Brain Advance Access originally published online on December 8, 2003
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Brain, Vol. 127, No. 2, 385-397, 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh047
Abnormal cortex-muscle interactions in subjects with X-linked Kallmann’s syndrome and mirror movements
1 National Hospital for Neurology and Neurosurgery, 2 Department of Physiology, University College London and 3 Department of Neurology, St Mary’s Hospital, London, UK
Correspondence to: Dr Simon Farmer, Department of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK E-mail: s.farmer{at}ion.ucl.ac.uk
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Summary |
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X-linked Kallmann’s (XKS) subjects, who display mirror movements, have abnormal corticospinal tracts which innervate motoneurons of the left and right distal muscles of the upper limb. The size of the abnormal ipsilateral projection is variable. We have used coherence and cumulant analysis between EEG and first dorsal interosseous muscle (1DI) EMG to explore mechanisms underlying mirror movements in three XKS subjects. Results are compared with those of three normal subjects. We argue that significant coherence is functionally relevant when associated with a negative cumulant at an appropriate lag. Given this, normal subjects showed coherence at
22 Hz between the EEG recorded over the sensori-motor cortex contralateral to the voluntarily moved hand and the 1DI EMG of this hand. No significant coherence was seen between 1DI EMG and the sensori-motor cortex ipsilateral to the muscle activity. In contrast, two of the XKS subjects (K2 and K4) had significant coherence at 22 Hz, together with a negative cumulant at an appropriate lag, between the ipsilateral cortical EEG and the 1DI EMG of the voluntarily activated hand. This implies that activity in the abnormal ipsilateral corticospinal projection can contribute to the voluntary drive. For these two subjects, the ipsilateral corticospinal projection was greater than the contralateral projection, as revealed using magnetic brain stimulation. In one of these subjects, K4, significant 22 Hz coherence and negative cumulant was also seen between the EMG of the voluntarily activated hand and the cortex contralateral to this hand. In the third subject, K4a, coherence and negative cumulant was detected between the EMG of the voluntary side and the cortical activity contralateral to this hand. The contralateral cortico spinal projection of this subject was greater than the ipsilateral projection. Regarding the mirroring hand of the XKS subjects, coherence (with negative cumulant at an appropriate lag) was seen in all three subjects between the EMG recorded from the mirroring hand and cortical EEG ipsilateral to this hand. This provides evidence that activity in the aberrant ipsilateral projection is involved in producing the drive that results in mirror movements. In one subject, K4, coherence and negative cumulant was also seen between the EMG of the mirroring hand and motor cortical activity contralateral to this hand. Thus, in this subject, activity in the corticospinal projection contralateral to the mirroring hand also contributed to the mirror movements. In conclusion, this study has provided further evidence that the 22 Hz coherence seen between EEG and EMG is dependent upon corticospinal activity and has furthered our understanding of mechanisms underlying mirror movements.
Key Words: mirror movements; EEG; EMG; oscillation; motor cortex
Abbreviations: 1DI= first dorsal interosseous muscle; FCI = Functional cumulant imaging; I/C = ipsilateral/contralateral; rCBF = regional cerebral blood flow; TMS = transcranial magnetic stimulation; XKS = X-linked Kallmann’s syndrome
Received February 1, 2003. Accepted September 29, 2003.
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Introduction |
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Subjects with congenital mirror movements produce unintended activation of homologous muscles when attempting to unilaterally activate one or other hand. In these subjects, focal transcranial magnetic stimulation (TMS) produces simultaneous short-latency responses in both left and right hand muscles, thus revealing abnormal fast-conducting corticospinal projections to spinal motoneurons (Farmer et al., 1990
; Britton et al., 1991; Cohen et al., 1991; Mayston et al., 1997). Mayston et al. (1997) investigated mirror movements in subjects with X-linked Kallmann’s syndrome (XKS) using neurophysiological techniques and suggested that activity in their aberrant corticospinal projection could be responsible, at least in part, for the mirror movements. This conclusion was supported by a PET study (Krams et al., 1997), in which some of the subjects studied by Mayston et al. (1997) participated. This PET study indicated that activation of the motor cortex was greater in the cortex contralateral to the voluntarily moved hand; the relatively smaller motor cortical activation contralateral to the mirroring hand could result from sensory feedback from the mirroring hand (Krams et al., 1997).
The firing of the motor units of the left and right homologous muscles that are co-activated, thus leading to mirror movements, shows correlation as revealed by a short duration peak in the cross-correlogram (Mayston et al., 1997) and coherence analysis (Koster et al., 1998; Mayston et al., 2001). Coherence between the discharges of single motor units is normally detected in the ranges 1–12 and 16–32 Hz (Farmer et al., 1993). Recent studies indicate that motor unit coherence in a frequency range between 11 and 45 Hz results from oscillatory activity in the primary motor cortex; in humans and macaque monkeys simultaneous recordings of MEG, EEG or field potentials with EMG have shown coherence (range: 11–45 Hz; with maxima at 22 Hz) between signals recorded from over the motor cortex and EMG of contralateral limb muscles (Conway et al., 1995; Baker et al., 1997; Salenius et al., 1997; Brown et al., 1998; Halliday et al., 1998; Mima et al., 2000). The scalp distribution of MEG/EEG-EMG cortex-muscle coherence has been mapped for different muscles and broadly reflects the primary motor cortex homunculus (Salenius et al., 1997; Mima et al., 2000). Furthermore, a majority of studies have now shown that for the frequency range 11–45 Hz there is a phase delay between coupled EEG/MEG oscillations and EMG oscillations (Brown et al., 1998; Feige et al., 2000; Gross et al., 2000; Mima et al., 2000, 2001). Taken together, this evidence strongly suggests that EMG oscillations result from oscillations in motor cortex neural activity transmitted to the spinal motoneurons via fast-conducting corticospinal pathways. However, there is as yet no more direct evidence that this is the case. Furthermore, it is not known whether the oscillatory drive to motoneurons revealed by EEG–EMG correlation is indicative of the voluntary motor activity. We hypothesize that if cortex-muscle coherence in man reflects transmission of oscillatory activity via fast conducting corticospinal pathways, then the scalp distribution of maximal coupling between EEG and EMG should reflect the distribution of the aberrant corticospinal pathways revealed in subjects with mirror movements by focal TMS and long-latency reflex testing. Using magnetoencephalography (MEG), Pohja et al. (2002) recently described coupling between the motor cortex and EMG in a single subject with Kallmann’s syndrome. During a unilateral contraction, coherence was present between the EMG of the intentionally activated hand and the contralateral motor cortex, and between this same cortex and the EMG of the mirroring hand. No other neurophysiological details were provided for this one subject. Our previous study (Mayston et al., 1997) showed that XKS subjects do not comprise a uniform group, particularly so when considering their corticospinal projections as revealed using TMS. In the present study, we have investigated three XKS subjects with differing degrees of ipsilateral versus contralateral corticospinal projections to see if coherence and cumulant analysis of EEG and EMG signals can further our understanding of how motor cortical activity results in obligatory mirror movements. In addition, we were interested in whether this analysis would allow us to draw any conclusions regarding the role of the aberrant ipsilateral corticospinal projection during a voluntary movement of one hand. This is of particular interest in a subject whose corticospinal projection, as revealed using magnetic stimulation, is predominantly ipsilateral. Some of these data have been presented previously in abstract form (Farmer et al., 2001, 2003).
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Subjects
Experiments were performed with both local ethical approval of St Mary’s NHS Trust according to the Declaration of Helsinki and the subjects’ informed written consent. We studied three subjects with XKS and mirror movements K2, K4 and K4a (aged 27, 34 and 36 years, respectively), two of whom were brothers (K4 and K4a). These subjects have been studied previously (Krams et al., 1997
; Mayston et al., 1997) and the terminology for naming them is the same as before. The results were compared with a detailed study of three normal control subjects (ages 25, 49 and 55 years; two male), who displayed no mirror movements. TMS at 5% above threshold in normal subjects evokes short-latency responses in contralateral hand muscles [the first dorsal interosseous (1DI) muscle was studied]; at this intensity, no ipsilateral hand muscle responses are observed. In contrast, TMS at 5% above threshold in the XKS subjects revealed aberrant fast-conducting corticospinal pathways. TMS and reflex testing have been performed previously in these subjects (Mayston et al., 1997). TMS data from the XKS subjects reported in the previous study have been included in the present study (see Table 1) [In Mayston et al. (1997) Table 4, the ipsilateral/contralateral TMS ratio for K4a was shown, in error, as contralateral/ipsilateral]. The TMS responses in these XKS subjects are bilateral at short latency, but with varying degrees of asymmetry ranging from ipsilateral predominance through symmetrically bilateral to contralateral predominance.
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Neurophysiological recording
EEG and EMG were acquired (sampling rate 512 Hz) and stored digitally using a PC-based system custom built by Oxford Instruments, Medical Systems Division, Old Woking, Surrey, UK. In all the normal control and the XKS subjects, we recorded common average reference EEGs (band pass filter: 4–256 Hz). During common average recording (see also Mima et al., 2001
), EEG were obtained from 22–24 Ag/AgCl electrodes (Oxford Medical Instruments) set out according to the modified Maudsley system (Pampiglione, 1956; Margerison et al., 1970). The head was measured and distances in millimetres between the scalp electrodes were recorded in order to determine accurately the electrodes’ positions relative to anatomical landmarks and to each other. For all subjects, left and right EMGs from the 1DI muscles were recorded using pre-gelled bipolar electrodes (Oxford Medical; band pass filter: 4–256 Hz) during tonic co-contraction along with simultaneous EEG. The impedance of the scalp and EMG electrodes was maintained <5 k
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Experimental procedure
Subjects were asked either to perform a pincer grip of index finger and thumb or index finger abduction to produce a steady isometric activation of 1DI at 10–20% maximal voluntary contraction. The magnitude of the EMG associated with 20% maximal voluntary contraction was determined. Subjects were asked to maintain this for 2 min, and the experimenters monitored the EMG signal magnitude on-line during each experimental run giving verbal feedback as necessary. The subjects did not find the tasks fatiguing. Subjects were asked to keep their eyes open and to try to avoid excessive eye blinks and swallowing. Each data collection run lasted for 2 min. The quality of the EEG and EMG data was monitored on-line by the experimenter and the run was terminated if major artefacts appeared. During separate runs, subjects co-activated right and left 1DI, or attempted unilateral activation of the right and then the left 1DI.
Data analysis
Analysis was performed off-line from text files created by the EEG/EMG recording apparatus. Data analysis was performed using a suite of programs written in MATLAB by D. Halliday (University of York, UK), for coherence and cumulant analysis, and by J. Stephens (UCL, London, UK) for cumulant mapping (functional cumulant imaging, FCI). The data were first scrutinized using a commercially available program (Profile reader software version 2.2.187 developed by Tauglering and supplied by Oxford Instruments); data were excluded if there were contaminants from 50 Hz power supply interference or if electrode impedance changes lead to baseline drift. Data with major eye-blink or other artefacts were also excluded. The EMG signals from the right and left 1DI were full-wave rectified. The data were analysed in the frequency domain using the finite Fourier transform. The data length was 120 s and was segmented into 1 s segments, each consisting of 512 data points. Auto-spectra, cross-spectra, coherence and phase were then calculated. The inverse Fourier transform was applied to calculate the second order cumulant density. The second order cumulant gives, for any given relative temporal displacement between two continuous signals (e.g. EEG versus EMG), a value for the co-variance. In all cases, the 95% confidence limits for the coherence and cumulant were calculated and are shown on the figures (see Halliday et al., 1995). Coherence, phase and cumulant were calculated between the following signal pairs: left EEG–right EMG, left EEG–left EMG, right EEG–left EMG and right EEG–right EMG. To visualize the cumulant data in a three-dimensional way, cumulant maps were made using triangle-based linear interpolation to fit a hypersurface to the cumulant values obtained at a given lag by each electrode. This hypersurface was then interpolated at points on the surface of the white matter using co-ordinates supplied by the Anatomical Model of Normal Brain (Collins et al., 1998). These values were used to colour the surface at that those points. Interpolation was based on a Delaunay triangulation of values that uses qhull (Watson 1992; Barber et al., 1996). Brodmann area 4 is indicated by black dots on the surface of the white matter using co-ordinates from the Talairach atlas (Talairach and Tournoux, 1988). Images were produced using cumulant magnitudes recorded from the different EEG recording electrodes at a selected lag. For each data set, the lag chosen was that at which the most negative cumulant value was found in the range 0–30 ms. Within this range, the maximum negative cumulant was detected for motor cortex electrodes and the corresponding lag values for the different subjects were within the range of cortex-muscle TMS latencies (Hess et al., 1987) [mean lag of the most negative cumulant value 19.0 ms ± SEM 0.8 ms; n = 6 (three XKS subjects and three normal controls)]. Negative cumulant values are shown as orange and positive values, indicating a polarity reversal, as purple. Within this range, the most negative cumulant was always associated with the maximum 22 Hz EEG–EMG.
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Results |
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Coherence and cumulant data obtained from normal subjects are presented first. They are followed by a section that discusses the use of the cumulant in guiding interpretation of coherence measurements. We then compare data from control and XKS subjects.
Scalp distribution of EEG–EMG interactions in normal subjects
Figure 1 illustrates coherence and cumulant data from a control subject recorded during contraction of the left 1DI. Data are shown for 22 EEG electrodes superimposed on a diagram of the head. Coherence was maximal when recording EEG from the C4 electrode; the corresponding cumulant showed a positive–negative–positive pattern displaced to the right of time zero (with the EEG as reference, this reflects a shift to positive lags such that oscillatory EMG activity occurs after the EEG). The slope of the phase frequency plot from the C4 electrode associated with these data indicated a delay of 24 ms between EEG and EMG. The C4 electrode was situated on the scalp over the right motor cortex, i.e. the motor cortex contralateral to the voluntary EMG. The localization of cumulant values illustrated in Fig. 1B can be visualized three-dimensionally on the FCI plot shown in Fig. 5A. During a pincer grip using the left hand, the negative cumulant was centred over the right motor cortex (cumulant values >95% confidence limit).
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For all control subjects, significant coherence (>95% confidence limit) was seen between the 1DI EMG and the EEG of the contralateral motor cortex (see, for example, Fig. 2A). For calculation of confidence limits for coherence and cumulant estimates, see Halliday et al. (1995
). In control subjects, no significant coherence or positive–negative–positive pattern cumulant was detected between EEG recorded over the motor cortex ipsilateral to the activated hand and the 1DI EMG of this hand (Fig. 2A and C). The results for the control subjects are summarized in Table 1.
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Cumulant density polarity reversal—normal subjects
Normal subjects, in whom the EEG–EMG coherence was strong, displayed significant EEG–EMG coherence at electrode sites distant from the hand area of the contralateral motor cortex. Typically these sites were anterior electrodes, situated midline and contralateral to the activated cortex. Although the maximal coherence was always recorded from electrodes lying close to the anatomical site of the contralateral primary motor cortex (right motor cortex electrodes: C4, C2, FC4 and FC2; left motor cortex electrodes: C3, C1, FC3 and FC1), the widespread finding of coherence does present potential problems during interpretation, particularly when trying to detect abnormal EEG–EMG interaction corresponding to aberrant corticospinal pathways. Coherence is a measure of the linear association between signals and, without phase information, can be misleading. Of importance is the fact that in normal subjects, coherence was much reduced at electrodes adjacent to the ‘active’ electrode and absent over the homologous opposite hemisphere electrode (see Figs 1 and 2).
Widespread coherence at non motor cortex scalp electrodes can be understood in terms of the voltage field produced on the scalp by activity in the primary motor area—a current sink surrounded by a more widespread current source. If this is the case, then time domain representations should reveal oscillatory patterns with polarity reversal. This approach has been previously adopted for electro-corticography recordings (Marsden et al., 2000).
Figure 3A and B shows cumulant polarity reversal in a normal subject performing co-contraction of the right and left 1DI muscles. In Fig. 3A, the bold line is the cumulant between the EEG recorded from C3 and the right 1DI EMG; the dotted and dashed lines show the cumulant plotted to the same scale between the right 1DI EMG and C2 and Fz EEGs. In Fig. 3B, the EEG data used to construct the cumulant are identical to that in Fig. 3A but, in this case, the cumulant has been constructed using EMG from the left 1DI. The bold line in Fig. 3B is the cumulant between left 1DI EMG and the EEG recorded from the C4 electrode; the dashed and dotted lines are the Fz and C1 electrodes, respectively. Maximum coherence was seen between the EEG recorded from C3 (left motor cortex) and right 1DI EMG, and between the EEG recorded from C4 (right motor cortex) and the left 1DI EMG (see also Fig. 5A). The cumulant plots show the characteristic positive–negative–positive deflection, with the negative deflection displaced to the right of time zero indicating a delay with respect to the EEG. The polarity of the cumulant reverses for the Fz electrodes and for the C2 and C1 electrodes, respectively, contralateral to the C3 and C4 electrodes. Our interpretation of such data is that the presence of significant coherence between the EEG and EMG—together with a cumulant with a negative peak at an appropriate lag (i.e. 20 ms)—infers that the cortical region underlying the EEG electrode is producing a descending drive to the lower motoneurons; in our case, those of the 1DI muscle (see Discussion).
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Delay between the EEG signal and the EMG
The quality of the data and the strength of coherence between EEG and EMG varied between subjects. In two normal subjects (C1 and C3) and two XKS subjects (K4 and K4a), the frequency domain data allowed calculation of the temporal delay between EEG and EMG from an estimation of the slope of the phase relationship between the two signals. The range of delays was 18–25 ms; this is within the range of cortex muscle motor conduction time.
Scalp distribution of EEG-EMG interactions in XKS subjects with mirror movements
Kallmann’s subjects with mirror movements all have an abnormal fast-conducting ipsilateral corticospinal projection. The size of this projection, as determined using focal magnetic brain stimulation, is variable (Mayston et al., 1997). This abnormal distribution of fast-conducting corticospinal pathways in XKS subjects is reflected in the coherence and cumulant between EEG and EMG during steady muscle contraction.
Figure 2B and D show data for the analyses performed between L 1DI EMG and the L and R cortical electrode positions from subject K2 during co-abduction of the left and right index fingers (normal subject is shown for comparison in Fig. 2A and C). For the XKS subject, the ipsilateral corticospinal projection, as revealed by TMS, from each cortex is greater than the contralateral projection (Table 1). In this example, the coherence and cumulant are maximal for L EMG/EEG analysis when the EEG is recorded from the C3 electrode site; this site is located over the hand motor area of the left cortex. Thus, we have evidence for the presence of an oscillatory drive from the left cortex to a hand muscle of the left hand via the abnormal corticospinal tract.
Figure 3C and D and the FCI plots in Fig. 4A–D show data from a further XKS subject, K4a. In contrast to subject K2, focal magnetic stimulation revealed that, for K4a, the contralateral corticospinal projection was greater for each side than the abnormal ipsilateral projection (Table 1). The subject was instructed to perform unilateral contractions of first the left and then the right 1DI, and then to activate simultaneously the left and right muscles. Fig. 3C and D provide the cumulant density functions when the EEG was recorded from three different electrode positions; for 3C, the EMG signal was recorded from the voluntarily activated left hand and, for 3D, the EMG signal was recorded from the mirroring hand. It can be seen that a negative cumulant at an appropriate lag was present when recording the EEG from the C4 position (i.e. the right motor cortex), for both the active hand and the mirroring hand. Simultaneously recorded EEG–EMG cumulants when recording EEG from C1 and Fz are shown; there is a reversal of polarity. Figure 4C displays the FCI plot for the active left hand and Fig. 4D for the mirroring right hand (maximum negative cumulant values >95% confidence limits). It is again clear that, in both instances, the negative cumulant was centred over the motor cortex of the right side. When asked to attempt a unilateral pincer grip using only the right hand, the FCI plots show that now the left motor cortex provided the drive to both the voluntarily activated hand and the mirroring hand (Fig. 4A and B). The associated coherence values are given in Table 1. Thus, the drive to the voluntarily activated hand and to the mirroring hand in K4a originated in the cortex contralateral to the intentionally moved hand.
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An interesting change in cumulant polarity occurred when the same XKS subject produced co-activation of right and left 1DI (Fig. 3E and F). In this case, the maximum coherence between the EEG and the right and left hand EMG was seen when recording from the C2 electrode. That the maximum cumulant was from the more medial C2 electrode rather than C4 probably represents signal summation effects (see Discussion: functional interpretation of EEG–EMG interactions). The cumulant, when recording from the C2 electrode, showed a typical positive–negative–positive pattern with the negative displaced to the right of time zero. Co-contraction alters the polarity of the cumulant when recording from the Fz and contralateral C1 electrodes. It can be seen that, in contrast to the unilateral contraction condition (Fig. 3C and D), the co-contraction condition produced the positive–negative–positive cumulant deflection with the negative displaced to the right of time zero. The pattern was the same as for the C2 electrode indicating that, compared with unilateral activation during intended bilateral muscle contraction, both left and right hemispheres were now providing a descending drive to the motoneuron pools of both the left and right 1DI.
Comparison of normal and XKS subjects during a unilateral hand movement
Figure 5 compares FCI plots from a normal control subject with those of the three XKS subjects during attempted unilateral activation of either the right or left 1DI. Subjects are ordered according to the ratio of the magnitude of the ipsilateral: contralateral 1DI EMG responses evoked by TMS. Figure 5A, C, E and G show FCI plots using EMG recorded from the voluntarily activated 1DI and Fig. 5B, D, F and H show plots from the opposite hand of the corresponding subjects. In the control subject (Fig. 5A and B), TMS produced only contralateral EMG responses; in subject K4a (Fig. 5C and D), TMS produced larger contralateral (C) than ipsilateral (I) EMG responses I/C<1. In subjects K4 (Fig. 5E and F) and K2 (Fig. 5G and H), TMS produced larger ipsilateral than contralateral EMG responses I/C >1 (K2 had the larger ipsilateral responses).
FCI plots from the control subject (Fig. 5A) showed that left 1DI activation was associated with a patch of cumulant negativity centred over the right hemisphere. Subject K4a (Fig. 5C) showed a less well-defined patch of cumulant negativity, but with the maximal negative cumulant values centred over the cortex contralateral to the voluntarily activated right hand. In Subject K4 (Fig. 5E), however, the negative cumulant was centred over the cortex ipsilateral to the voluntarily activated hand. Subject K2 (Fig. 5G) had the highest ratio of I/C TMS responses and, in this case, the FCI showed a patch of negative cumulant centred over the right cortex–again ipsilateral to the voluntarily activated right hand.
Figure 5B, D, F and H show FCI plots calculated from the same EEG data as used for Fig. 5A, C, E and G, but with the EMG signal recorded from the non-voluntarily activated hands being used in the analysis. For the normal control (Fig. 5B), there was no EMG and therefore the cumulant was zero (shown in blue). In subject K4a (Fig. 5D), a negative cumulant focus was centred over the cortex ipsilateral to the non-voluntarily activated hand. In subject K4 (Fig. 5F), the FCI showed negative cumulant centred over the midline, covering both the cortex ipsilateral and contralateral to the non-voluntarily activated hand. In subject K2 (Fig. 5H), the most ipsilaterally organized subject with respect to the corticospinal tract, a negative cumulant focus was centred over the cortex ipsilateral to the non-voluntarily activated hand.
The results of all interactions are summarized in Table 1, which shows coherence values (>95% confidence limits) found with negative cumulant values at an appropriate lag.
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Discussion |
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This study is the first to have used EEG–EMG coherence and cumulant measurements to demonstrate abnormal oscillatory drive to hand muscles in subjects with aberrant corticospinal pathways. The results support the hypothesis that fast-conducting direct corticospinal inputs to hand muscle motoneurons are responsible for motor cortex-muscle
22 Hz coherence in man and reveal how the generation of mirror movements in XKS is related to the relative strength of the abnormal ipsilateral to contralateral projection.
Functional interpretation of EEG–EMG interactions
EEG–EMG interactions: normal subjects
In the present study, in normal subjects, the maximum 22 Hz EEG–EMG coherence was detected from scalp electrodes placed over the primary motor cortex situated in the hemisphere contralateral to the hand from which EMG was recorded, regardless of whether the subject was carrying out a voluntary activation of one hand or a co-contraction of both. But some significant coherence was also found at distant electrode sites, including those over the hemisphere ipsilateral to the hand from which EMG is recorded
Functional interpretation of such widespread EEG–EMG coherence flows from consideration of the corresponding cumulant plots. When recorded from electrode sites over the contralateral motor cortex, these showed characteristic positive–negative–positive deflections with the negative deflection displaced to the right of time zero, indicating EMG delay with respect to the EEG. Recordings from surrounding electrodes over the entire scalp show that the cumulant undergoes polarity reversal. The EEG electrode with the most negative-going component of the cumulant was always the one with the maximum 22 Hz coherence, and the latency of the negative component after time zero was at lags, consistent with cortex-1DI conduction time as assessed by TMS (Hess et al., 1987). The finding that a negative cumulant was recorded over the motor cortex contralateral to the intended movement, and with a latency appropriate for nervous conduction, is commensurate with the known underlying physiology—namely that activity in a cortical area results in that area becoming a current sink relative to surrounding areas. In addition, we have visualized these data by constructing FCI plots based on the interpolation of estimates of cumulant density between EEG and EMG recorded from different scalp electrode sites at a given lag. Such cumulant density estimates are a simple representation based on a measure of covariance between the two signals (see Halliday et al., 1995). In comparison to a more sophisticated methodology, in which source localization algorithms have been applied to correlation measures (Brown et al., 1998; Feige et al., 2000; Gross et al., 2001), our approach has reduced spatial resolution due to the smearing effects on electrical signals as they pass through the skull. Furthermore, two or more sources with identical frequency and phase information may summate spatially and cannot be separated. This could account for the finding of significant negative cumulant at more widespread electrode sites in some XKS subjects than in normal subjects.
EEG–EMG interactions: XKS subjects
In XKS subjects, coherence and negative cumulant at an appropriate lag were detected from scalp electrodes ipsilateral to 1DI EMG. Maximal coherence occurred over electrode sites close to where TMS evoked maximal responses in 1DI (left hemisphere: C3, C1, FC3 and FC5; right hemisphere: C4, C2, FC4 and FC6). The oscillatory interactions between motor cortex EEG and EMG were similar to those of normal subjects but, due to the presence of aberrant corticospinal projections, these were also present ipsilaterally.
EEG–EMG interaction: frequency content
The frequency of the oscillatory interaction in normal control subjects incorporated the 11–40 Hz range of EEG–EMG coherence described previously in normal subjects (for a review, see Farmer, 1998); the frequency of maximum coherence was 22 Hz. In the XKS subjects, the coherence between EEG and EMG also incorporated the 11–40 Hz frequency range with a maximum coherence at 22 Hz.
EEG–EMG interaction: recording from scalp electrodes over sensory cortex
In four subjects (two normal controls and two XKS), additional electrodes were placed at PC3 and PC4, i.e. equidistant between C3 and P3, and C4 and P4, respectively. Even with these additional electrodes over the sensory cortex, we were unable to detect any effects in the correlation between EEG and EMG that could be interpreted as afferent. A previous study using cortical muscle coherence indicated that somatosensory area S1–EMG interactions are unlikely to result from activity in afferent pathways (see Ohara et al., 2000).
EEG–EMG delay estimates
Although temporal delays associated with cortex muscle oscillatory interaction were not demonstrated initially (Conway et al., 1995; Halliday et al., 1998), a majority of studies (including our own) now indicate that oscillatory interaction between MEG/EEG and EMG occurs with a temporal delay of 20 ms (Salenius et al., 1997; Brown et al., 1998; Feige et al., 2000; Gross et al., 2000; Mima et al., 2000, 2001). If cortical oscillations are transmitted to the spinal motoneuron pool via fast-conducting corticospinal pathways, then the temporal delay between MEG/EEG and EMG should correspond to the conduction time between motor cortex and muscle, i.e. 20 ms if assessed with TMS. However, the published range of lags is wide. Thus, it remains difficult, on the basis of temporal delay alone, to accept or reject the hypothesis that in humans it is the fast-conducting direct corticospinal pathways that provide common oscillatory drive to motoneurons and are responsible for 22 Hz coherence between EEG and EMG, and between motor units within a muscle or between different muscles.
Oscillatory activation of corticospinal neurons
The negative component of the cumulant and the associated coherence represent oscillatory activation of corticospinal neurons, which then provide a rapidly conducting drive to hand muscle spinal motoneurons. Support for this idea comes from the following considerations. First, the negative component of the cumulant appears at lags consistent with transmission via corticospinal pathways. Secondly, the electrode sites from which this is recorded in normal subjects and XKS subjects lie over motor cortical areas. Thirdly, the abnormal ipsilateral pathways in XKS subjects are represented by EEG–EMG cumulant and coherence. Using the independent neurophysiological measures of TMS and cutaneomuscular reflex testing, these aberrant pathways have been demonstrated to be those of the fast conducting corticospinal tract (Mayston et al., 1997). Furthermore, for each individual with XKS, the relative strength of these corticospinal pathways, as assessed by the ratio of the relative size of ipsilateral/contralateral TMS responses, is reflected in the laterality of the cumulant and coherence. Fourthly, in subject K2 only ipsilateral EEG–EMG cumulant and coherence was demonstrated. Interestingly, Mayston et al. (1997) demonstrated normal contralateral somatosenstory evoked potentials in this subject; furthermore, his long-latency cutaneomuscular reflexes were detected only from muscles of the non-stimulated hand, which in the context of very ipsilateral TMS responses, implies that afferent signals resulting from digital nerve stimulation reach the contralateral cortex as normal. This points to the fact that EEG–EMG coherence/cumulant analysis is unable to detect cortical activation brought about by afferent input that does not influence EMG activity. Fifthly, despite co-activation of both left and right motor cortices and left and right 1DI muscles, the negative cumulant is only detected during co-contraction in normal subjects between primary motor cortex electrodes and the EMG of the contralateral hand. The cumulant between non-motor areas and areas ipsilateral to the recorded muscle is positive or zero. Finally, in subject K4a (I/C <1), the scalp distribution of the negative cumulant is sensitive to the voluntary command. Thus, when a normal subject activates, for example, their left hand, the only negative cumulant is between the right motor cortex and the left 1DI EMG (there is no right EMG in this situation). However, when subject K4a unilaterally activated one hand (e.g. the left) while relaxing the right, the negative cumulant was between the right cortex EEG and both left and right EMGs (see Figs 3 and 4); note that the cumulant between the frontal EEG ipsilateral to the voluntarily activated hand was positive or zero. The same XKS subject was then asked to co-contract both hands. Compared with the previous task, he was now voluntarily ‘activating’ his left motor cortex as well as the right. The cumulant between the left cortex and both hands now changed its polarity; instead of being positive or zero with respect to the left and right index fingers it becomes negative. When K4a tried to activate the right hand only, the situation was reversed with the negative cumulant between the left cortex and both hands only (see Fig. 4). It is important to note that the XKS subject is unique because, unlike the normal subject, the ‘relaxed’ 1DI during unilateral activation of the opposite hand actually produces EMG activity due to abnormal drive from the motor cortex ipsilateral to the mirroring hand. Thus, the mirrored EMG can be used to calculate coherence and cumulants with the whole scalp EEG. We suggest that this is direct evidence that a negative EEG–EMG cumulant is indicative of motor cortex activation. This is a clear example of intended cortical activation influencing cumulant structure and, by implication, the coherence. This experiment can only be performed in mirroring subjects because only they can ‘involuntarily’ and then ‘voluntarily’ produce the EMG in such a way that the cumulant can be calculated in the two situations; voluntary motor cortex activation is accompanied by a change in cumulant polarity.
Origin of mirror movements in XKS subjects
A number of studies investigating mirror movements have shown that an intended unilateral hand movement is associated with bilateral activation of both motor cortices. For example Mayer et al. (1999) used dipole source analysis to demonstrate bilateral activation in subjects with mirror movements resulting from an autosomal-dominant trait, and Leinsinger et al. (1997) used functional MRI to demonstrate bilateral activation in subjects with the same trait and in three subjects with XKS.
In previous studies, we drew together the results of electrophysiological and PET studies with a view to understanding the cortical origin of mirror movements in individual subjects with XKS (Krams et al., 1997; Mayston et al., 1997). But the outcome was not decisive because the PET activation data related to the primary motor cortex were unable to distinguish between that activation brought about by afferent activity from regions that project to the primary motor cortex, and activity in the output cells of this region. These output neurons include those that provide axons that travel in the corticospinal tract to synapse with lower motoneurons that innervate the distal hand muscles which produce the intended and unintended (or mirror) movements. The present study—using coherence analysis and the FCI method—helps to resolve this issue. In contrast to PET images, significant coherence together with a negative cumulant at an appropriate lag and EEG–EMG FCI was only seen when a cortical area was active and contributing to corticospinal activity.
Consider subject K2 whose fast-conducting ipsilateral corticospinal projection is much greater than his contralateral projection (TMS I/C >>1; Table 1). If this subject were to activate only the corticospinal projection (as revealed using TMS), which is contralateral to the voluntarily activated 1DI, then one could hypothesize that the voluntary EMG would be much less than the involuntary, mirroring EMG. But this is not the case. Table 4 of Mayston et al. (1997) indicates that this mirroring EMG is much less than would be predicted from a consideration of the relative sizes of the ipsilateral and contralateral TMS responses. PET images showed bilateral primary motor cortex cortical activation when this subject made a voluntary unilateral hand movement accompanied by unintended mirroring of the other hand (Krams et al., 1997; Fig. 1). The increase in regional cerebral blood flow (rCBF) was significantly greater contralateral, rather than ipsilateral, to the voluntarily moved hand. Based on the observations made using passive movements, Krams et al. (1997) concluded that the cortical activation contralateral to the mirroring hand most likely resulted from sensory feedback from the mirroring hand. The results of the current study further our understanding of the origin of the corticospinal outflow in this subject. The coherence data and EEG–EMG FCI for EMG recorded from the voluntarily activated hand indicate that the cortex ipsilateral to this hand is active (see Fig. 5 and Table 1). In contrast to a normal subject, voluntary EMG is being generated by activity originating in the ipsilateral rather than contralateral cortex. Coherence analysis and the EEG–EMG FCI for EMG recorded from mirroring hand indicate that the cortex ipsilateral to the mirroring hand was active and providing a drive to this mirroring hand. Therefore, our study has demonstrated that, for this subject, there is an ipsilateral source of corticospinal activity that contributes to the voluntary drive and an ipsilateral source that contributes to the drive of the mirroring hand. We cannot rule out the existence of a weak contralateral corticospinal drive to the voluntarily activated hand. This would be expected on the basis of our TMS study (Mayston et al., 1997), which demonstrated the existence of a fast-conducting contralateral corticospinal projection and the presence of relatively weak short-term synchronization between motor unit spikes of the left and right 1DI. In this subject, the contralateral corticospinal pathway is below the threshold of detection using EEG–EMG coherence/FCI. Our previous study (Mayston et al., 1997) indicated that the sensory input to the cortex of this subject is normal, i.e. the projection is contralateral. Assuming subject K2 employs some contralateral drive via his fast corticospinal projection, albeit weak, then sensory feedback from the voluntarily activated hand can be used by the cortex contralateral to this voluntarily activated hand to modify, if necessary, the motor outflow.
Consider subject K4a who has an abnormal fast conducting ipsilateral corticospinal tract, but the projection is less than the contralateral projection (TMS I/C <1; Table 1). Based on the TMS data, one would predict that, by utilising the contralateral corticospinal projection, the voluntary 1DI EMG should be greater than the mirroring 1DI EMG and this is indeed the outcome (Table 4, Mayston et al., 1997). PET images show bilateral, but asymmetrical, primary motor cortex cortical activation when this subject made an intended unilateral voluntary hand movement accompanied by unintended mirroring of the other hand (Krams et al., 1997; Table 5). During an intended movement of the left hand, the increase in rCBF of the right cortex was greater and more extensive than that of the left cortex. During passive movement of the right hand, the increase in rCBF of the left hemisphere was not significantly different from that observed during mirroring by the right hand when the left was activated voluntarily. This suggests that the increase in rCBF in the left cortex, seen during an intended movement by the left hand, was the result of afferent activity generated by the mirroring right hand rather than activity producing a motor output. But this inference can only be indirect. Our coherence data and the EEG–EMG FCI for EMG recorded from either the intended hand or the mirroring hand indicate cortical activity in the cortex contralateral to the voluntarily moved hand (Table 1). This cortical activation is responsible for the drive to the voluntarily activated hand and the drive to the mirroring hand. For this subject, our earlier inferences based on a comparison of rCBF estimates during active and passive movements were correct (Krams et al., 1997).
There are no PET data for subject K4, whose fast-conducting corticospinal tracts are more symmetrical than K2, yet exhibit ipsilateral predominance (TMS I/C > 1; Table 1). If this subject were to utilize only his contralateral corticospinal projection during a unilateral hand movement, then, as predicted for K2, the mirroring 1DI EMG should be greater than the voluntary 1DI EMG. But again, this was not the case. Table 4 of Mayston et al., (1997) indicates that this mirroring EMG was much less than would be predicted from a consideration of the relative sizes of the ipsilateral and contralateral TMS responses. The coherence data and the EEG–EMG FCI for EMG recorded from either the intended or mirroring side revealed that both cortices were active, with both a contralateral and ipsilateral drive to the voluntarily activated hand and to the mirroring hand. Thus although the ipsilateral corticospinal projection was greater than the contralateral projection, we were able in this subject, in contrast to K2, to demonstrate via our coherence data and FCI that, during an intended hand movement, the cortex contralateral to this hand was active and the descending corticospinal drive from this cortex was responsible, at least in part, for activation of the muscles of the voluntarily activated hand.
Our data have therefore revealed that the origin of the mirror movements in XKS subjects is not uniform. In subjects in whom the contralateral corticospinal projection is much greater than the aberrant ipsilateral projection (e.g. K4a), activation of the cortex contralateral to the voluntarily activated hand provides the necessary drive to this hand and, in addition, activity in the aberrant ipsilateral projection results in mirroring by the other hand. However, in those subjects where the ipsilateral corticospinal projection is greater than the contralateral projection, activation of the ipsilateral projection is seen during an intended unilateral hand movement (K2 and K4). It has previously been suggested by Mayer et al. (1999) that this provides a compensatory strategy whereby the subject can achieve sufficient force in the muscles of the hand to be activated voluntarily. Our data support this hypothesis, but such activation of the cortex ipsilateral to the activated hand is not essential for those XKS subjects in whom the contralateral projection provides an adequate drive.
Conclusions
This study has used the technique of EEG–EMG coherence and cumulant mapping to demonstrate abnormal oscillatory drive to hand muscles from the motor cortex in subjects with aberrant corticospinal pathways. The results support the hypotheses that fast-conducting direct corticospinal inputs to hand muscle motoneurons are responsible for 22 Hz coherence between motor cortex and muscle in man and that the associated EEG–EMG cumulant structure reflects the voluntary motor cortex activation. In addition, the results suggest that subjects with aberrant corticospinal pathways adapt functionally to their presence in a manner that depends on the relative strength of the abnormal ipsilateral compared with the contralateral projection. For the generation of an intended unilateral hand movement, the relative contribution of activity in the ipsilateral and contralateral corticospinal projections to produce movement on the intended side is related to the relative strength of the abnormal ipsilateral to contralateral projection. The accompanying mirror movements are generated by activity in the abnormal corticospinal pathway ipsilateral to the mirroring hand and/or by activity in the corticospinal projection contralateral to the mirroring hand.
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We wish to thank the subjects for their kind help, Drs Peter Misra and Stephen White for their help with EEG and EMG data interpretation and Dr David Halliday and Professor Jay Rosenberg for previous collaboration and for making their data analysis programmes available to us.
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Baker SN, Olivier E, Lemon RN. Coherent oscillations in monkey motor cortex and hand muscle EMG show task-dependent modulation. J Physiol 1997; 501: 225–41.[CrossRef][ISI][Medline]
Barber CB, Dobkin DP, Huhdanpaa H. The quickhull algorithm for convex hulls. ACM Trans Math Software (TOMS) 1996; 22: 469–83.[CrossRef]
Britton TC, Meyer BU, Benecke R. Central motor pathways in patients with mirror movements. J Neurol Neurosurg Psychiatry 1991; 54: 505–10.[Abstract]
Brown P, Salenius S, Rothwell JC, Hari R. Cortical correlate of the Piper rhythm in humans. J Neurophysiol 1998; 80: 2911–7.
Cohen LG, Meer J, Tarkka I, Bierner S, Leiderman DB, Dubinsky RM, et al. Congenital mirror movements. Abnormal organization of motor pathways in two patients. Brain 1991; 114: 381–403.
Collins DL, Zijdenbos AP, Kollokian V, Sled JG, Kabani NJ, Holmes CJ, et al. Design and construction of a realistic digital brain phantom. IEEE Trans Med Imaging 1998; 17: 463–8.[CrossRef][ISI][Medline]
Conway BA, Halliday DM, Farmer SF, Shahani U, Maas P, Weir AI, et al. Synchronization between motor cortex and spinal motoneuronal pool during the performance of a maintained motor task in man. J Physiol 1995; 489: 917–24.[ISI][Medline]
Farmer SF. Rhythmicity, synchronization and binding in human and primate motor systems. [Review]. J Physiol 1998; 509: 3–14.
Farmer SF, Ingram DA, Stephens JA. Mirror movements studied in a patient with Klippel-Feil syndrome. J Physiol 1990; 428: 467–84.
Farmer SF, Bremner FD, Halliday DM, Rosenberg JR, Stephens JA. The frequency content of common synaptic inputs to motoneurons studied during voluntary isometric contraction in man. J Physiol 1993; 470: 127–55.
Farmer SF, Harrison LM, Stephens JA, Mayston MJ. Abnormal cortex-muscle coherence in subjects with mirror movements [abstract]. Soc Neurosci Abstr 2001; 31: 304.9.
Farmer SF, James L, Parekh A, Harrison LM, Mayston MJ, Stephens J.A. Abnormal oscillatory drive to motor neurons in Kallmann’s syndrome [abstract]. J Neurol Neurosurg Psychiatry 2003; 74: 410.
Feige B, Aertsen A, Kristeva-Feige R. Dynamic synchronization between multiple cortical motor areas and muscle activity in phasic voluntary movements. J Neurophysiol 2000; 84: 2622–9.
Gross J, Tass PA, Salenius S, Hari R, Freund HJ, Schnitzler A. Cortico-muscular synchronization during isometric muscle contraction in humans as revealed by magnetoencephalography. J Physiol 2000; 527: 623–31.
Gross J, Kujala J, Hamalainen M, Timmermann L, Schnitzler A, Salmelin R. Dynamic imaging of coherent sources: studying neural interactions in the human brain. Proc Natl Acad Sci USA 2001; 98: 694–9.
Halliday DM, Rosenberg JR, Amjad AM, Breeze P, Conway BA, Farmer SF. A framework for the analysis of mixed time series/point process data–theory and application to the study of physiological tremor, single motor unit discharges and electromyograms. Prog Biophys Mol Biol 1995; 64: 237–78.[CrossRef][ISI][Medline]
Halliday DM, Conway BA, Farmer SF, Rosenberg JR. Using electroencephalography to study functional coupling between cortical activity and electromyograms during voluntary contractions in humans. Neurosci Lett 1998; 241: 5–8.[CrossRef][ISI][Medline]
Hess CW, Mills KR, Murray NM. Responses in small hand muscles from magnetic stimulation of the human brain. J Physiol Lond 1987; 388: 397–419.
Koster B, Lauk M, Timmer J, Winter T, Guschlbauer B, Glocker FX, et al. Central mechanisms in human enhanced physiological tremor. Neurosci Lett 1998; 241: 135–8.[CrossRef][ISI][Medline]
Krams M, Quinton R, Mayston MJ, Harrison LM, Dolan RJ, Bouloux P-MG, et al. Mirror movements in X-linked Kallmann’s syndrome II. A PET study. Brain 1997; 120: 1217–28.
Leinsinger GL, Heiss DT, Jassoy AG, Pfluger T, Hahn K, Danek A. Persistent mirror movements: functional MR imaging of the hand motor cortex. Radiology 1997; 203: 545–52.
Margerison JH, Binnie CD, McCaul, IR. Electroencephalographic signs employed in the location of ruptured intracranial arterial aneurysms. Electroencephalogr Clin Neurophysiol 1970; 28: 296–306.[CrossRef][ISI][Medline]
Marsden JF, Werhahn KJ, Ashby P, Rothwell J, Noachtar S, Brown P. Organization of cortical activities related to movement in humans. J Neurosci 2000; 20: 2307–14.
Mayer M, Schulze S, Danek A, Botzel K. Dipole source analysis in persistent mirror movements. Brain Topogr 1999; 12: 49–60.[CrossRef][ISI][Medline]
Mayston MJ, Harrison LM, Quinton R, Stephens JA, Krams M, Bouloux PM. Mirror movements in X-linked Kallmann’s syndrome. I. A neurophysiological study. Brain 1997; 120: 1199–216.
Mayston MJ, Harrison LM, Stephens JA, Farmer SF. Physiological tremor in human subjects with X-linked Kallmann’s syndrome and mirror movements. J Physiol 2001; 530: 551–63.
Mima T, Steger J, Schulman AE, Gerloff C, Hallett M. Electroencephalographic measurement of motor cortex control of muscle activity in humans. Clin Neurophysiol 2000; 111: 326–37.[CrossRef][ISI][Medline]
Mima T, Matsuoka T, Hallett M. Information flow from the sensorimotor cortex to muscle in humans. Clin Neurophysiol 2001; 112: 122–6.[CrossRef][ISI][Medline]
Ohara S, Nagamine T, Ikeda A, Kunieda T, Matsumoto R, Taki W, et al. Electrocorticogram-electromyogram coherence during isometric contraction of hand muscle in human. Clin Neurophysiol 2000; 111: 2014–24.[CrossRef][ISI][Medline]
Pampiglione G. Some anatomical considerations upon electrode placement in routine EEG. Proc Electrophysiol Technol Assoc 1956; 7: 20–30.
Pohja M, Salenius S, Hari R. Cortico-muscular coupling in a human subject with mirror movements—a magnetoencephalographic study. Neurosci Lett 2002; 327: 185–8.[CrossRef][ISI][Medline]
Salenius S, Portin K, Kajola M, Salmelin R, Hari R. Cortical control of human motoneuron firing during isometric contraction. J Neurophysiol 1997; 77: 3401–5.
Talairach J, Tournoux P. Co-planar stereotaxic atlas of the human brain. Stuttgart: Thieme; 1988.
Watson DF. Contouring: a guide to the analysis and display of spatial data. Oxford: Pergamon Press; 1992.
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