
brevis (APB) after stimulation of either M1 were larger than in the
contralateral APB. Adapted from Cincotta et al. (2003b).
749
of the time intervals between each EMG spike recorded
in one muscle and the nearest spike recorded in the contra-
lateral homologous muscle. In patients with congenital
MM associated with Klippel-Feil syndrome (Farmer
et al., 1990) and Kallmann’s syndrome (Mayston et al.,
1997), the presence of a short duration peak around the
time interval 0 ms (central peak) in the cross-correlograms
indicates a common drive to the homologous spinal moto-
neuron pools in both sides of the spinal cord. This common
drive may result either from synchronous activation of
intermingled ipsilaterally and contralaterally projecting
corticospinal neurons in M1 (Mayston et al., 1997), or
from abnormal branching of crossed corticospinal fibers
to the ipsilateral side (Farmer et al., 1990).
As these data strongly support the role of ipsilateral
corticospinal pathways in mediating congenital MM, other
pathophysiological aspects of this phenomenon require
further discussion. One point is whether the uncrossed cor-
ticospinal projection is the sole substrate of MM or
whether activation of the M1 contralateral to the MM
(mirror M1) also contributes. Positron emission tomogra-
phy studies in otherwise normal patients with persistent
congenital MM (Cohen et al., 1991a) and in MM patients
with X-linked Kallmann’s syndrome (Krams et al., 1997)
showed abnormal bilateral M1 activation during intended
unimanual movements. However, activation of the M1
ipsilateral to the ‘voluntary’ hand was similar to that dur-
ing passive movements of the mirror hand (Krams et al.,
1997). This raised the possibility that activation in the mir-
ror M1 was not due to motor activity but due to the sen-
sory feedback from the mirror hand. Bilateral M1
activation during intended unilateral movements was also
suggested by functional magnetic resonance imaging
(fMRI), although a control experiment using passive
movements was not performed (Leinsinger et al., 1997;
Maegaki et al., 2002; Verstynen et al., 2007). Finally,
MRCP recordings showed that the premovement negativ-
ity (NS’) which is normally distributed in the centropari-
etal region contralateral to the intended movement was
distributed bilaterally in patients with MM (Shibasaki
and Nagae, 1984; Cohen et al., 1991a; Mayer et al.,
1995). As this measure is not confounded by sensory feed-
back, it appears that both M1 contribute to the prepara-
tion of intended unimanual movements. However, this
does not necessarily imply that the mirror M1 produced
actual motor output. In order to clarify this further, Cin-
cotta et al. (1996) found that, in an otherwise healthy
woman with strong and sustained MM (grade 3 according
to the criteria of Woods and Teuber, 1978), unilateral focal
TMS of either M1 during an intended unilateral isometric
contraction of a hand muscle resulted in a clearly shorter
SP in the voluntarily active and mirror muscles when com-
pared to the contralateral cortical SP of normal controls.
Similar findings were reported in one MM patient suffering
from mild perinatal ischemic damage (Balbi et al., 2000).
These experiments strongly suggest a bilateral contribution
of bilateral M1 to the motor output during intended uni-
750 M. Cincotta, U. Ziemann / Clinical Neurophysiology 119 (2008) 744–762

manual movements. The implication is that if MM were
solely caused by activity along an ipsilateral corticospinal
projection from the voluntarily active M1, then focal
TMS of this M1 would have been expected to produce a
long-lasting, complete suppression of the motor output,
resulting in a cortical SP of normal duration in the volun-
tarily active muscle and the homologous mirror muscle
(Fig. 3A). In contrast, the observed short-lasting SP can
be explained most parsimoniously by motor output from
the non-stimulated M1, starting as soon as the short-last-
ing interhemispheric and segmental inhibition produced
by focal TMS of M1 has disappeared (Fig. 3B). The com-
peting hypothesis that the short-lasting SP is caused by
impaired inhibitory circuitry in the stimulated voluntarily
active M1 was ruled out by a control experiment: bilateral
disruption of the motor output by simultaneous focal TMS
of both M1 during an intended unilateral hand muscle
contraction resulted in a normalization of the cortical SP
in either hand (Figs. 3C–E) (Cincotta et al., 2002). Finally,
as conditioning peripheral electric stimulation induced a
shortening of the cortical SP in healthy volunteers (Hess
et al., 1999; Classen et al., 2000), the short-lasting SP elic-
ited by unilateral M1 stimulation in patients with congen-
ital MM could theoretically be due to a peculiar
proprioceptive input resulting from the presence of strong
MM. Again, the normal duration of the SP produced by

Fig. 3. (A–D) models to show the expected effects of focal TMS of one (left) M1 and simultaneous bilateral stimulation of both M1 in patients with
congenital MM not associated with other relevant motor abnormalities during intended unilateral (right) hand contraction. Saw-toothed lines indicate the
cortical motor output. Expected cortical silent period (SP) recordings are shown on the right of each model for the right (upper trace in each diagram) and
left (lower trace) hand muscle. If MM exclusively depended on the presence of uncrossed corticospinal fibers, then unilateral stimulation of the M1
contralateral to the voluntary motor task would produce a normal, long-lasting cortical SP in both the voluntarily contracted (right) and mirror (left) hand
muscles (A). In contrast, if motor output from the ipsilateral (right) M1 also contributes to MM, then unilateral TMS of the opposite (left) M1 would elicit
a bilaterally shortened cortical SP (B), whereas simultaneous bilateral stimulation of the M1 would lead to a cortical SP normalization (C). Finally, if the
bilaterally shortened cortical SP observed after unilateral stimulation of the left M1 were due to impaired inhibitory mechanisms, bilateral M1 stimulation
would not result in CSP normalization (D). (E) cortical SP following focal TMS of either the left or right M1 at an intensity of 20% above the resting
motor threshold (RMT) or bilateral simultaneous stimulation of both M1 (at an intensity of 20% or 10% above the RMT to match MEP size with the
MEP size in the unilateral TMS conditions) delivered during an intended unilateral isometric contraction of the right abductor pollicis brevis (APB) in an
otherwise healthy 15-year-old girl with persistent congenital MM. Each trace is the average of 10 rectified EMG responses. The vertical dotted lines
indicate the time of TMS. The SP duration was calculated from the stimulus to the point when the mean post-MEP EMG reached again 20% of the mean
pre-stimulus EMG. Arrows indicate the end of the SP. Unilateral stimulation of either M1 produced a short cortical SP in both APB, whereas the duration
of the SP following bilateral stimulation was normal. Adapted from Cincotta et al. (2003a).
 M. Cincotta, U. Ziemann / Clinical Neurophysiology 119 (2008) 744–762
E right APB
focal TMS of the
left M1
focal TMS of the
right M1
bilateral stimulation
(20% above the RMT)
bilateral stimulation
(10% above the RMT)
Fig. 3 (continued)
bilateral simultaneous TMS of both M1 also largely ruled
out this possibility.
Another point relates the anatomy of the ipsilateral cor-
ticospinal projection. One hypothesis favors abnormal
branching of crossed corticospinal fibers (Farmer et al.,
1990). Another hypothesis postulates an ipsilateral projec-
tion that is anatomically distinct from the one projecting to
the contralateral side (Mayston et al., 1997). In persistent
congenital MM, the possibility that ipsilateral fast-con-
ducting pathways depend, at least in part, on distinct,
uncrossed corticospinal neurons is supported by recordings
of ipsilateral MEP that were larger than the homologous
contralateral ones in some patients (Mayston et al., 1997;
Cincotta et al., 2003b) (Fig. 2). This finding has been con-
firmed by a single case-report from Ueki et al. (2005), who
used the triple stimulation technique (Magistris et al., 1998)
to provide a better quantification of the contribution of the
cortical-motor neuron pool to the target muscle. Poten-
tially, however, these data could also be explained by an
‘asymmetrical’ axonal branching of crossed corticospinal
axons, providing more synaptic input to the ipsilateral than
contralateral spinal motoneurons. Further insight into the
origin of the ipsilateral corticospinal pathways was pro-
vided by paired-pulse TMS experiments that tested task-
related modulation of SICI (Cincotta et al., 2003b). SICI
refers to a marked inhibitory effect of a weak conditioning
751
left APB
500 uV
100 ms
TMS pulse on a MEP elicited in the resting target muscle
by a suprathreshold test pulse 1–5 ms later (Kujirai et al.,
1993). SICI is mediated by inhibitory cortical circuits pro-
jecting onto the fast-conducting corticospinal fibers (Zie-
mann et al., 1996; Di Lazzaro et al., 1998). In normal
subjects, voluntary contraction of the target muscle pro-
duces a significant reduction of SICI (Ridding et al.,
1995; Zoghi and Nordstrom, 2007). If ipsilateral MEP were
exclusively due to branching of crossed corticospinal neu-
rons, then intended unilateral contraction of a hand muscle
would produce the same SICI reduction in the ‘task’ and
mirror hand muscle. This, however, is not what was found.
In two otherwise normal patients with strong and sustained
congenital MM, SICI in the voluntarily active M1
decreased markedly in the contralateral ‘task’ abductor
pollicis brevis (APB) muscle, but remained unchanged in
the ipsilateral mirror APB, when compared with the rest
condition (Fig. 4) (Cincotta et al., 2003b). This restriction
of SICI reduction to the task muscle indicates a dissocia-
tion of the fast-conducting projections from the stimulated
M1 and, therefore, the existence of a distinct ipsilateral cor-
ticospinal projection. The pathogenetic mechanisms lead-
ing to the presence of these abnormal, uncrossed
corticospinal neurons are largely unknown. However,
TMS data support the existence of a strong ipsilateral cor-
ticomotoneuronal projection in healthy newborns (Eyre
752 M. Cincotta, U. Ziemann / Clinical Neurophysiology 119 (2008) 744–762
right APB left APB
30% 32%
rest
141% 31%
minimal right
contraction
26% 118%
minimal left
contraction
500 µV
20 ms
Fig. 4. Effect of different motor tasks on SICI in a 15-year-old girl with
persistent congenital MM not associated to other abnormalities. MEP
were recorded from both abductor pollicis brevis (APB) after focal paired-
pulse TMS of the right M1 (inter-stimulus interval, 3 ms). All traces are
the average of 10 unconditioned (thin lines) or conditioned (thick lines)
MEP. In each condition, percentages indicate peak-to-peak amplitude of
the conditioned over the unconditioned MEP. Note that during minimal
contraction of either APB, SICI was completely suppressed in the
voluntarily activated APB but remained unchanged in the mirror APB,
when compared with the rest condition. Adapted from Cincotta et al.
(2003b).
et al., 2001). Withdrawal of these ipsilaterally projecting
neurons mainly occurs in the first 15–18 postnatal months
(Eyre et al., 2001). In older children, ipsilateral MEP
become increasingly smaller, and develop higher threshold
and longer latency than the contralateral ones (Müller
et al., 1997; Eyre et al., 2001). Therefore, an intriguing
hypothesis is that congenital persistent MM in otherwise
healthy adults depend on genetic or sporadic alterations
of the physiological postnatal withdrawal of the ipsilateral
corticospinal projection.
One limitation of most electrophysiological data in
patients with congenital MM not associated with other rel-
evant motor abnormalities is that they have been obtained
at rest (TMS studies) or during tonic motor tasks (TMS
studies and cross-correlation analysis of EMG activity)
and not during phasic movements. In addition, the current
TMS data focus on the M1 and corticospinal fibers,
whereas the role of SMA and premotor cortex in voluntary
movement lateralization is underinvestigated in these
patients. Nevertheless, coexistence of bilateral motor out-
put and contralateral and ipsilateral corticospinal projec-
tions is strongly supported from the available
neurophysiological data and may be relevant from a func-
tional point of view. Anatomically distinct, but not
branched projections would allow modulation of M1 out-
put as a function of the intended side of movement.
According to Mayer et al. (1995), during intended unilate-
ral movements of the left hand, involuntary MM in the
right hand could be reduced by preferential activation of
intended unilateral intended unilateral
movement of the left hand movement of the right hand
Fig. 5. Schematic drawing that shows anatomically distinct crossed and
uncrossed corticospinal fibers and bilateral motor output with intended
unimanual movements in otherwise normal adults with congenital MM.
Black and grey lines indicate the preferentially and non-preferentially
activated pathways, respectively. The amount of mirror activity could be
reduced by preferentially activating the crossed corticospinal neurons
from the right hemisphere and the ipsilateral tract from the left hemisphere
during intended unilateral movements of the left hand, and vice versa
during intended unilateral movements of the right hand. Adapted from
Cincotta et al. (2003a).
the contralaterally projecting corticospinal fibers from the
right M1 and the ipsilaterally projecting neurons from
the left M1 (Fig. 5). Vice versa, reduction of MM in the left
hand during intended unilateral voluntary movements of
the right hand could rely on preferential activation of the
crossed corticospinal neurons from the left M1 and the
uncrossed fibers from the right M1 (Fig. 5). This may
explain why some patients are capable of exerting some
degree of voluntary control over the amount of MM, albeit
with effort, and why different tasks may be differently
affected in individual patients (Schott and Wyke, 1981;
Poizner and Kritchevsky, 1991; Paulson and Gill, 1995;
Hermsdörfer et al., 1995). Furthermore, this model of the
physiology of congenital MM provides a rationale for
rehabilitation. Accordingly, the 15-year-old girl with strong
and sustained congenital MM underwent a 7-month reha-
bilitative program designed to facilitate unilateral finger
movements by performing asymmetrical movements of
increasing complexity with the fingers of both hands, and
motor imagery of unilateral movements (Cincotta et al.,
2003b). After the rehabilitative training, the magnitude of
MM was markedly reduced compared to the pre-training
condition. Improvement involved specifically the trained
phasic finger movements, whereas movements that were
not trained remained largely unmodified. In addition, pain-
ful contraction of the left shoulder muscles during right-
hand writing, which likely represented a maladaptive com-
pensatory motor strategy, disappeared after the training.
3.2. MM associated with severe congenital hemispheric
lesions
Plastic changes that occur after prenatal or perinatal
brain damage may result in different patterns of functional
 M. Cincotta, U. Ziemann / Clinical Neurophysiology 119 (2008) 744–762
reorganization (Carr et al., 1993; Forssberg, 1999). TMS
and fMRI data suggest that the earlier the insult occurs
during the prenatal period, the greater is the efficacy of sen-
sorimotor reorganization (Staudt et al., 2004, 2006).
In a subset of patients, severe congenital hemiparesis is
associated with the presence of MM during voluntary acti-
vation of either the unaffected or the affected upper extrem-
ity (Green, 1967; Woods and Teuber, 1978; Nass, 1985;
Carr et al., 1993; Nezu et al., 1999; Staudt et al., 2004). Sev-
eral TMS studies showed bilateral MEP of symmetrically
normal latency in the resting hand muscles after focal stim-
ulation of the unaffected M1, whereas no MEP were elic-
ited by focal stimulation of the lesioned hemisphere
(Farmer et al., 1991; Carr et al., 1993; Maegaki et al.,
1995; Nirkko et al., 1997; Nezu et al., 1999; Cincotta
et al., 2000; Eyre et al., 2001; Jang et al., 2001; Staudt
et al., 2002, 2004). Recent data from Eyre et al. (2007) sug-
gest that loss of surviving crossed corticospinal projections
from the affected hemisphere may occur in the first two
years of life due to competitive displacement by the
increased ipsilateral projections from the undamaged
motor cortex and is associated with severe impairment.
In addition, during bilateral voluntary contraction of
homologous hand muscles, a short-duration central peak
occurs in the EMG cross-correlogram constructed from
motor unit spikes (Farmer et al., 1991; Carr et al., 1993;
Cincotta et al., 2000; Eyre et al., 2001). Taken together,
these findings strongly support the view that the cortical
motor output to both the unaffected hand and the paretic
hand is provided from the undamaged hemisphere and that
MM are due to the presence of fast-conducting corticospi-
nal connections between the unaffected M1 and ipsilateral
and contralateral spinal motoneurons. However, to some
extent these patients may be capable of lateralizing volun-
tary motor activity, as shown by Cincotta et al. (2000) in a
39-year-old man with a severe right spastic hemiparesis
resulting from a large congenital porencephalic lesion in
the left hemisphere, mainly involving the frontal and pari-
etal lobes. In this patient, strong and sustained MM were
observed in either hand, although less pronounced than
the voluntary movements (grade 3 according to the criteria
of Woods and Teuber, 1978). Focal TMS of the intact right
M1 resulted in ipsilateral MEP in resting muscles of the
affected hand that had the same latency and a lower ampli-
tude than MEP recorded in the homologous muscles of the
contralateral intact hand (Fig. 6B). As to the neural sub-
strate of movement lateralization, three experimental sets
data suggested that lateralized activation of the paretic
hand was mediated through an anatomically distinct ipsi-
lateral projection from the undamaged right hemisphere,
by-passing the system of fast-conducting corticospinal
fibers. First, a central peak in the cross-correlogram con-
structed from motor unit spikes was observed during bilat-
eral voluntary contraction of the APB muscle and during
intended unilateral left APB contraction but not during
intended unilateral contraction of the right APB despite
mirror activity in the good hand (Fig. 6A). Second, when
753
paired-pulse TMS of the unaffected M1 was delivered dur-
ing intended unilateral contraction of the paretic hand,
SICI was not down-regulated in either the right or left
APB, compared with the rest condition (Fig. 6E). Third,
the cortical SP recorded in the voluntarily contracting right
APB after stimulation of the unaffected M1, albeit normal
in absolute duration, was shorter than the SP observed in
the unaffected APB or the SP recorded bilaterally during
voluntary contraction of the left APB. These findings
strongly suggested that voluntary contraction of the paretic
hand was at least in part due to motor cortical output
along a separate ipsilateral projection, which is less suscep-
tible to TMS-induced inhibition than the fast-conducting
corticospinal projection. One candidate is an abnormally
retained ipsilateral oligosynaptic corticoreticulospinal
pathway, which has been demonstrated in healthy adults,
although it is unlikely that this normally very weak path-
way is relevant for hand movements from a functional
point of view (Wassermann et al., 1994; Ziemann et al.,
1999). However, a delayed ipsilateral MEP that would be
expected if mediated by this pathway could not be tested
in this patient because of the presence of a large short-
latency ipsilateral MEP mediated by the fast-conducting
corticospinal neurons. Partial movement lateralization dur-
ing intended unilateral contraction of the good hand likely
relied on preferential activation of a subset of strictly
crossed fast-conducting corticospinal neurons. This view
is supported by paired-pulse TMS data recorded during
intended unilateral isometric contraction of the unaffected
APB, showing selective SICI suppression in the good hand,
but not in the paretic one (Fig. 6E).
Finally, somatosensory function in patients with severe
congenital hemiparesis can be clinically preserved in the
affected arm, despite a largely complete alteration of the
afferent pathways from this arm to the affected hemisphere.
Somatosensory evoked potential (SEP) recordings showed
slow-conducting, probably non-lemniscal connections
between the affected arm and the ipsilateral non-primary
somatosensory cortex that may have been responsible for
the preserved somatosensory function in the affected arm
(Ragazzoni et al., 2002). In contrast, in these patients,
motor function is often poor despite the presence of fast-
conducting ipsilateral cortico-motoneuronal output from
the M1 of the undamaged hemisphere to the affected
arm. Moreover, in patients with large unilateral periven-
tricular brain lesions occurring in the early third trimester
of pregnancy, when the development of thalamocortical
somatosensory projections is still incomplete, the primary
somatosensory representation of the paretic hand in the
contralateral hemisphere can be preserved, in spite of a
strictly ipsilateral motor representation (Staudt et al.,
2006). Magnetic resonance diffusion tractography sug-
gested that outgrowing somatosensory projections had
apparently by-passed the lesion by curving around it (Sta-
udt et al., 2006). These observations point to different
forms and efficiency of functional reorganization of
somatosensory and motor pathways.
754 M. Cincotta, U. Ziemann / Clinical Neurophysiology 119 (2008) 744–762

Fig. 6. Effect of different motor tasks on cross-correlation analysis of surface EMG signals (A), on MEP in the right and left abductor pollicis brevis
(APB) after focal TMS of the right M1 at the optimal position (B, C, E), and on the H-reflex in the left flexor radialis carpi (FRC; D) in a 39-year-old man
with persistent MM associated to a severe right congenital hemiparesis. (A) Cross-correlograms constructed from at least 2000 motor unit spikes recorded
simultaneously from both APB (sampling rate, 5000 Hz) during intended unilateral contraction at intermediate strength. Note that a central peak was
present during voluntary contraction of the left APB but not during voluntary contraction of the right APB. (B) Three consecutive short-latency responses
recorded at rest after TMS at 80% of the maximum output. Note that the MEP amplitude was greater in the left APB (19% of the maximal M wave) than
in the right one (10% of the maximal M wave). (C) Traces show the average of 10 MEP after TMS at 5% above resting motor threshold intensity, delivered
at rest (thin lines) and during a slight contraction of the right APB (thick lines). Note that right voluntary contraction reduced the MEP amplitude in the
left APB (69% of the MEP size recorded at rest), despite mirror EMG activity and normal right APB facilitation. (D) Traces show the average of 10H-
reflexes recorded at rest (thin trace), during a slight left FRC contraction (thick trace), and during a strong right FRC contraction (grey line). Note that
similar voluntary and mirror EMG levels produced the same facilitation of the H-reflex amplitude compared with the rest condition (2.1 mV versus
0.6 mV). (E) MEP after the paired-pulse TMS paradigm at a 3-ms interstimulus interval. All traces are the average of 10 unconditioned (thin lines) or
conditioned (thick lines) MEP. In each condition, the numeric value represents the peak-to-peak amplitude of the conditioned MEP expressed as a
percentage of the unconditioned one. Note the increase in intracortical inhibition in the left APB with intended right APB contraction. Adapted from
Cincotta et al. (2000).

3.3. What can clinical neurophysiologists learn from
persistent congenital MM?
In patients with persistent congenital MM, the presence
of fast-conducting corticospinal fibers connecting abnor-
mally the hand area of the M1 with both sides of the spinal
cord represents an outstanding model to investigate the
neural pathways underlying neurophysiological and clini-
cal phenomena involving the motor pathways. Two exam-
ples are long-latency reflex EMG responses and enhanced
physiological tremor.
In normal subjects, electrical stimulation of a mixed
nerve at wrist (Deuschl and Lücking, 1990) or a cutaneous
digital nerve (Jenner and Stephens, 1982) as well as the
stretch of a hand muscle (Matthews, 1991) produce short-
and long-latency reflex EMG responses in the hand
muscles. While the short-latency response depends on a
monosynaptic Ia excitation of spinal motoneurons, the
long-latency one is thought to be mainly mediated through
a transcortical loop, the afferent and efferent branches of
which involve Ia fibers and the fast-conducting corticospi-
nal pathway, respectively (Jenner and Stephens, 1982;
 M. Cincotta, U. Ziemann / Clinical Neurophysiology 119 (2008) 744–762
Deuschl and Lücking, 1990; Matthews, 1991, 2006). A
number of studies conducted in patients affected by con-
genital MM without other relevant motor abnormalities
strongly supported this hypothesis by showing that either
cutaneous or mixed nerve stimulation as well as muscle
stretch produced a strictly unilateral short-latency EMG
response but bilateral simultaneous long-latency reflex
responses in the hand muscles (Farmer et al., 1990; Mat-
thews et al., 1990; Capaday et al., 1991; Cincotta et al.,
1994; Fellows et al., 1996; Köster et al., 1998; Mayston
et al., 2001). As SEP recordings showed strictly contralat-
eral short-latency responses in the primary somatosensory
cortex in this type of patients (Farmer et al., 1990; Capaday
et al., 1991; Cohen et al., 1991a; Cincotta et al., 1994;
Fellows et al., 1996), the observed bilateral pattern of
long-latency reflexes in the hand muscles indicates that
the underlying circuitry involves the ipsilaterally projecting
fast-conducting corticospinal neurons demonstrated by
focal transcranial stimulation of the M1. Of note, Fellows
et al. (1996) found that, in contrast to the hand muscles, the
long-latency reflex EMG response to the stretch reflex was
strictly ipsilateral in the biceps brachii muscle of a patient
with congenital MM. In addition, Lourenço et al. (2006)
have recently reported that the late response elicited in
the flexor carpi radialis by electrical stimulation of the
ulnar nerve at the wrist was also exclusively ipsilateral in
a patient with congenital MM. Accordingly, data in
healthy volunteers obtained by post-stimulus time histo-
grams of single motor units, ulnar nerve cooling, and selec-
tive pharmacological modulation by tizanidine intake
suggest that the more reproducible component of the
long-latency reflex response in the forearm muscles is med-
iated through a spinal circuit via muscle spindle group II
afferents, although a less reproducible transcortical sub-
component may be present too (Lourenço et al., 2006).
In conclusion, several findings suggest distinct substrates
for long-latency reflexes in proximal and distal upper limb
muscles, with transcortical pathways playing a major role
in the hand muscles and polysynaptic, group II afferent-
mediated spinal circuits mainly involved in forearm and
arm muscles (Matthews, 2006).
Physiological tremor in humans is thought to depends
on both mechanical and neurogenic mechanisms (Köster
et al., 1998). However, it was found difficult to determine
the relative contribution of these components to the tremor
(Mayston et al., 2001) due to frequency overlapping
(McAuley et al., 1997). Analysis in the time and frequency
domains of surface EMG recorded bilaterally from homol-
ogous muscles of the upper extremities showed a significant
left-right coherence of either salbutamol-induced enhanced
physiological tremor (Köster et al., 1998) or non-enhanced
physiological tremor (Mayston et al., 2001) in patients with
congenital MM not associated to other relevant motor
abnormalities. These data suggest that the circuitry under-
lying physiological tremor in congenital MM patients
involves a transcortical pathway via the uncrossed and
crossed fast-conducting corticospinal fibers identified by
755
focal TMS of the M1 and is in keeping with a central origin
of the neurogenic component of physiological tremor in
healthy humans (Köster et al., 1998; Mayston et al., 2001).
It is likely that the persistent congenital MM model will
prove useful in investigating further clinical aspects of
motor control and its neurophysiological measures in nor-
mal subjects and in pathological conditions.
4. Acquired MM
4.1. MM associated with PD
First reported by Guttmann et al. in 1939, MM associ-
ated to PD have received increasing attention in the past
few years (Nassetti et al., 1999; van den Berg et al., 2000;
Vidal et al., 2003; Espay et al., 2005, 2006; Cincotta
et al., 2006a,b; Li et al., 2007; Ottaviani et al., 2007). Data
from selected case series documented strong and sustained
MM in untreated patients with early and asymmetric PD
and demonstrated that MM are more frequently observed
in the less affected limb when the more affected limb is per-
forming a voluntary motor task (Vidal et al., 2003; Espay
et al., 2005). However, when clinically detectable MM of
slight intensity are also considered, findings from a large
unselected case series suggested that the overall frequency
of MM in PD is lower than in healthy controls (Ottaviani
et al., 2007).
In PD, the time of onset of mirror compared to volun-
tary EMG activity varies between 15 and 37 ms but can
start simultaneously (personal observation in a single
patient performing self-paced unilateral thumb abduction).
Surface EMG and TMS data obtained in four PD patients
with strong and sustained MM provided evidence that MM
do not depend on unmasking of ipsilateral corticospinal
projections but are explained by motor output along the
crossed corticospinal projection from the M1 ipsilateral
to the voluntary motor task (Fig. 7A) (Cincotta et al.,
2006a). Focal TMS of either M1 did not elicit abnormal
ipsilateral MEP in the hand muscles. The cross-correlo-
gram constructed from the surface EMG of motor unit
spikes did not support the presence of a common motor
drive to homologous hand muscles during intended uni-
manual tasks. A common motor drive would have been
expected if MM were due to the synchronous activation
of ipsilaterally and contralateral projecting corticospinal
neurons that originate from the same M1 (Mayston
et al., 1997). These findings have been recently confirmed
in a group of thirteen PD patients with MM (Li et al.,
2007). During either mirror or voluntary isometric contrac-
tion of a hand muscle, single-pulse focal TMS of the con-
tralateral M1 resulted in a long-lasting SP, whereas
stimulation of the ipsilateral M1 produced a short-lasting
SP. Likewise, during either mirror or voluntary finger tap-
ping, 5-Hz rTMS of the contralateral M1 produced a
marked disruption of EMG activity in the target hand mus-
cle, whereas the effect of rTMS of the ipsilateral M1 was by
far less (Fig. 7B). In addition, focal paired-pulse TMS of
756 M. Cincotta, U. Ziemann / Clinical Neurophysiology 119 (2008) 744–762

A intended unilateral B
movement of the right hand
right FDI

main task
left M1
stimulation
control task

main task
right M1
stimulation
control task

right hand left hand 500 uV

muscle muscle
1s

Fig. 7. (A) Schematic drawing that shows bilateral cortical motor output along crossed corticospinal tracts during intended unimanual movements in PD
patients with MM. Black and grey lines indicate the voluntarily and non-voluntarily activated pathways, respectively. (B) Effects of 5-Hz focal rTMS of
either the left or right M1 delivered during the main and control tasks in a representative PD patient with MM. The main task consisted of intended
unilateral tapping with the index finger of the left hand (activation of which produced larger motor overflow to the contralateral right hand than vice
versa). The control task consisted of voluntary bilateral tapping. All traces are raw surface EMG recordings from the patient’s right first dorsal
interosseous (FDI). In all recordings, the 15 thin vertical lines represent the stimulus artifacts (the arrow indicates the artifact produced by the first pulse of
the 5 Hz rTMS train). Suprathreshold rTMS of the left M1 markedly disrupted either mirror (main task) or voluntary (control task) tapping of the
contralateral right FDI, whereas the effects of suprathreshold rTMS of the ipsilateral right M1 were by far less during both tasks. Findings are consistent
with the model shown in Fig. 7A. Adapted from Cincotta et al. (2006a).

M1 showed that SICI was similarly down-regulated during
either voluntary or mirror contraction of the contralateral
target hand muscle compared to the resting condition. In
summary, in these selected PD patients, strong and sus-
tained MM reflect an enhancement of ‘physiological’ mir-
roring (cf. section ‘Voluntary movement lateralization in
healthy humans’).
In PD, bradykinesia likely depend on a failure of basal
ganglia output to energize the cortical mechanisms that
prepare and execute the movements (Berardelli et al.,
2001). Similarly, a deficient basal ganglia output could also
fail to support the cortical network that is involved in
enabling the corticospinal system to execute strictly uni-
manual movements (Cincotta et al., 2006a). According to
this hypothesis, Li et al. (2007) recently reported that, in
PD patients with MM only on one side, the ipsilateral SP
was reduced in the hand affected by MM compared to
the non-MM side and compared to healthy controls, and
that the IHI tested by paired-pulse TMS at long interstim-
ulus intervals (20–50 ms) was more pronounced in PD
patients without MM than in PD patients affected by
MM and controls. When healthy volunteers and mildly
to moderately affected PD patients without clinically overt
MM were selected, surface EMG data also support the
notion that voluntary movement lateralization is altered
in PD (Cincotta et al., 2006b). When requested to perform
unilateral phasic thumb abduction movements during a
sustained tonic contraction of the opposite APB (cf.
Fig. 1 for the experimental protocol), the magnitude of
involuntary mirror EMG activity in the tonically contract-
ing APB was greater in the group of 12 PD patients than in
age-matched controls, no matter whether the PD patients
were on or off anti-dopaminergic therapy (Cincotta et al.,
2006b). Furthermore, in PD patients performing unimanu-
al voluntary movements, a deficient lateralization of move-
ment-related brain activity also involving basal ganglia is
supported by local field potential (LFP) activity recorded
in the subthalamic nuclei (STN) from the electrodes used
for deep brain stimulation (DBS) (Androulidakis et al.,
2007). Functional neuroimaging (Rao et al., 1993) as well
as neurophysiological studies (Tinazzi and Zanette, 1998;
Ziemann and Hallett, 2001) suggest that activation of ipsi-
lateral motor areas increases with the complexity of a uni-
manual task. This raises the possibility that, in PD patients,
increased difficulty to perform relatively simple motor tasks
as a consequence of motor impairment could per se favor
MM. However, at least two arguments strongly point
against the notion that MM depend on the increased vol-
untary effort alone. First, strong and sustained MM have
been mainly reported in mildly affected rather than
advanced PD patients (Espay et al., 2005). Second, a fol-
low-up assessment in a group of PD patients on chronic
dopaminergic treatment showed that when testing was per-
formed at least 12 h after the last intake of dopaminergic
drug (‘off’ condition), the mean MM score was not higher
than during maximal benefit from the dopaminergic treat-
 M. Cincotta, U. Ziemann / Clinical Neurophysiology 119 (2008) 744–762
ment (‘on’ condition) although in the ‘off’ condition motor
impairment, as tested by the UPDRS (Fahn and Elton,
1987), was greater than in the ‘on’ condition (Espay
et al., 2006). Moreover, in these patients, a correlation
between changes in motor impairment and change in
MM was seen: namely, from ‘off’ to ‘on’ condition, MM
increased in patients with greater improvement in UPDRS
motor score and decreased in those with less improvement.
In conclusion, although a minor role of task effort cannot
be ruled out, it is likely that in PD patients who perform
intended unilateral movements, the presence and degree
of MM mainly depends on the balance of two opposite
mechanisms: dysfunction of voluntary movement laterali-
zation (an alteration that mainly occurs in the hemisphere
contralateral to the voluntary motor task), and altered task
execution in the motor areas contralateral to the mirror
hand. Altered unimanual motor control accounts for the
occurrence of strong and sustained MM, which represent
an abnormal enhancement of ‘physiological’ mirroring.
Conversely, deficient activation of cortical motor areas
likely reduces voluntary and mirror output to the contra-
lateral hand, resulting in bradykinesia and less expression
of MM, respectively. This could account for the observa-
tion that MM are particularly observed in the less affected
hand (Vidal et al., 2003; Espay et al., 2005; Ottaviani et al.,
2007). Whether deficient lateralization of voluntary move-
ments acts together with cardinal parkinsonian signs to
impair motor tasks requiring independent (nonsymmetri-
cal) movements of both hands (van den Berg et al., 2000;
Almeida et al., 2002) has still to be clarified. If so, rehabil-
itative programs aiming to favor bimanual decoupling may
prove useful in improving complex bimanual motor skills
in PD.
4.2. Acquired MM associated with other conditions
In addition to PD, several diseases may present MM or
contralateral motor overflow, the pathophysiological sub-
strates of which are still under-investigated.
Force transduction measurements performed during
intended unimanual tonic movements showed that contra-
lateral motor overflow was greater in patients with schizo-
phrenia than in healthy volunteers, in particular at low
force levels (Hoy et al., 2004b). In a group of patients with
schizophrenia, focal TMS of M1 failed to elicit ipsilateral
MEP in the hand muscles (Hoy et al., 2007). In addition,
focal TMS of the M1 produced a normal long-lasting cor-
tical SP in the contralateral hand, no matter if contracting
through voluntary or mirror activity (Hoy et al., 2007). In
accordance to the observations reported in PD (Cincotta
et al., 2006a), these findings support the hypothesis that
contralateral motor overflow in schizophrenia is also due
to activation of the crossed corticospinal tract originating
from the mirror M1, and therefore, represents an abnormal
enhancement of the ‘physiological’ mirroring. IHI and ipsi-
lateral SP data suggested altered interhemispheric inhibi-
tory mechanisms in schizophrenia (Boroojerdi et al.,
757
1999; Fitzgerald et al., 2002; Bajbouj et al., 2004). Hence,
it was hypothesized that increased mirroring observed in
schizophrenia depends on a deficient transcallosal transfer
of inhibitory control (Hoy et al., 2004b).
Abnormally increased mirroring during intended uni-
manual phasic or tonic movements was also demonstrated
in patients with Huntington’s disease using surface EMG
(Hashimoto et al., 2001) and force transduction techniques
(Georgiou-Karistianis et al., 2004). In most patients, dur-
ing phasic movements, mirror and voluntary EMG activity
started at the same time (Hashimoto et al., 2001). During
tonic movements, the degree of motor overflow correlated
positively with the overall motor impairment (Georgiou-
Karistianis et al., 2004). Neurophysiological data that
address the neural substrate of enhanced contralateral
motor overflow are not yet available in these patients,
but it has been hypothesized that motor overflow in Hun-
tington’s disease reflects a general failure to inhibit exces-
sive neural activity during voluntary movement
(Hashimoto et al., 2001; Georgiou-Karistianis et al., 2004).
Occasional MM and frequent contralateral motor over-
flow were also reported in patients with hemiparesis due to
adult-onset stroke (Hopf et al., 1974; Weiller et al., 1993;
Netz et al., 1997; Nelles et al., 1998). Surface EMG record-
ings showed that contralateral motor overflow may be
delayed by several hundred milliseconds with respect to
the onset of voluntary movement, in particular in the
affected limb during voluntary movement of the unaffected
one (Hopf et al., 1974). When these long delays occur, the
term synkinesias (Marie and Foix, 1916) is probably more
appropriate to indicate unintended motor activity (Cohen
et al., 1991a). Using computerized dynamometer record-
ings in a group of twenty-three stroke patients, Nelles
et al. (1998) showed that MM observed in the unaffected
hand during intended unilateral squeezing of the paretic
hand were significantly more frequent than MM observed
in the paretic hand. The incidence of the latter did not differ
from MM observed in either hand of control subjects. In
addition, the presence of MM in the unaffected hand was
associated with greater motor deficit in the affected hand,
whereas in patients showing MM in the paretic hand motor
function was better than in patients without MM. In a
group of chronic stroke patients, Werhahn et al. (2003)
found that focal TMS of either the unaffected or the
lesioned M1 delayed simple RT in the contralateral hand
but not in the ipsilateral hand, suggesting that recovered
motor function in the paretic hand mainly relied on motor
output from the reorganized affected hemisphere. Several
studies demonstrated ipsilateral MEP in the upper extrem-
ities following focal TMS of the lesioned or non-lesioned
hemisphere: while some authors reported that ipsilateral
MEP are associated with good motor recovery, others
found an association between the presence of ipsilateral
MEP and poor outcome (for review, see Rossini and Pauri,
2003). As to the association between ipsilateral MEP and
MM in adult stroke patients, Netz et al. (1997) found that
focal TMS of the unaffected hemisphere elicited ipsilateral
758 M. Cincotta, U. Ziemann / Clinical Neurophysiology 119 (2008) 744–762
MEP in the hand muscles of all patients with incomplete
recovery. In nine of these 10 patients, the latency of the
ipsilateral MEP was longer (mean value 6 ms) than the
latency of the contralateral MEP and no MM were
observed. In contrast, the unique patient whose ipsilateral
MEP had the same latency of the contralateral ones pre-
sented MM in the unaffected hand during voluntary move-
ment of the paretic hand. Taken together, these clinical and
neurophysiological findings suggest that in most cases of
adult-onset hemiparetic stroke, increased MM in the intact
hand during voluntary motor activation of the paretic
hand depend on an abnormally enhanced activation of
crossed corticospinal pathways in the unaffected M1,
resulting from a dysfunctional network responsible for vol-
untary movement lateralization in the lesioned hemisphere.
In addition, an excessive effort to move the paretic hand
may contribute.
Recently, it was reported that patients affected by ALS
may sporadically present MM (Krampfl et al., 2004; Witt-
stock et al., 2007). Of note, deficient ipsilateral SP and
enhanced ipsilateral MEP have been also observed in
ALS patients. However, a significant correlation between
the presence of ipsilateral MEP or a deficient ipsilateral
SP and the occurrence of MM was lacking (Wittstock
et al., 2007). Hence, further studies are needed to clarify
the mechanisms that underlie MM in ALS.
Acknowledgements
This work was supported by a Grant from ‘Ente Cassa
di Risparmio di Firenze’, Florence, Italy. We are grateful
to our patients and healthy volunteers and to our cowork-
ers in this field. A special thanks to Prof. Franco Barontini
who taught clinical aspects of mirror movements to Massi-
mo Cincotta in 1991.
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