neurophysiology of unimanual motor control and mirror movements

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Clinical Neurophysiology 119 (2008) 744–762

Invited review

Neurophysiology of unimanual motor control and mirror movements

M. Cincotta a,*, U. Ziemann b

a Unita Operativa di Neurologia, Azienda Sanitaria di Firenze, Ospedale Piero Palagi, Viale Michelangiolo, 41, 50125 Firenze, Italyb Neurologische Klinik, J.W. Goethe-Universitat, Frankfurt/Main, Germany

Accepted 23 November 2007Available online 9 January 2008

Abstract

In humans, execution of unimanual motor tasks requires a neural network that is capable of restricting neuronal motor output activityto 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 largelycrossed 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 unintendedmotor 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 MMare the focus of this review.� 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

Human beings have a highly specialized largely crossedsystem of fast-conducting axons providing monosynapticconnections between the primary motor cortex (M1) andthe contralateral spinal motoneurons to support digital dex-terity or individuated finger movements (Porter and Lemon,1993). The execution of strictly unilateral motor tasksrequires restriction of motor output activity in the M1 con-tralateral to the voluntary movement (Carson, 2005). Sincethe seminal kinematic data of Kelso et al. (1979), severalstudies showed that patterns of bimanual coordination inwhich the symmetrical contraction of homologous musclegroups occurs simultaneously (voluntary mirror move-ments) are more stable than those in which the engagement

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* Corresponding author. Tel.: +39 055 6577476; fax: +39 055 6577693.E-mail address: [email protected] (M. Cincotta).

of homologous muscles occurs in alternation (parallel move-ments) and identified a number of spatial and temporal con-straints that limit the execution of asymmetrical bimanualtasks (for review, see Swinnen, 2002; Swinnen and Wende-roth, 2004). Hence, motor programs responsible for mir-ror-symmetrical bimanual voluntary movements representa basic coordinative behavior of the central nervous system,whereas asymmetrical bimanual movements require morecomplex patterns of neural activity. Likewise, unimanualvoluntary movements are thought to require the activity ofa neural network that is capable of operating the so-called‘non-mirror transformation’ of default ‘symmetrical’ motorprograms (Chan and Ross, 1988). This view is supported byscalp and subdural movement-related cortical potential(MRCP) recordings (for review, see Shibasaki and Hallett,2006). Both unimanual and bimanual self-paced voluntarytasks are preceded by an initial, diffusely distributed slownegativity (Bereitschaftspotential) starting about 2 s beforethe movement onset, which is generated by activation of

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M. Cincotta, U. Ziemann / Clinical Neurophysiology 119 (2008) 744–762 745

bilateral supplementary motor area (SMA) and dorsal pre-motor cortex (dPMC). In contrast, the subsequent steepernegative slope (NS 0) starting about 400 ms before the move-ment onset is focused on the M1 and dPMC contralateral tothe intended unilateral movement, suggesting that processesacting to transform bilateral to lateralized neural activityoccur relatively late during preparation of self-initiated uni-lateral hand movements. There is growing evidence that theneural network underlying this voluntary movement lateral-ization involves different cortical areas and interhemisphericmechanisms.

Alteration or even transient functional deficiency ofmotor programs and neural circuits responsible for unilat-eral voluntary movements may result in motor overflowacross the midline (Hoy et al., 2004a). This unintended pro-cess may produce movements which are mirror reversals ofthe contralateral voluntary ones (mirror movements, MM)(Schott and Wyke, 1981; Carson, 2005). Although, to ourknowledge, the term MM was first used by Bauman in1932, the phenomenon had been already described in thelate nineteenth century (Drinkwater, 1914). MM mainlyinvolve 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 beseen in healthy children up to 10 years of age, likely due toimmaturity of the motor system, but their intensitydecreases with age (Lazarus and Todor, 1987; Armataset al., 1994; Reitz and Muller, 1998; Mayston et al.,1999). In adulthood, the persistence or the reappearanceof MM is considered abnormal, although a tendency forthe movements of the upper extremities to be drawntowards one another is suggested by the subtle mirroringthat can be present also in healthy adults during intendedunilateral tasks (Cernacek, 1961; Armatas et al., 1994; Bod-well et al., 2003; Baliz et al., 2005).

The aetiology of pathological MM is diverse. Persistentcongenital MM can be observed in different clinical condi-tions, ranging from the absence of other neurologicalabnormalities to severe congenital hemispheric lesions(Schott and Wyke, 1981; Rasmussen, 1993; Carr et al.,1993). Congenital MM not associated with other relevantmotor abnormalities may be sporadic or familial (Schottand Wyke, 1981; Cohen et al., 1991a; Cincotta et al.,2002) and can occur in otherwise normal subjects or areassociated 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 cervicalmeningocele (Odabasi et al., 1998). When familial congen-ital MM occur in otherwise healthy subjects, the pattern ofinheritance is usually autosomal dominant (Guttmannet al., 1939; Haerer and Currier, 1966; Regli et al., 1967;Cincotta et al., 1996). Acquired MM and contralateralmotor overflow have also been reported in patients withseveral conditions, such as Parkinson’s disease (PD) (Gutt-

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 lesionsinvolving the SMA (Chan and Ross, 1988), amyotrophiclateral sclerosis (ALS) (Krampfl et al., 2004; Wittstocket al., 2007), and schizophrenia (Levin, 1954; Hoy et al.,2004b, 2007).

As to pathophysiological mechanisms responsible forMM, two main hypotheses have been put forward. First,MM may depend on motor output from the voluntarilyactive M1 via functionally active corticofugal projectionsto the ipsilateral spinal motoneurons. The neural substrateof 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 theother M1 that is not voluntarily active (mirror M1). Thesehypotheses are not mutually exclusive. According to theaetiological diversity of MM, the pathophysiology of thisphenomenon may vary across different pathological condi-tions (Cincotta et al., 2003a). Non-invasive clinical neuro-physiology and, above all, the availability of transcranialelectrical and magnetic stimulation techniques providedvaluable means of investigating this issue in the last twodecades. In particular, transcranial magnetic stimulation(TMS) allows a detailed evaluation of several aspects ofmotor control in MM. First, focal TMS allows studyingseparately the corticospinal projections from either M1 inintact humans (Cohen et al., 1991b; Ziemann et al.,1999). Second, TMS provides a non-invasive technique toassess distinct excitatory and inhibitory neural circuitswithin the M1 (Ziemann et al., 1996; Rossini and Rossi,1998; Chen, 2000; Hallett, 2000). Third, TMS can testwhether (and when) a cortical area is necessary for a giventask, with a high temporal resolution and a good spatialresolution (Pascual-Leone et al., 2000; Hallett, 2000). Inthe present paper, we review various ways how TMS andother non-invasive electrophysiological techniques havebeen used to investigate the neural mechanisms underlyingnormal and altered voluntary movement lateralization. Inthe first section, we will provide a synopsis on the availabledata regarding the neural network responsible for volun-tary movement lateralization and the mechanisms underly-ing ‘physiological’ mirroring in healthy humans. In thesecond section, we will review the current knowledge onthe 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 movementsrequires 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 healthychildren (Lazarus and Todor, 1987; Reitz and Muller,1998; Mayston et al., 1999). In contrast, normal adultsare usually able to perform unilateral movements in dailylife (Schott and Wyke, 1981), although a slight, involuntarymirroring can often be observed (Cernacek, 1961; Armataset al., 1994; Bodwell et al., 2003; Baliz et al., 2005). Thisunintended mirror activity has been mainly reported usingEMG (Cernacek, 1961; Hopf et al., 1974; Mayston et al.,1999; Leocani et al., 2000; Zijdewind and Kernell, 2001;Aranyi and Rosler, 2002; Bodwell et al., 2003; Cincottaet 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; Uttneret al., 2007) techniques. In healthy adults, the amount ofmirror EMG activity increases with more demandingmotor tasks, fatigue, cognitive distraction, decrease inattentional capacity, and age (Hopf et al., 1974; Zijdewindand Kernell, 2001; Aranyi and Rosler, 2002; Bodwell et al.,2003; Baliz et al., 2005; Uttner et al., 2005; Addamo et al.,2007). However, in a large unselected series of elderlyhealthy volunteers, clinically detectable slight MM havebeen 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 particularin right-handers (Liederman and Foley, 1987; Armataset al., 1994, 1996; Uttner et al., 2007), although the reversepattern (Cernacek, 1961) or no difference between thehands (Armatas and Summers, 2001) has also been found.It has been hypothesized that the asymmetry of MMdepends on the type of task (Parlow, 1990; Armataset al., 1996; Armatas and Summers, 2001). In addition,healthy left-handers tend to exhibit more mirror activitythan right-handers (Armatas et al., 1996; Armatas andSummers, 2001).‘Physiological’ mirroring appears to beinfluenced by the preceding motor activity, as involuntarymirror EMG activity is enhanced following in-phase sym-metric bimanual movements or, in other words, voluntaryMM (Vardy et al., 2007). Mayston et al. (1999) showedthat time of onset of mirror compared to voluntaryEMG 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 thecrossed corticospinal tract originating from the M1 ipsilat-eral to the voluntary movement (mirror M1). Whenhealthy subjects perform an unilateral strong isometriccontraction of a hand muscle, amplitudes of the TMS-induced motor evoked potentials (MEP) in the mirror handreveal an increased excitability of the crossed corticospinalsystem originating from the mirror M1 even when no overtMM 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 spinalalpha-motoneurons suggests that part of this facilitationmay 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 corticalinvolvement (Muellbacher et al., 2000). However, studieswhich addressed the effects of phasic hand movements onthe excitability of corticospinal neurons in the ipsilateralM1 reported complex and somewhat conflicting results:Tinazzi and Zanette (1998) and Ziemann and Hallett(2001) found enhanced MEP elicited from the mirror M1during 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 lesspronounced when the dominant hand rather than the non-dominant hand performed the task (Ziemann and Hallett,2001). In contrast, other authors reported a decrease ofMEP amplitude elicited from the mirror M1 during self-paced phasic movements of the ipsilateral hand (Liepertet al., 2001; Sohn et al., 2003), and either before (Leocaniet 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 themirror M1 was significantly more pronounced when volun-tary movements were performed with the dominant ratherthan 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 possibilityto explain why results on excitability of the corticomoto-neuronal system in the mirror M1 during hand movementspartly differ from those before movement onset is that dur-ing the motor task, the ipsilateral M1 could be influencedby proprioceptive afferences, whereas this does not happenduring movement preparation. Two findings indirectly sup-port this notion. First, the excitability of the M1, as testedby TMS, is modulated by contralateral passive movementat 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 withrespect to contralateral passive movements alone, suggest-ing a role of the proprioceptive input from the ipsilateralupper limb to the stimulated M1 (Stinear and Byblow,2002). However, facilitation and inhibition of corticospinalneurons in the mirror M1 seems to be modulated by manyadditional 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 movementkinematics (Duque et al., 2005). Further studies are neededto improve our understanding of this complex interactionbetween the voluntary active and mirror M1.

There is more evidence in favor of an activation of themirror M1 during intended unimanual movement of theipsilateral hand: the amplitude of the E2 component ofthe cutaneomuscular reflex recorded in a hand muscle after


electrical finger stimulation increases if the homologousmuscle 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 reflexEMG response is thought to be mainly mediated via atranscortical circuit (Jenner and Stephens, 1982; Farmeret 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) usedfocal TMS to disrupt the motor output from either M1in healthy adults according to a paradigm first applied byCincotta 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 upperlimb muscle, TMS of the contralateral M1 produces a long-lasting disruption of the voluntary cortical motor outputresulting in an absolute cortical silent period (SP) of upto a few hundred milliseconds in the ongoing EMG (forreview, see Hallett, 1995). In contrast, stimulation of theM1 ipsilateral to the contracting target muscle producesonly 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 transferto 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 ofone biceps muscle produces unintended contraction ofthe biceps muscle of the other side and that, no matterwhether activation in this target biceps muscle was volun-tary or mirror, focal TMS of the contralateral M1 alwaysproduced a long-lasting SP, as expected if the unintendedmotor output was entirely generated in the stimulatedhemisphere. On the contrary, focal TMS of the ipsilateralM1 always produced a by far shorter SP, as expected ifthe motor output responsible for mirroring was solely gen-erated in the non-stimulated hemisphere and TMS dis-rupted it via interhemispheric inhibitory influences. It iswell known that, in normal adults, focal TMS of one M1fails to elicit ipsilateral MEP of the same short latency ascontralateral MEP (Ziemann et al., 1999). This finding isa robust argument against the existence of ipsilateral fast-conducting corticomotoneuronal fibers that could accountfor ‘physiological’ mirroring. However, when healthyadults perform a strong contraction of the target upperlimb muscle, high-intensity focal TMS of the ipsilateralM1 elicits low-amplitude MEP. The latency of this ipsilat-eral MEP exceeds the latency of a size-matched MEP in thecontracting homologous contralateral muscle by 5–7 ms(Wassermann et al., 1994; Ziemann et al., 1999). Dissocia-tion of ipsilateral and contralateral MEP by differences incortical map location, preferred stimulating current direc-tion, and effects of head rotation, as well as the presenceof ipsilateral MEP in a patient with agenesis of the corpuscallosum suggested that the ipsilateral MEP is mediated byan ipsilateral oligosynaptic pathway such as the corticoret-iculospinal or corticopropriospinal projection (Ziemannet al., 1999). However, the above mentioned pattern of

motor output disruption produced by focal TMS of thevoluntarily active and the mirror M1 (Zijdewind et al.,2006) renders it rather unlikely that this weak ipsilateraloligosynaptic pathway contributes significantly to MM.Otherwise, one would expect that focal TMS of the contra-lateral (voluntarily non-active) M1 to result in an onlyshort-lasting disruption of mirror activity via interhemi-spheric pathways. One limitation of data addressingTMS-induced disruption of unintended motor output inhealthy humans is that they refer to biceps rather than tohand muscles (Zijdewind et al., 2006). However, withrespect 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 pathwaydoes not play a relevant role in mediating ‘physiological’mirroring in biceps muscles, as suggested by the work ofZijdewind et al. (2006), then this is even less likely in handmuscles.

The ability of healthy subjects to restrict partially orcompletely production of motor output in the hemispherecontralateral to the voluntary movement depends on a dis-tributed cortical network, whose functional organization isstill 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 involvedin voluntary movement lateralization. TMS induced inter-ference with the function of the SMA or the dPMC causeda transition from out-of-phase to in-phase bilateral handmovements but not vice versa (Meyer-Lindenberg et al.,2002). In addition, PET data demonstrated that activationof the right dPMC is more prominent during out-of-phasethan in-phase finger movements of the two hands (Sadatoet al., 1997). These findings pointed to a role also of thedPMC in this process. Recently, this hypothesis has beentested more specifically using repetitive TMS (rTMS) (Cin-cotta et al., 2004; Giovannelli et al., 2006). In a group ofeleven healthy adults, whilst performing an unilateral iso-metric contraction of a left hand muscle, on-line disruptionof the right dPMC by 20 Hz rTMS increased the excitabil-ity of the left (mirror) M1, as probed by MEP amplitude tothe 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 rTMSof the right M1 (Cincotta et al., 2004). In addition, rTMSof the right dPMC increased the excitability of the corti-comotoneuronal system in the left M1 only if the rightM1 was engaged in voluntary contraction of the left handmuscle but not if at rest (Cincotta et al., 2004). This taskdependence led to the conclusion that rTMS of the rightdPMC disrupted activity of a cortical network that is cru-cial to focus production of motor output in the right M1during 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


was observed. Hence, in a subsequent experiment, an easilyreproducible motor task that generally induces mirrorEMG activity even in normal adults was used to testwhether off-line disruption of the dPMC produced behav-ioral effects in addition to the previously observed electro-physiological effects (Giovannelli et al., 2006). Involuntarymirror EMG activity occurs if the subject maintains aslight background isometric muscle contraction in the mir-ror hand, whilst performing an intended unilateral briefphasic contraction with the homologous muscle of theother hand (Mayston et al., 1999) (Fig. 1). In a group oftwelve healthy volunteers, this ‘physiological’ mirrorEMG activity in the right hand increased after 15 minsuprathreshold 1 Hz rTMS (Chen et al., 1997) deliveredto the right dPMC when compared to the baseline (Gio-vannelli et al., 2006). In contrast, no significant increaseof mirror EMG activity in the right hand occurred withsham rTMS of the right dPMC, real rTMS of the rightM1, 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 movementand not an unimanual voluntary task sensu strictu, thesefindings further support the view that, during a phasic con-

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Fig. 1. Measurement of the mirror EMG activity in a representativehealthy subject performing a phasic abduction of the left thumb (APBvol),while sustaining a tonic contraction of the right abductor pollicis brevismuscle (APBmirror) at the minimum strength level that he could steadilymaintain against resistance. Striped area between the two vertical barsrepresents the EMG activity in the APBMIRROR during 50 ms followingthe onset of the phasic EMG burst in the APBvol. Each trace is the averageof 20 rectified trials. Mean EMG amplitude in this time interval wasexpressed as a percentage of the mean background EMG level in theAPBmirror in the time window of 1 s before APBvol burst onset. Reprintedfrom Giovannelli et al. (2006) with kind permission of Springer Scienceand Business Media.

tralateral voluntary movement, the right dPMC is involvedin the ‘non-mirror transformation’ of motor programs.

The notion that the neural processes responsible formovement lateralization mainly occur upstream the M1(in order to restrict motor output to the M1 contralateralto 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 TMSstudies support the existence of such a last-stage inhibitionof unwanted motor activity in healthy individuals. Inter-hemispheric inhibition (IHI), as tested by a paired-pulsefocal TMS protocol with the conditioning pulse deliveredto one M1 and the test pulse delivered 10 ms later to theopposite M1, slightly increases during an unilateral musclecontraction in the hand contralateral to the conditioningstimulus compared to the rest condition (Ferbert et al.,1992). Similarly, the ipsilateral SP, which also reflects inter-hemispheric inhibitory influences from the stimulated tothe non-stimulated M1 (Ferbert et al., 1992; Meyer et al.,1995), is enhanced by real and imagined motor tasks ofthe hand contralateral to the stimulated M1 (Cincottaet al., 2006c). In addition, the ipsilateral SP (Heinenet al., 1998) and the IHI (Mayston et al., 1999) are absentin children. This could explain why ‘physiological’ mirror-ing in children is by far greater than in adults, although itshould be noted that the TMS findings could merely reflectimmaturity of callosal fibers, which may not be accessibleby TMS due to a high threshold (Mayston et al., 1999).Focal 1 Hz rTMS of one M1 in healthy adults changedIHI from this M1 to the other non-stimulated M1, andthe magnitude of this change correlated inversely with aconcomitant change in ‘physiological’ mirror EMG activityin the hand contralateral to the stimulated M1 (Hubers andZiemann, 2006). Finally, during a simple reaction time(RT) that was performed by right-handed volunteers withtheir dominant hand, IHI from the mirror M1 to the volun-tarily active M1 reversed to facilitation close to reactiononset, whereas the influence from the voluntarily activeM1 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 M1was not observed prior to onset of movements of thenon-dominant hand. As this imbalance refers to interhemi-spheric interaction from the mirror M1 to the voluntarilyactive M1, it remains to be elucidated how exactly and towhat extent the neural mechanisms underlying IHI influ-ence the excitability of the crossed corticomotoneuronalsystem in the mirror M1 and act to suppress unintendedMM 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 notassociated with other motor abnormalities, the onset of


MM is nearly simultaneous to that of voluntary move-ments, as shown by surface EMG recordings duringintended unilateral phasic movements (Conrad et al.,1978; Forget et al., 1986; Cohen et al., 1991a; Cincottaet al., 1994).

The neurophysiological hallmark of persistent congeni-tal MM is the presence of fast-conducting corticospinalpathways connecting abnormally the hand area of eitherM1 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 TMSstudies, showing that focal stimulation of either the leftor 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; Daneket al., 1992; Cincotta et al., 1994, 2002; Fellows et al.,1996; Kanouchi et al., 1997; Mayston et al., 1997; Odabasiet al., 1998; Reitz and Muller, 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 theipsilateral MEP with respect to homologous contralateralones may vary across different upper extremity muscles(Verstynen et al., 2007). The pathophysiological relevanceof fast-conducting projections connecting abnormally M1to the ipsilateral spinal motoneurons is supported by across-correlation analysis of the EMG spikes recordedfrom bilaterally contracting homologous hand muscles.The cross-correlation analysis measures the distribution

right M1stimulation

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Fig. 2. Three consecutive MEP recordings from the resting right and leftabductor pollicis brevis (APB) after focal TMS of either M1 at the optimalposition 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 motorabnormalities. TMS was delivered at 70% of the maximum stimulatoroutput. In both patients, bilateral MEP of normal latency were elicited.Note that in Patient 1 the MEP recorded in the ipsilateral abductor pollicisbrevis (APB) after stimulation of either M1 were larger than in thecontralateral APB. Adapted from Cincotta et al. (2003b).

of the time intervals between each EMG spike recordedin one muscle and the nearest spike recorded in the contra-lateral homologous muscle. In patients with congenitalMM associated with Klippel-Feil syndrome (Farmeret al., 1990) and Kallmann’s syndrome (Mayston et al.,1997), the presence of a short duration peak around thetime interval 0 ms (central peak) in the cross-correlogramsindicates a common drive to the homologous spinal moto-neuron pools in both sides of the spinal cord. This commondrive may result either from synchronous activation ofintermingled ipsilaterally and contralaterally projectingcorticospinal neurons in M1 (Mayston et al., 1997), orfrom abnormal branching of crossed corticospinal fibersto the ipsilateral side (Farmer et al., 1990).

As these data strongly support the role of ipsilateralcorticospinal pathways in mediating congenital MM, otherpathophysiological aspects of this phenomenon requirefurther discussion. One point is whether the uncrossed cor-ticospinal projection is the sole substrate of MM orwhether activation of the M1 contralateral to the MM(mirror M1) also contributes. Positron emission tomogra-phy studies in otherwise normal patients with persistentcongenital MM (Cohen et al., 1991a) and in MM patientswith X-linked Kallmann’s syndrome (Krams et al., 1997)showed abnormal bilateral M1 activation during intendedunimanual movements. However, activation of the M1ipsilateral 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 M1activation during intended unilateral movements was alsosuggested by functional magnetic resonance imaging(fMRI), although a control experiment using passivemovements 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 wasdistributed bilaterally in patients with MM (Shibasakiand 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, thisdoes not necessarily imply that the mirror M1 producedactual motor output. In order to clarify this further, Cin-cotta et al. (1996) found that, in an otherwise healthywoman with strong and sustained MM (grade 3 accordingto the criteria of Woods and Teuber, 1978), unilateral focalTMS of either M1 during an intended unilateral isometriccontraction of a hand muscle resulted in a clearly shorterSP 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 sufferingfrom mild perinatal ischemic damage (Balbi et al., 2000).These experiments strongly suggest a bilateral contributionof bilateral M1 to the motor output during intended uni-


manual movements. The implication is that if MM weresolely caused by activity along an ipsilateral corticospinalprojection from the voluntarily active M1, then focalTMS of this M1 would have been expected to produce along-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 canbe explained most parsimoniously by motor output fromthe non-stimulated M1, starting as soon as the short-last-ing interhemispheric and segmental inhibition producedby focal TMS of M1 has disappeared (Fig. 3B). The com-peting hypothesis that the short-lasting SP is caused by

Fig. 3. (A–D) models to show the expected effects of focal TMS of one (leftcongenital MM not associated with other relevant motor abnormalities duringcortical motor output. Expected cortical silent period (SP) recordings are shownleft (lower trace) hand muscle. If MM exclusively depended on the presencecontralateral to the voluntary motor task would produce a normal, long-lastingmuscles (A). In contrast, if motor output from the ipsilateral (right) M1 also cona bilaterally shortened cortical SP (B), whereas simultaneous bilateral stimulatibilaterally shortened cortical SP observed after unilateral stimulation of the leftwould not result in CSP normalization (D). (E) cortical SP following focal TMmotor threshold (RMT) or bilateral simultaneous stimulation of both M1 (atMEP size in the unilateral TMS conditions) delivered during an intended unilaotherwise healthy 15-year-old girl with persistent congenital MM. Each traceindicate the time of TMS. The SP duration was calculated from the stimulus topre-stimulus EMG. Arrows indicate the end of the SP. Unilateral stimulation ofof the SP following bilateral stimulation was normal. Adapted from Cincotta

impaired inhibitory circuitry in the stimulated voluntarilyactive M1 was ruled out by a control experiment: bilateraldisruption of the motor output by simultaneous focal TMSof both M1 during an intended unilateral hand musclecontraction resulted in a normalization of the cortical SPin either hand (Figs. 3C–E) (Cincotta et al., 2002). Finally,as conditioning peripheral electric stimulation induced ashortening of the cortical SP in healthy volunteers (Hesset 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 peculiarproprioceptive input resulting from the presence of strongMM. Again, the normal duration of the SP produced by

) M1 and simultaneous bilateral stimulation of both M1 in patients withintended unilateral (right) hand contraction. Saw-toothed lines indicate the

on the right of each model for the right (upper trace in each diagram) andof uncrossed corticospinal fibers, then unilateral stimulation of the M1

cortical SP in both the voluntarily contracted (right) and mirror (left) handtributes to MM, then unilateral TMS of the opposite (left) M1 would eliciton of the M1 would lead to a cortical SP normalization (C). Finally, if theM1 were due to impaired inhibitory mechanisms, bilateral M1 stimulationS of either the left or right M1 at an intensity of 20% above the resting

an intensity of 20% or 10% above the RMT to match MEP size with theteral isometric contraction of the right abductor pollicis brevis (APB) in an

is the average of 10 rectified EMG responses. The vertical dotted linesthe point when the mean post-MEP EMG reached again 20% of the meaneither M1 produced a short cortical SP in both APB, whereas the durationet al. (2003a).

right APB left APB

500 uV

100 ms

focal TMS of the left M1

focal TMS of the right M1

bilateral stimulation (20% above the RMT)

bilateral stimulation (10% above the RMT)

E

Fig. 3 (continued)


bilateral simultaneous TMS of both M1 also largely ruledout this possibility.

Another point relates the anatomy of the ipsilateral cor-ticospinal projection. One hypothesis favors abnormalbranching of crossed corticospinal fibers (Farmer et al.,1990). Another hypothesis postulates an ipsilateral projec-tion that is anatomically distinct from the one projecting tothe contralateral side (Mayston et al., 1997). In persistentcongenital MM, the possibility that ipsilateral fast-con-ducting pathways depend, at least in part, on distinct,uncrossed corticospinal neurons is supported by recordingsof ipsilateral MEP that were larger than the homologouscontralateral 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), whoused the triple stimulation technique (Magistris et al., 1998)to provide a better quantification of the contribution of thecortical-motor neuron pool to the target muscle. Poten-tially, however, these data could also be explained by an‘asymmetrical’ axonal branching of crossed corticospinalaxons, providing more synaptic input to the ipsilateral thancontralateral spinal motoneurons. Further insight into theorigin of the ipsilateral corticospinal pathways was pro-vided by paired-pulse TMS experiments that tested task-related modulation of SICI (Cincotta et al., 2003b). SICIrefers to a marked inhibitory effect of a weak conditioning

TMS pulse on a MEP elicited in the resting target muscleby 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 normalsubjects, voluntary contraction of the target muscle pro-duces a significant reduction of SICI (Ridding et al.,1995; Zoghi and Nordstrom, 2007). If ipsilateral MEP wereexclusively due to branching of crossed corticospinal neu-rons, then intended unilateral contraction of a hand musclewould produce the same SICI reduction in the ‘task’ andmirror hand muscle. This, however, is not what was found.In two otherwise normal patients with strong and sustainedcongenital MM, SICI in the voluntarily active M1decreased markedly in the contralateral ‘task’ abductorpollicis brevis (APB) muscle, but remained unchanged inthe ipsilateral mirror APB, when compared with the restcondition (Fig. 4) (Cincotta et al., 2003b). This restrictionof SICI reduction to the task muscle indicates a dissocia-tion of the fast-conducting projections from the stimulatedM1 and, therefore, the existence of a distinct ipsilateral cor-ticospinal projection. The pathogenetic mechanisms lead-ing to the presence of these abnormal, uncrossedcorticospinal neurons are largely unknown. However,TMS data support the existence of a strong ipsilateral cor-ticomotoneuronal projection in healthy newborns (Eyre

right APB left APB

rest

minimal rightcontraction

minimal leftcontraction

20 ms

500 µV

118%

31%141%

26%

30% 32%

Fig. 4. Effect of different motor tasks on SICI in a 15-year-old girl withpersistent congenital MM not associated to other abnormalities. MEPwere recorded from both abductor pollicis brevis (APB) after focal paired-pulse TMS of the right M1 (inter-stimulus interval, 3 ms). All traces arethe average of 10 unconditioned (thin lines) or conditioned (thick lines)MEP. In each condition, percentages indicate peak-to-peak amplitude ofthe conditioned over the unconditioned MEP. Note that during minimalcontraction of either APB, SICI was completely suppressed in thevoluntarily activated APB but remained unchanged in the mirror APB,when compared with the rest condition. Adapted from Cincotta et al.(2003b).

intended unilateralmovement of the left hand

intended unilateralmovement of the right hand

Fig. 5. Schematic drawing that shows anatomically distinct crossed anduncrossed corticospinal fibers and bilateral motor output with intendedunimanual movements in otherwise normal adults with congenital MM.Black and grey lines indicate the preferentially and non-preferentiallyactivated pathways, respectively. The amount of mirror activity could bereduced by preferentially activating the crossed corticospinal neuronsfrom the right hemisphere and the ipsilateral tract from the left hemisphereduring intended unilateral movements of the left hand, and vice versaduring intended unilateral movements of the right hand. Adapted fromCincotta et al. (2003a).


et al., 2001). Withdrawal of these ipsilaterally projectingneurons mainly occurs in the first 15–18 postnatal months(Eyre et al., 2001). In older children, ipsilateral MEPbecome increasingly smaller, and develop higher thresholdand longer latency than the contralateral ones (Mulleret al., 1997; Eyre et al., 2001). Therefore, an intriguinghypothesis is that congenital persistent MM in otherwisehealthy adults depend on genetic or sporadic alterationsof the physiological postnatal withdrawal of the ipsilateralcorticospinal projection.

One limitation of most electrophysiological data inpatients with congenital MM not associated with other rel-evant motor abnormalities is that they have been obtainedat rest (TMS studies) or during tonic motor tasks (TMSstudies and cross-correlation analysis of EMG activity)and not during phasic movements. In addition, the currentTMS data focus on the M1 and corticospinal fibers,whereas the role of SMA and premotor cortex in voluntarymovement lateralization is underinvestigated in thesepatients. Nevertheless, coexistence of bilateral motor out-put and contralateral and ipsilateral corticospinal projec-tions is strongly supported from the availableneurophysiological data and may be relevant from a func-tional point of view. Anatomically distinct, but notbranched 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 theright hand could be reduced by preferential activation of

the contralaterally projecting corticospinal fibers from theright M1 and the ipsilaterally projecting neurons fromthe left M1 (Fig. 5). Vice versa, reduction of MM in the lefthand during intended unilateral voluntary movements ofthe right hand could rely on preferential activation of thecrossed corticospinal neurons from the left M1 and theuncrossed fibers from the right M1 (Fig. 5). This mayexplain why some patients are capable of exerting somedegree of voluntary control over the amount of MM, albeitwith effort, and why different tasks may be differentlyaffected in individual patients (Schott and Wyke, 1981;Poizner and Kritchevsky, 1991; Paulson and Gill, 1995;Hermsdorfer et al., 1995). Furthermore, this model of thephysiology of congenital MM provides a rationale forrehabilitation. Accordingly, the 15-year-old girl with strongand sustained congenital MM underwent a 7-month reha-bilitative program designed to facilitate unilateral fingermovements by performing asymmetrical movements ofincreasing complexity with the fingers of both hands, andmotor imagery of unilateral movements (Cincotta et al.,2003b). After the rehabilitative training, the magnitude ofMM was markedly reduced compared to the pre-trainingcondition. Improvement involved specifically the trainedphasic finger movements, whereas movements that werenot 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 perinatalbrain damage may result in different patterns of functional


reorganization (Carr et al., 1993; Forssberg, 1999). TMSand fMRI data suggest that the earlier the insult occursduring 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 isassociated 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 symmetricallynormal 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; Cincottaet al., 2000; Eyre et al., 2001; Jang et al., 2001; Staudtet al., 2002, 2004). Recent data from Eyre et al. (2007) sug-gest that loss of surviving crossed corticospinal projectionsfrom the affected hemisphere may occur in the first twoyears of life due to competitive displacement by theincreased ipsilateral projections from the undamagedmotor cortex and is associated with severe impairment.In addition, during bilateral voluntary contraction ofhomologous hand muscles, a short-duration central peakoccurs in the EMG cross-correlogram constructed frommotor 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 corticalmotor output to both the unaffected hand and the paretichand is provided from the undamaged hemisphere and thatMM are due to the presence of fast-conducting corticospi-nal connections between the unaffected M1 and ipsilateraland contralateral spinal motoneurons. However, to someextent these patients may be capable of lateralizing volun-tary motor activity, as shown by Cincotta et al. (2000) in a39-year-old man with a severe right spastic hemiparesisresulting from a large congenital porencephalic lesion inthe left hemisphere, mainly involving the frontal and pari-etal lobes. In this patient, strong and sustained MM wereobserved in either hand, although less pronounced thanthe voluntary movements (grade 3 according to the criteriaof Woods and Teuber, 1978). Focal TMS of the intact rightM1 resulted in ipsilateral MEP in resting muscles of theaffected hand that had the same latency and a lower ampli-tude than MEP recorded in the homologous muscles of thecontralateral intact hand (Fig. 6B). As to the neural sub-strate of movement lateralization, three experimental setsdata suggested that lateralized activation of the paretichand was mediated through an anatomically distinct ipsi-lateral projection from the undamaged right hemisphere,by-passing the system of fast-conducting corticospinalfibers. 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 duringintended unilateral left APB contraction but not duringintended unilateral contraction of the right APB despitemirror activity in the good hand (Fig. 6A). Second, when

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 leftAPB, compared with the rest condition (Fig. 6E). Third,the cortical SP recorded in the voluntarily contracting rightAPB after stimulation of the unaffected M1, albeit normalin absolute duration, was shorter than the SP observed inthe unaffected APB or the SP recorded bilaterally duringvoluntary contraction of the left APB. These findingsstrongly suggested that voluntary contraction of the paretichand was at least in part due to motor cortical outputalong a separate ipsilateral projection, which is less suscep-tible to TMS-induced inhibition than the fast-conductingcorticospinal projection. One candidate is an abnormallyretained ipsilateral oligosynaptic corticoreticulospinalpathway, 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 functionalpoint of view (Wassermann et al., 1994; Ziemann et al.,1999). However, a delayed ipsilateral MEP that would beexpected if mediated by this pathway could not be testedin this patient because of the presence of a large short-latency ipsilateral MEP mediated by the fast-conductingcorticospinal neurons. Partial movement lateralization dur-ing intended unilateral contraction of the good hand likelyrelied on preferential activation of a subset of strictlycrossed fast-conducting corticospinal neurons. This viewis supported by paired-pulse TMS data recorded duringintended unilateral isometric contraction of the unaffectedAPB, showing selective SICI suppression in the good hand,but not in the paretic one (Fig. 6E).

Finally, somatosensory function in patients with severecongenital hemiparesis can be clinically preserved in theaffected arm, despite a largely complete alteration of theafferent pathways from this arm to the affected hemisphere.Somatosensory evoked potential (SEP) recordings showedslow-conducting, probably non-lemniscal connectionsbetween the affected arm and the ipsilateral non-primarysomatosensory cortex that may have been responsible forthe 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 fromthe M1 of the undamaged hemisphere to the affectedarm. Moreover, in patients with large unilateral periven-tricular brain lesions occurring in the early third trimesterof pregnancy, when the development of thalamocorticalsomatosensory projections is still incomplete, the primarysomatosensory representation of the paretic hand in thecontralateral hemisphere can be preserved, in spite of astrictly ipsilateral motor representation (Staudt et al.,2006). Magnetic resonance diffusion tractography sug-gested that outgrowing somatosensory projections hadapparently by-passed the lesion by curving around it (Sta-udt et al., 2006). These observations point to differentforms and efficiency of functional reorganization ofsomatosensory and motor pathways.

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 manwith persistent MM associated to a severe right congenital hemiparesis. (A) Cross-correlograms constructed from at least 2000 motor unit spikes recordedsimultaneously from both APB (sampling rate, 5000 Hz) during intended unilateral contraction at intermediate strength. Note that a central peak waspresent during voluntary contraction of the left APB but not during voluntary contraction of the right APB. (B) Three consecutive short-latency responsesrecorded 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) thanin 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, deliveredat rest (thin lines) and during a slight contraction of the right APB (thick lines). Note that right voluntary contraction reduced the MEP amplitude in theleft 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 thatsimilar voluntary and mirror EMG levels produced the same facilitation of the H-reflex amplitude compared with the rest condition (2.1 mV versus0.6 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) orconditioned (thick lines) MEP. In each condition, the numeric value represents the peak-to-peak amplitude of the conditioned MEP expressed as apercentage of the unconditioned one. Note the increase in intracortical inhibition in the left APB with intended right APB contraction. Adapted fromCincotta et al. (2000).


3.3. What can clinical neurophysiologists learn from

persistent congenital MM?

In patients with persistent congenital MM, the presenceof fast-conducting corticospinal fibers connecting abnor-mally the hand area of the M1 with both sides of the spinalcord represents an outstanding model to investigate theneural pathways underlying neurophysiological and clini-cal phenomena involving the motor pathways. Two exam-ples are long-latency reflex EMG responses and enhancedphysiological tremor.

In normal subjects, electrical stimulation of a mixednerve at wrist (Deuschl and Lucking, 1990) or a cutaneousdigital nerve (Jenner and Stephens, 1982) as well as thestretch of a hand muscle (Matthews, 1991) produce short-and long-latency reflex EMG responses in the handmuscles. While the short-latency response depends on amonosynaptic Ia excitation of spinal motoneurons, thelong-latency one is thought to be mainly mediated througha transcortical loop, the afferent and efferent branches ofwhich involve Ia fibers and the fast-conducting corticospi-nal pathway, respectively (Jenner and Stephens, 1982;


Deuschl and Lucking, 1990; Matthews, 1991, 2006). Anumber of studies conducted in patients affected by con-genital MM without other relevant motor abnormalitiesstrongly supported this hypothesis by showing that eithercutaneous or mixed nerve stimulation as well as musclestretch produced a strictly unilateral short-latency EMGresponse but bilateral simultaneous long-latency reflexresponses 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; Koster et al., 1998; Maystonet al., 2001). As SEP recordings showed strictly contralat-eral short-latency responses in the primary somatosensorycortex in this type of patients (Farmer et al., 1990; Capadayet al., 1991; Cohen et al., 1991a; Cincotta et al., 1994;Fellows et al., 1996), the observed bilateral pattern oflong-latency reflexes in the hand muscles indicates thatthe underlying circuitry involves the ipsilaterally projectingfast-conducting corticospinal neurons demonstrated byfocal transcranial stimulation of the M1. Of note, Fellowset al. (1996) found that, in contrast to the hand muscles, thelong-latency reflex EMG response to the stretch reflex wasstrictly ipsilateral in the biceps brachii muscle of a patientwith congenital MM. In addition, Lourenco et al. (2006)have recently reported that the late response elicited inthe flexor carpi radialis by electrical stimulation of theulnar nerve at the wrist was also exclusively ipsilateral ina patient with congenital MM. Accordingly, data inhealthy volunteers obtained by post-stimulus time histo-grams of single motor units, ulnar nerve cooling, and selec-tive pharmacological modulation by tizanidine intakesuggest that the more reproducible component of thelong-latency reflex response in the forearm muscles is med-iated through a spinal circuit via muscle spindle group IIafferents, although a less reproducible transcortical sub-component may be present too (Lourenco et al., 2006).In conclusion, several findings suggest distinct substratesfor long-latency reflexes in proximal and distal upper limbmuscles, with transcortical pathways playing a major rolein the hand muscles and polysynaptic, group II afferent-mediated spinal circuits mainly involved in forearm andarm muscles (Matthews, 2006).

Physiological tremor in humans is thought to dependson both mechanical and neurogenic mechanisms (Kosteret al., 1998). However, it was found difficult to determinethe 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 frequencydomains of surface EMG recorded bilaterally from homol-ogous muscles of the upper extremities showed a significantleft-right coherence of either salbutamol-induced enhancedphysiological tremor (Koster et al., 1998) or non-enhancedphysiological tremor (Mayston et al., 2001) in patients withcongenital MM not associated to other relevant motorabnormalities. These data suggest that the circuitry under-lying physiological tremor in congenital MM patientsinvolves a transcortical pathway via the uncrossed andcrossed fast-conducting corticospinal fibers identified by

focal TMS of the M1 and is in keeping with a central originof the neurogenic component of physiological tremor inhealthy humans (Koster et al., 1998; Mayston et al., 2001).

It is likely that the persistent congenital MM model willprove useful in investigating further clinical aspects ofmotor 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 pastfew years (Nassetti et al., 1999; van den Berg et al., 2000;Vidal et al., 2003; Espay et al., 2005, 2006; Cincottaet al., 2006a,b; Li et al., 2007; Ottaviani et al., 2007). Datafrom selected case series documented strong and sustainedMM in untreated patients with early and asymmetric PDand demonstrated that MM are more frequently observedin the less affected limb when the more affected limb is per-forming a voluntary motor task (Vidal et al., 2003; Espayet al., 2005). However, when clinically detectable MM ofslight intensity are also considered, findings from a largeunselected case series suggested that the overall frequencyof MM in PD is lower than in healthy controls (Ottavianiet al., 2007).

In PD, the time of onset of mirror compared to volun-tary EMG activity varies between �15 and 37 ms but canstart simultaneously (personal observation in a singlepatient performing self-paced unilateral thumb abduction).Surface EMG and TMS data obtained in four PD patientswith strong and sustained MM provided evidence that MMdo not depend on unmasking of ipsilateral corticospinalprojections but are explained by motor output along thecrossed corticospinal projection from the M1 ipsilateralto the voluntary motor task (Fig. 7A) (Cincotta et al.,2006a). Focal TMS of either M1 did not elicit abnormalipsilateral MEP in the hand muscles. The cross-correlo-gram constructed from the surface EMG of motor unitspikes did not support the presence of a common motordrive to homologous hand muscles during intended uni-manual tasks. A common motor drive would have beenexpected if MM were due to the synchronous activationof ipsilaterally and contralateral projecting corticospinalneurons that originate from the same M1 (Maystonet al., 1997). These findings have been recently confirmedin 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, whereasstimulation of the ipsilateral M1 produced a short-lastingSP. Likewise, during either mirror or voluntary finger tap-ping, 5-Hz rTMS of the contralateral M1 produced amarked disruption of EMG activity in the target hand mus-cle, whereas the effect of rTMS of the ipsilateral M1 was byfar less (Fig. 7B). In addition, focal paired-pulse TMS of

right handmuscle

left handmuscle

intended unilateral movement of the right hand

right handmuscle

left handmuscle

right handmuscle

left handmuscle

intended unilateral movement of the right hand

right M1stimulation

right FDI

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main task

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1 s

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right M1stimulation

right FDI

main task

control task

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left M1stimulation

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A B

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


M1 showed that SICI was similarly down-regulated duringeither voluntary or mirror contraction of the contralateraltarget hand muscle compared to the resting condition. Insummary, in these selected PD patients, strong and sus-tained MM reflect an enhancement of ‘physiological’ mir-roring (cf. section ‘Voluntary movement lateralization inhealthy humans’).

In PD, bradykinesia likely depend on a failure of basalganglia output to energize the cortical mechanisms thatprepare and execute the movements (Berardelli et al.,2001). Similarly, a deficient basal ganglia output could alsofail to support the cortical network that is involved inenabling the corticospinal system to execute strictly uni-manual movements (Cincotta et al., 2006a). According tothis hypothesis, Li et al. (2007) recently reported that, inPD patients with MM only on one side, the ipsilateral SPwas reduced in the hand affected by MM compared tothe non-MM side and compared to healthy controls, andthat the IHI tested by paired-pulse TMS at long interstim-ulus intervals (20–50 ms) was more pronounced in PDpatients without MM than in PD patients affected byMM and controls. When healthy volunteers and mildlyto moderately affected PD patients without clinically overtMM were selected, surface EMG data also support thenotion that voluntary movement lateralization is alteredin PD (Cincotta et al., 2006b). When requested to performunilateral phasic thumb abduction movements during asustained tonic contraction of the opposite APB (cf.

Fig. 1 for the experimental protocol), the magnitude ofinvoluntary mirror EMG activity in the tonically contract-ing APB was greater in the group of 12 PD patients than inage-matched controls, no matter whether the PD patientswere 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 issupported by local field potential (LFP) activity recordedin the subthalamic nuclei (STN) from the electrodes usedfor deep brain stimulation (DBS) (Androulidakis et al.,2007). Functional neuroimaging (Rao et al., 1993) as wellas 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 tasksas a consequence of motor impairment could per se favorMM. However, at least two arguments strongly pointagainst the notion that MM depend on the increased vol-untary effort alone. First, strong and sustained MM havebeen mainly reported in mildly affected rather thanadvanced PD patients (Espay et al., 2005). Second, a fol-low-up assessment in a group of PD patients on chronicdopaminergic treatment showed that when testing was per-formed at least 12 h after the last intake of dopaminergicdrug (‘off’ condition), the mean MM score was not higherthan during maximal benefit from the dopaminergic treat-


ment (‘on’ condition) although in the ‘off’ condition motorimpairment, as tested by the UPDRS (Fahn and Elton,1987), was greater than in the ‘on’ condition (Espayet al., 2006). Moreover, in these patients, a correlationbetween changes in motor impairment and change inMM was seen: namely, from ‘off’ to ‘on’ condition, MMincreased in patients with greater improvement in UPDRSmotor score and decreased in those with less improvement.In conclusion, although a minor role of task effort cannotbe ruled out, it is likely that in PD patients who performintended unilateral movements, the presence and degreeof MM mainly depends on the balance of two oppositemechanisms: dysfunction of voluntary movement laterali-zation (an alteration that mainly occurs in the hemispherecontralateral to the voluntary motor task), and altered taskexecution in the motor areas contralateral to the mirrorhand. Altered unimanual motor control accounts for theoccurrence of strong and sustained MM, which representan abnormal enhancement of ‘physiological’ mirroring.Conversely, deficient activation of cortical motor areaslikely reduces voluntary and mirror output to the contra-lateral hand, resulting in bradykinesia and less expressionof MM, respectively. This could account for the observa-tion that MM are particularly observed in the less affectedhand (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 toimpair 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 mayprove useful in improving complex bimanual motor skillsin PD.

4.2. Acquired MM associated with other conditions

In addition to PD, several diseases may present MM orcontralateral motor overflow, the pathophysiological sub-strates of which are still under-investigated.

Force transduction measurements performed duringintended unimanual tonic movements showed that contra-lateral motor overflow was greater in patients with schizo-phrenia than in healthy volunteers, in particular at lowforce levels (Hoy et al., 2004b). In a group of patients withschizophrenia, focal TMS of M1 failed to elicit ipsilateralMEP 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 contractingthrough voluntary or mirror activity (Hoy et al., 2007). Inaccordance to the observations reported in PD (Cincottaet al., 2006a), these findings support the hypothesis thatcontralateral motor overflow in schizophrenia is also dueto activation of the crossed corticospinal tract originatingfrom the mirror M1, and therefore, represents an abnormalenhancement of the ‘physiological’ mirroring. IHI and ipsi-lateral SP data suggested altered interhemispheric inhibi-tory mechanisms in schizophrenia (Boroojerdi et al.,

1999; Fitzgerald et al., 2002; Bajbouj et al., 2004). Hence,it was hypothesized that increased mirroring observed inschizophrenia depends on a deficient transcallosal transferof inhibitory control (Hoy et al., 2004b).

Abnormally increased mirroring during intended uni-manual phasic or tonic movements was also demonstratedin 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 activitystarted at the same time (Hashimoto et al., 2001). Duringtonic movements, the degree of motor overflow correlatedpositively with the overall motor impairment (Georgiou-Karistianis et al., 2004). Neurophysiological data thataddress the neural substrate of enhanced contralateralmotor 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 toadult-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 bedelayed by several hundred milliseconds with respect tothe onset of voluntary movement, in particular in theaffected limb during voluntary movement of the unaffectedone (Hopf et al., 1974). When these long delays occur, theterm synkinesias (Marie and Foix, 1916) is probably moreappropriate to indicate unintended motor activity (Cohenet al., 1991a). Using computerized dynamometer record-ings in a group of twenty-three stroke patients, Nelleset al. (1998) showed that MM observed in the unaffectedhand during intended unilateral squeezing of the paretichand were significantly more frequent than MM observedin the paretic hand. The incidence of the latter did not differfrom MM observed in either hand of control subjects. Inaddition, the presence of MM in the unaffected hand wasassociated with greater motor deficit in the affected hand,whereas in patients showing MM in the paretic hand motorfunction was better than in patients without MM. In agroup of chronic stroke patients, Werhahn et al. (2003)found that focal TMS of either the unaffected or thelesioned M1 delayed simple RT in the contralateral handbut not in the ipsilateral hand, suggesting that recoveredmotor function in the paretic hand mainly relied on motoroutput from the reorganized affected hemisphere. Severalstudies demonstrated ipsilateral MEP in the upper extrem-ities following focal TMS of the lesioned or non-lesionedhemisphere: while some authors reported that ipsilateralMEP are associated with good motor recovery, othersfound an association between the presence of ipsilateralMEP and poor outcome (for review, see Rossini and Pauri,2003). As to the association between ipsilateral MEP andMM in adult stroke patients, Netz et al. (1997) found thatfocal TMS of the unaffected hemisphere elicited ipsilateral


MEP in the hand muscles of all patients with incompleterecovery. In nine of these 10 patients, the latency of theipsilateral MEP was longer (mean value 6 ms) than thelatency of the contralateral MEP and no MM wereobserved. In contrast, the unique patient whose ipsilateralMEP 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 andneurophysiological findings suggest that in most cases ofadult-onset hemiparetic stroke, increased MM in the intacthand during voluntary motor activation of the paretichand depend on an abnormally enhanced activation ofcrossed 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 handmay contribute.

Recently, it was reported that patients affected by ALSmay sporadically present MM (Krampfl et al., 2004; Witt-stock et al., 2007). Of note, deficient ipsilateral SP andenhanced ipsilateral MEP have been also observed inALS patients. However, a significant correlation betweenthe presence of ipsilateral MEP or a deficient ipsilateralSP and the occurrence of MM was lacking (Wittstocket al., 2007). Hence, further studies are needed to clarifythe mechanisms that underlie MM in ALS.

Acknowledgements

This work was supported by a Grant from ‘Ente Cassadi Risparmio di Firenze’, Florence, Italy. We are gratefulto our patients and healthy volunteers and to our cowork-ers in this field. A special thanks to Prof. Franco Barontiniwho taught clinical aspects of mirror movements to Massi-mo Cincotta in 1991.

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neurophysiology of unimanual motor control and mirror movements

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