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MS 10724 Received 15 February 2000; accepted after revision 21 June 2000.
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ABSTRACT |
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INTRODUCTION |
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When a subject holds and manipulates an object using a precision grip, grasp stability is supported by various sensorimotor mechanisms that depend on tactile information from the digits (for an overview see Johansson, 1996). If the task is to restrain an object subjected to unpredictably imposed changes in load tangential to the grasped surfaces, subjects reactively modulate their grip force based on somatosensory input related to the load changes (Cole & Abbs, 1988; Johansson & Westling, 1988; Johansson et al. 1992a,b,c; Jones & Hunter, 1992). These automatic grip responses are scaled to the rate and amplitude of the change in load (Johansson et al. 1992b,c) and to the friction between the fingertips and the grasped surfaces (Cole & Johansson, 1993). Signals from cutaneous mechanoreceptors convey information necessary for both the appropriate initiation and scaling of these responses (Johansson et al. 1992a; Macefield et al. 1996a; see also Häger-Ross & Johansson, 1996; Macefield & Johansson, 1996).
The central neural pathways involved in these grip reactions are unknown. The onset latency of the reflex increase in electromyographic activity (EMG) recorded from the first dorsal interosseous muscle in response to a rapid increase in load is usually 50-60 ms (Cole & Abbs, 1988; Johansson et al. 1992b, 1994; Macefield & Johansson, 1994; Macefield et al. 1996b). This latency is too long for a fast spinal reflex (usually about 35 ms), but it is similar to that of 'long-latency' reflexes which can be recorded from finger muscles following muscle stretch (Marsden et al. 1976; Matthews, 1991) or following electrical stimulation of the digital nerves (Evans et al. 1989). A number of authors have inferred that such reflex responses are mediated through transcortical pathways (Marsden et al. 1976; Jenner & Stephens, 1982; Matthews, 1991; Palmer & Ashby, 1992), with the most convincing evidence coming from studies of reflex responses of patients with pathological mirror movements (Matthews et al. 1990; Capaday et al. 1991; Carr et al. 1993; Mayston et al. 1997).
To gain insight into the neural pathways that mediate reactive grip responses for grasp stability, in the present study we examined their expression in subjects with X-linked Kallmann's syndrome (XKS). These subjects show a normal pattern of cortical sensory evoked potentials following median nerve stimulation (Mayston et al. 1997) but have an abnormal ipsilateral fast conducting corticospinal projection from each motor cortex (Danek et al. 1992; Mayston et al. 1997). Furthermore, XKS subjects often show pathological mirror movements, i.e. unintentional movements of one side of the body that accompany and mirror intentional movements of the other side (Kallmann et al. 1944). The mechanism behind their pathological mirroring is not clear, but activity in the ipsilateral corticospinal tract is considered to be one possible causative factor (Mayston et al. 1997).
For three (subjects K1-3) out of the 13 XKS subjects examined by Mayston et al. (1997), this fast conducting corticospinal projection is, in essence, ipsilateral when revealed using focal magnetic stimulation over the hand area of the motor cortex. Furthermore, when stimulating the digital nerves of the index finger of these three subjects, only a spinal reflex response is seen on the stimulated side; the transcortical reflex components only appear contralateral to the stimulated side (Mayston et al. 1997). If the grip force response to fingertip loading during precision grip also depends upon a fast transcortical route that involves the fast conducting corticospinal projection we would expect to see a grip response contralateral, rather than ipsilateral, to the operating hand in these subjects. In addition, the reactive control of grasp stability in these subjects would be poor. Here, we analysed the reactive performance of the precision grip in the two subjects of these three who were available for investigation. We compared their grip performance with that of one XKS subject who has a largely symmetrical bilateral fast conducting corticospinal projection, and with four age-matched control subjects.
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METHODS |
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Subjects
Experiments were performed on four healthy volunteers (C1-4; 2 female, 1 left handed and 2 male, both right handed) aged between 26 and 67 years, and on three male subjects with XKS aged between 24 and 62 years. These three subjects had been previously investigated using neurophysiological techniques (Mayston et al. 1997) and were subjects K1, K2 and K8.
For subjects K1 and K2, the fast conducting corticospinal projection, as revealed using focal magnetic stimulation over the hand area of either motor cortex, is essentially ipsilateral, while for subject K8 it is bilateral (Mayston et al. 1997). Figure 1A exemplifies recordings obtained in the experiments by Mayston et al. 1997 from the left and right first dorsal interosseous muscles (L1DI, R1DI) of subject K2 when the left hemisphere was stimulated. Note the short-latency ipsilateral response, but no obvious contralateral response. In normal subjects, focal magnetic brain stimulation of either motor cortex evoked only a short-latency contralateral response.
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A, surface EMGs recorded simultaneously from the left and right first dorsal interosseus muscles (L1DI and R1DI) during focal transcranial magnetic stimulation (TMS) of the hand area of the left motor cortex (5 superimposed responses). Note the short-latency ipsilateral response recorded from the L1DI and the absence of a contralateral response in the R1DI. B, cutaneomuscular reflexes recorded from L1DI and R1DI following stimulation of the digital nerves of the right index finger at 3 Hz, at a stimulus strength twice the threshold for perception during simultaneous sustained isometric voluntary abduction of the left and right index fingers. Surface EMG activity was rectified and averaged for 500 sweeps, time locked to the time of stimulation. The response recorded from R1DI ipsilateral to the stimulus only comprises an E1 component; this component is thought to be of spinal origin. The reflex response recorded from L1DI contralateral to the stimulus comprises I1 and E2 components; these components are believed to be of supraspinal origin. (Data from Mayston et al. 1997.) | ||
As a result of the ipsilateral organization of the corticospinal tract in subjects K1 and K2, the 'long-latency' components (I1 and E2) of the cutaneomuscular reflex recorded from the first dorsal interosseous muscle (1DI) following electrical stimulation of the digital nerves of the index finger could only be recorded contralateral to the stimulated side (Fig. 1B). Only the spinal component of the reflex (E1) appeared on the stimulated side (Mayston et al. 1997). In normal subjects, both the 'long-latency' components (I1 and E2) and the spinal component (E1) of the cutaneomuscular reflex only appear on the stimulated side (Carr et al. 1993).
Subject K8 was representative of the majority of XKS subjects in whom transcranial magnetic stimulation over the hand area of the motor cortex had revealed a bilateral fast conducting corticospinal projection (Mayston et al. 1997). For these XKS subjects the 'long-latency' components of the cutaneomuscular reflex are expressed both ipsi- and contralateral to the stimulus, with the spinal component of the reflex (E1) being present only on the stimulated side (Mayston et al. 1997). (No cutaneomuscular reflex responses could be recorded from K8 (Mayston et al. 1997).)
Sensory evoked potentials following stimulation of the median nerve had previously been recorded from all three XKS subjects used in the present study and from three of the control subjects; all showed contralateral N20 components with no obvious differences between the XKS and control subjects (Mayston et al. 1997).
The study was performed according to the Declaration of Helsinki and with ethical approval from the Joint University College and University College Hospital Committee on the Ethics of Human Research. Experiments were undertaken with the understanding and written consent of each subject.
General procedure
Subjects were seated in an office chair with the upper arms parallel to the trunk and the forearms extended anteriorly in the horizontal plane. A tabletop supported the forearms up to the palms and the hands were in mid-pronation (ulnar edge of the palms down). Using a precision grip that engaged the tips of the thumb and index finger of the operating hand (right or left), subjects restrained a manipulandum from moving when it was subjected to unpredictable pulling forces in the distal direction (see Johansson et al. 1992a). The three ulnar fingers were held slightly flexed in a relaxed position. The hand contralateral to the operating hand (termed non-operating hand) held an object (weight 200 g) freely in the air with a grasp configuration similar to that of the operating hand. The subjects were blindfolded during the experiments and the apparatus was quiet, i.e. it provided no sound cues.
Apparatus
Operating hand. The two grip surfaces of the manipulandum consisted of parallel discs, 30 mm in diameter and spaced 25 mm apart. Fine grain sandpaper (no. 400) covered the discs. The disc contacted by the thumb was immovable, while that contacted by the index finger was attached to a servo-controlled force motor (Johansson et al. 1992c). This motor, controlled by a computer, was used to generate load forces tangential to the movable grip surface in the distal direction (0-10 N, 0-15 Hz bandwidth, noise less than 0·05 N). Strain gauges transduced the load force and the grip force perpendicular to the movable grip surface (0-120 Hz); the load force signal was used to servo-regulate the load force. The position of the movable grip surface was recorded with an effective resolution of 0·05 mm. It was servo-regulated to a constant position during periods when the manipulandum was not touched, such that the grip surfaces were aligned (i.e. a line joining their centres would be perpendicular to both surfaces).
Non-operating hand. The grasp surfaces of the object held by the non-operating hand were also parallel discs (30 mm diameter) covered by fine grain sandpaper (no. 400), but spaced 50 mm apart. To measure possible grip force responses generated by the non-operating hand during the restraint task (i.e. reflex 'mirroring' activity) this object was instrumented with a transducer (Nano F/T transducer, ATI Industrial Automation, Garner, NC, USA) interposed between the grasp surfaces.
Load trials delivered to the operating hand
The load force trials of the operating hand consisted of a force increase in the distal direction (load phase) starting from a 0·2 N baseline load force, a period of maintained load (plateau phase) and a sustained force decrease that returned the load to 0·2 N (unloading phase). For all trials the duration of the plateau phase was randomized between 1 and 2 s and the intertrial delay between 2 and 4 s. The 0·2 N baseline load was automatically applied after the grasp plate was contacted and ensured that subjects maintained contact with the grasp plate between trials. Two test series were run, the 'step-load' series and the 'mixed-load' series.
The step-load series consisted of 20 consecutive trials. During the first 20 ms of the load phase the tangential load increased abruptly by 0·8 N from the 0·2 N baseline load. After this 'load step' the load continued to increase at a constant rate of 4 N s-1 for 0·5 s to the plateau phase (3 N constant force). The grasp plate was then unloaded at 4 N s-1 until the 0·2 N baseline force was reached. The initial load step served to trigger a normal force response of minimal latency and the following ramp load increase served to elicit a substantial response amplitude (Johansson et al. 1992b).
The mixed-load series was delivered to analyse the subject's ability to scale force responses to load force amplitude and rate (see Johansson et al. 1992b,c). The test series comprised 47 trials; 9 or 10 trials of each of the following five combinations of amplitude and rate: (i) 1·5 N at 2 N s-1; (ii) 1·5 N at 6 N s-1; (iii) 4·5 N at 2 N s-1; (iv) 4·5 N at 6 N s-1; and (v) the step-load trial as described above (3 N amplitude). These five types of trial were delivered in an unpredictable order during the test series.
Subjects were instructed to restrain the manipulandum from escaping from the grasp during the load trials, but not to use excessive grip forces. If the manipulandum escaped, it was returned to the initial position, re-grasped by the subject and the test series resumed by repeating the current trial. The two test series were applied to either hand, i.e. the operating hand was either the left or the right hand. Subjects had one practice session of each test series with either hand so that they became familiar with the task and the apparatus before data collection. Subjects were not blindfolded during these practice sessions, but were during the experimental trials.
EMG recording
Surface EMGs were recorded from the R1DI and L1DI using silver electrodes (2 mm in diameter) coated with electrode jelly, placed 12 mm apart over the muscle and firmly attached to the skin using double-sided adhesive tape. Preamplifiers (bandwidth 6 Hz to 2·5 kHz) were mounted on the skin directly above the surface electrodes.
Data collection and analysis
All signals were stored and analysed using the SC/ZOOM microcomputer-based data acquisition and analysis system (Section for Physiology, IMB, University of Umeå). The grip and load forces (DC to 120 Hz) were digitized (12 bits) at 400 Hz, and the position signal at 100 Hz. EMG from each channel was sampled at 3200 Hz. Event markers related to the timing of the various phases of each load trial were also sampled (±0·1 ms resolution). EMG data were root-mean-square (r.m.s.) processed with a rise and decay time constant of 1·0 ms. For each subject the processed EMG signal was averaged together with the force and the position signals across all trials. Data averaging was synchronized to the onset of the load force increase.
For each load trial, we derived the following measurements for statistical analysis. (i) The grip response latency is the time interval from the onset of the load force increase to the start of the grip force increase of the operating hand. The onset of this response was detected in single trials by inspecting the 1st and 2nd time derivatives of the grip force using a ±5 points numerical differentiation, i.e. force time derivatives were calculated within a window of ±12·5 ms. The local maximum of the second time derivative was taken as the onset of the grip force increase (Burstedt et al. 1997). (ii) The pre-response grip force is the grip force measured just before the onset of the grip force response. (iii) The plateau grip force is the mean grip force during a 0·5 s period that commenced 0·5 s after the start of the load force plateau. Furthermore, we measured the grip force at 50 and 200 ms after the onset of the grip force response. By subtracting the pre-response grip force from these measurements and dividing the value by the appropriate time, we estimated the mean grip force rate during the first 50 and 200 ms after the response onset, respectively. We also derived the corresponding force and force rate measurements from the non-operating hand when that held the instrumented 200 g weight. The rationale for measuring the grip force rate during these two fixed time windows was based upon visual inspection of the raw data. Reflex force mirroring was most marked at the very beginning of the grip response and attenuated quite rapidly during the development of the grip force response in the operating hand. The time windows chosen captured this aspect of the mirroring. Furthermore, by using fixed time windows we could compare directly the grip force rates of the two hands during the development of grip force responses; measurements of just the peak grip force rate would not allow this because the peak could occur at different times in the operating and the non-operating hand.
Using data from the mixed-load series, for each subject an ANOVA was used to evaluate any possible influence of the operating hand (right, left) and rate of load force increase (2 N s-1, 6 N s-1 and step load) on the grip response latency of the operating hand. Pearson product-moment correlations were used to evaluate the correlation between the amplitude of the plateau load force and the grip force increment from the pre-response value to the grip force at the load plateau (data from mixed-load series). Similarly, we investigated correlations between the rate of load force increase for ramp load trials (2 and 6 N s-1) and the rate of grip force increase as measured from the grip force increase during the first 200 ms of the grip force response. Finally, to evaluate mirroring activity we performed linear regression analyses between changes in grip force of the operating hand (independent variable) and of the non-operating hand (dependent variable). The level of probability selected as statistically significant for the ANOVAs and correlations was P < 0·01.
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RESULTS |
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Figure 2 shows experimental data during single 'step-load' trials carried out by the left and right hands. Forces generated by both the operating and non-operating hand are shown for two XKS subjects (K2 and K8) and one control subject (C2). Both the control and all three XKS subjects consistently responded with grip force changes in the operating hand to changes in fingertip load. Subject K8 also showed clear grip force responses in the non-operating hand. These responses are reminiscent of mirror movements previously described for XKS subjects during self-paced voluntary actions (Kallmann et al. 1944; Mayston et al. 1997). Reactive mirror responses were less obvious in K2 and did not occur in C2 (Fig. 2). In the first section of the Results, we compare the performance of the operating hand for XKS and control subjects. In the second section, we analyse mirrored activity.
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Time traces of grip forces of both the operating and non-operating hand together with the load force and position of the manipulandum for step-load trials delivered to the left and then the right hand of two X-linked Kallmann subjects (A and B) and one control subject (C). Five repeated trials from each hand are shown stacked and sorted to provide minimum overlap with regard to grip force traces (zero values are not indicated). Data taken from the mixed-load test series. Vertical lines refer to the onset of load force increase, approximate onset of grip force increase, end of load force increase and start and end of the unloading phase. Note the interrupted time scale. | ||
Responses of the operating hand
Accidental slippage. An obvious performance index of the present restraint task is the success rate in terms of the subject restraining the manipulandum without slippage. Figure 3A shows the frequency of accidental slips for each subject and for each hand based on pooled data from the step- and mixed-load series. The rate of slippage varied considerably across the subjects but there were no obvious differences between (i) the three XKS subjects and (ii) the XKS and control subjects. In fact, two of our control subjects (C1 and C4) showed a higher rate of slippage than any of the XKS subjects.
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A, frequency of accidental slips during which the subject lost the manipulandum is given for the left and right hands. Data pooled across the step- and mixed-load series; performance was similar in the two test series in terms of slippage. B, mean values of grip response latencies (+1 S.D. and -1 S.E.M., unilaterally represented by vertical bars); data pooled for left and right hand. The three lines join data points that refer to the different rates of load force increase: step-load increase and trials with sustained ramp increases in the load force at 6 and 2 N s-1. | ||
Grip response onset latency. For all subjects, the grip response latency measured from the onset of the load force increase to the onset of the grip response was independent of the choice of operating hand (right or left). However, the rate of load force increase influenced the grip response latency: the latency became shorter with a brisker load force increase (P < 0·01 for all subjects; Johansson et al. 1992b). Figure 3B shows grip response latencies of the operating hand for XKS and control subjects for step-load trials and trials with sustained ramp increases in the load force at 2 and 6 N s-1. Most importantly, there were no obvious differences between XKS and control subjects in this study and the normal subjects of previous studies (Johansson et al. 1992b). With step-load increases the mean values for all of our subjects were well within two standard deviations of the means reported in studies by Johansson et al. (1992b,c), and within the range reported for individual subjects by Cole & Abbs (1988). Figure 3B also shows the onset latencies of the grip force responses during step trials assessed from the averaged EMG signals recorded from the 1DI (
). Again, for all subjects, including the XKS subjects, the EMG responses were within the range reported for step-load increases (Cole & Abbs, 1988; Johansson et al. 1992b; Macefield & Johansson, 1994; Macefield et al. 1996a).
Amplitudes and rates of grip force responses. All subjects scaled the amplitude of the grip force response to the amplitude of the load force. Figure 4A shows the grip force increase from its pre-response value to that recorded at the load plateau as a function of load force for K2 and C2. Linear regression adequately described the relationship between the grip force increment and the amplitude of the load plateau for all subjects and for each hand. The slope coefficients for each subject were all significantly different from zero (P < 0·01). The coefficients of determination (r 2 values) were 0·59-0·76 for the XKS subjects and 0·48-0·81 for the controls. All subjects also scaled the grip force output with the rate of change of the load force. Figure 4B shows the grip force rate during the first 200 ms after the onset of the grip force response as a function of load force rate for subjects K2 and C2. Linear regression using data from trials with a sustained ramp load force increase resulted in slope coefficients that were significantly different from zero (P < 0·01 in all subjects and for both hands). The coefficients of determination were 0·26-0·52 for the XKS subjects and 0·28-0·69 for the control subjects.
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A, magnitude of the grip force increase from the pre-response grip force to the plateau grip force as a function of plateau load force for one Kallmann subject (K2) and one control subject (C2). Data points refer to mean values (vertical bars show ±1 S.E.M.) and the lines to linear regression for each hand. B, grip force rate during the first 200 ms after onset of the grip force response as a function of load force rate for the same subjects as in A. Regression lines refer to data from trials with a sustained ramp load increase and data points to mean values (±1 S.E.M.). C, slope coefficients of linear regression lines as in A derived from each subject and hand. The dotted vertical lines give the inverse of the coefficient of friction (mean value for left and right index fingers), i.e. a measure of slipperiness. The vertical bars indicate unilaterally the 95 % confidence intervals of the slope estimates. | ||
We conclude that our XKS subjects, as well as the control subjects, regulated their grip force output both to the magnitude of the load and to its rate of change. However, the gain of the reactive responses, assessed from the slope coefficients of the relationship between the amplitudes of the grip force response and the load force increase (Fig. 4C), tended to be lowest amongst the XKS subjects. For normal subjects, one factor that influences this gain is the friction between the digits and the contacted material (Cole & Johansson, 1993). By using data from trials in which the subjects lost the object due to slippage, we estimated the friction between the skin and the contact disc (Cole & Johansson, 1993). The vertical dotted lines in Fig. 4C give the inverse of the coefficient of friction, i.e. a measure of slipperiness. (Because there was no obvious difference in slipperiness between the left and right index fingers for the individual subjects, the measure given is the mean value for the two digits.) Importantly, the friction varied among the subjects and the slope coefficients tended to covary with the slipperiness. Thus, an adaptation to the current frictional status may explain the lower magnitudes of the grip responses of subjects K1 and K2 compared to, for instance, the responses of subjects C1 and C4. Interestingly, subjects K1 and K2 - who showed rather low slipperiness - had clear signs of ichthyosis, the dry scaly skin common in subjects with XKS.
Responses of the non-operating hand
Grip force responses could be recorded from the non-operating hand of all three XKS subjects but were most pronounced in K8 (Fig. 2). They were only rarely recorded from the control subjects. Inspection of single trials indicated that this reflex force mirroring was strongest at the very onset of the grip force response of the operating hand, i.e. during the first 50 ms.
Intensive aspects of force responses in the non-operating hand. To analyse further reflex force mirroring, we performed linear regression analyses between changes in grip force of the operating hand (independent variable) and the non-operating hand (dependent variable). Thus, if the changes in force were the same in the two hands, the slope coefficient would be unity (100 % mirroring) and if there were no mirroring it would be zero. We measured the changes in grip force at each of the two hands as the difference between the plateau grip force and the pre-response grip force. Because of the pronounced early effect, we also analysed the change in grip force during the first 50 and 200 ms after the onset of the grip response.
Figure 5A shows reflex force mirroring by either hand during the first 50 ms of the grip response for a control subject, C2, and the XKS subjects K2 and K8. The slope coefficients for these two XKS subjects were significantly different from zero (P < 0·01), whereas those of the control subject were not. Figure 5B summarizes reflex force mirroring in terms of significant slope coefficients (P < 0·01) for all subjects for both hands during the first 50 ms and the first 200 ms of the grip response, and during the load plateau phase. It is clear that mirroring occurred primarily among the XKS subjects, and was most apparent during the first 50 ms of the grip response. Subject K8 showed the most pronounced reflex force mirroring. For K1 and K2, reflex force mirroring was variable and even when consistently present it was quite weak, being less than 20 % of the responses in the operating hand. For all subjects displaying reflex force mirroring, its magnitude was asymmetrical.
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A, analysis of force mirroring by right and left hand during the first 50 ms of the grip response for two X-linked Kallmann subjects (K2 and K8) and one control subject (C2) based on linear regression between changes in grip force of the operating hand (independent variable) and of the non-operating hand (dependent variable). Regression lines are fitted to the data points that represent single trials; all trials in the mixed-load series are included. Note the different scales of the abscissa and the ordinate. B, summary of reflex force mirroring for all subjects during the first 50 ms and the first 200 ms after the onset of the grip response and during the plateau phase of the grip response. Columns give significant slope coefficients (P < 0·01) as a percentage of unity, i.e. if the changes in force were the same in the two hands, this would be represented as 100 % mirroring. Force mirroring by the left hand when the right hand is operating can be seen to the left of zero and reflex force mirroring by the right hand when the left hand is operating can be seen to the right of zero. | ||
Temporal aspects of responses elicited in the non-operating hand. In XKS subjects the onset of the force increases in the non-operating and operating hands occurred at virtually the same time. This was apparent both in single trials (Fig. 6A) and in data averaged across all trials in the step-load series (Fig. 6B and C). Likewise, the profiles of the time course of the grip force changes were strikingly similar during the first 50 ms of the response and furthermore they were subsequently similar with respect to the ripple in the force records (Fig. 6A). Finally, the early part of the 1DI EMG responses in data averaged across trials had a similar time course on the two sides (Fig. 6B and C).
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Temporal aspects illustrated by time traces of grip forces of the operating (continuous lines) and non-operating hands (dashed lines) together with the load forces for step-load trials. A, initial parts of single trials carried out by the left hand of subject K8. Five repeated trials are shown stacked (zero values are not indicated, grip force of operating and non-operating hand are vertically aligned at the onset of the load force increase). Same data as in Fig. 2B but with an expanded time base. Note the synchrony of the ripple in the force records of the operating and mirroring hand. B and C, ensemble averages of grip forces, EMGs (1DI), position of manipulandum and load force (zero values are not indicated) across all trials of the step-load test series. Note that the EMG traces referring to the operating and non-operating hand nearly superimpose during the onset of the grip force response. The vertical dotted line indicates the onset of the load force increase and the boxed section of the grip force traces marks the first 50 ms of the triggered grip force responses. Note the difference in the grip force scales referring to the non-operating hand in B and C. | ||
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DISCUSSION |
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When considering the operating hand, all three XKS subjects performed in a similar manner to the control subjects with regard to grip responses driven by tangential loading of the precision grip. In contrast to the control subjects, in addition our XKS subjects often showed distinct reactive responses in the non-operating hand, i.e. reflex force mirroring. We will first discuss grip responses recorded from the operating hand and then those recorded from the non-operating hand.
Operating hand
Reactive grip responses, similar to those of the control subjects, were seen in all three of our XKS subjects (K1, K2 and K8). The responses of the XKS subjects had onset latencies similar to those of normal subjects and were appropriately scaled to the rate and the amplitude of the load perturbation. These observations imply that adequate responses to perturbations of precision grip do not depend on transcortical pathways that engage the fast conducting corticospinal pathway.
In contrast to normal subjects, the fast conducting corticospinal tract of subjects K1 and K2 has few or no contralateral projections. The aberrant ipsilateral corticospinal projections revealed by focal magnetic brain stimulation in these and other XKS subjects probably originate from errors in decussation that result from their genetic defect. The affected gene product is believed to be involved in axon guidance (Franco et al. 1991) and is expressed in the brain at about the same time that pyramidal decussation occurs (fetal day 57; O'Rahilly & Müller, 1994). However, descending control of voluntary movements in K1 and K2 does not appear to depend upon direct activation of the fast conducting ipsilateral corticospinal projection. Using positron emission tomography (PET) techniques, we have recently demonstrated that the contralateral motor cortex is primarily activated during unilateral movements in XKS subjects, including subject K2 (Krams et al. 1997). With regard to ascending somatosensory pathways, recordings of cortical somatosensory evoked potentials indicate that the organization of these pathways in subjects K1 and K2 is similar to that of control subjects (Mayston et al. 1997); there was no evidence for any reorganization. Thus, for subjects K1 and K2, if fast transcortical pathways had mediated the reactive grip responses elicited by sensory input from the operating hand, these responses should have been seen in the contralateral non-operating hand. This was not the case. The reflex force mirroring that could be observed in the contralateral hand of these subjects was inconsistent and weak compared to the robust responses in the operating hand (Fig. 5B). Subjects K1 and K2 nevertheless have an operating reflex system that mediates 'long-latency' cutaneomuscular reflex components in the 1DI muscle elicited by electrical stimulation of the digital nerves (Mayston et al. 1997). However, possible reflex responses mediated via this transcortical pathway system could not have supported the observed grip behaviour because the long-latency components of the cutaneomuscular reflex only appear in the contralateral hand. As such, the contralateral response indicates that the 'long-latency' cutaneomuscular reflex components elicited by electrical stimulation of the digital nerves do have a transcortical origin and use the ipsilaterally organized fast conducting corticospinal system (Mayston et al. 1997).
In contrast to subjects K1 and K2, subject K8 has a largely symmetrically organized fast corticospinal tract with both contralateral and ipsilateral projections to the spinal cord (Mayston et al. 1997). That the reactive grip behaviour of all three XKS subjects was indistinguishable despite this difference further indicates that the fast conducting corticospinal system is not critical for reactive control of the precision grip. Interestingly, if we had only investigated subjects similar to K8, i.e. subjects with a considerable bilateral projection, then we would have falsely concluded that the response of the operating hand (as well as that of the mirroring hand) was mediated by transcortical pathways. Whether this applies to conclusions made in previous studies concerning cortical involvement of 'long-latency' reflexes using subjects with only aberrant bilateral corticospinal pathways is uncertain (see e.g. Farmer et al. 1990; Matthews et al. 1990; Capaday et al. 1991; Carr et al. 1993).
We thus conclude that moment-to-moment somatosensory driven control of the precision grip does not depend upon transcortical pathways that use the fast conducting corticospinal system in XKS subjects. There is indeed evidence available that questions the role of transcortical mechanisms in mediating these responses in normal subjects: (i) the timing of changes in cortical excitability as assessed using magnetic stimulation suggests a subcortical origin of response initiation (Johansson et al. 1994; see also Macefield & Johansson, 1994), although a later cortically mediated boosting of the response was inferred (Johansson et al. 1994); (ii) the differential effects of transcranial electrical and magnetic stimulation indicate that the reflex response to skin stretch is not mediated transcortically (Macefield et al. 1996b); (iii) behavioural evidence suggests a contribution from fast spinal regulatory mechanisms (Johansson et al. 1992b); and (iv) recordings from the primary and supplementary motor cortex of monkeys that produced grip force responses to load perturbation of a grasped object indicate that certain neurones do respond to load perturbations (Picard & Smith, 1992; Cadoret & Smith, 1997) but at a latency that seems too long to be responsible for the initial change in grip force. Finally, recent evidence has revealed that following stimulation of the digital nerves, an early suppression of the excitability of the motor cortex, rather than excitation, is seen in man (Tokimura et al. 2000).
Pathways possibly responsible for mediating reactive grip responses. Because activity via a fast transcortical pathway cannot explain the moment-to-moment control of the reactive responses in our precision grip task, subcortical mechanisms are likely to play a critical role, not only in our XKS subjects, but also in normal subjects. Reactive somatosensory control of grasp stability may be served by transbulbar neuronal pathways or a pathway involving the cerebellum.
Theoretically, several possible subcortical sensorimotor pathways may be involved in the reflex control of grip. With regard to the descending component of the reflex pathway, bulbospinal pathways provide a possible substrate. Alstermark et al. (1987) have demonstrated that a cat is capable of using these pathways to control its forepaw; it can use its forepaw to pick up a piece of food and bring it to its mouth following transection of both the corticospinal and rubrospinal tracts. In man, reticulospinal fibres descend bilaterally in the spinal cord; however, there is a preponderance of ipsilateral fibres (Nathan et al. 1996). Appropriate ascending projections are also present. In the monkey, low threshold spinoreticular neurons with cutaneous mechanosensitive receptive fields in the forelimbs project both contra- and bilaterally to the pontomedullary reticular formation (Haber et al. 1982). A further possible pathway involves the cerebellum; unilateral electrical stimulation of the median nerve in man evokes neuromagnetic activity in the cerebellum that precedes the onset of activity evoked in the primary sensorimotor cortex by some 5 ms (Tesche & Karhu, 1997). Tactile information from the forelimb reaches the cerebellar anterior lobe through both mossy fibre pathways and climbing fibre systems (e.g. Cooke et al. 1971; Ekerot & Larson, 1980) and neurons of the monkey cerebellar cortex can respond to load perturbations during grip restraint tasks (Dugas & Smith, 1992). Furthermore, collaterals of mossy fibres from the lateral reticular nucleus terminate in the cerebellar nuclei, including the interpositus nucleus (Eccles et al. 1972), and carry cutaneous afferent information from the ipsilateral forelimb (Clendenin et al. 1974). The output from the cerebellum through the rubrospinal system via the interpositus nucleus is certainly involved in the sensorimotor control of the hand in the monkey (van Kan et al. 1994; Gibson et al. 1996). The rubrospinal tract is, however, small in humans with sparse projections into the spinal cord (Nathan & Smith, 1982). Nevertheless, the interpositus also projects to the reticular formation (Gonzalo Ruiz & Leichnetz, 1990; Rothwell, 1994), and in man this projection may be of greater functional significance that that to the red nucleus.
The motor cortex and its descending projections are without doubt essential for the control of skilled finger and hand movements in primates. Descending cortical pathways not exposed by transcranial magnetic stimulation most probably have important roles in the organization of the motor output in normal subjects as well as in XKS subjects. These pathways include the vast ipsi- and contralateral corticobulbar projections (see Magni & Willis, 1964; Peterson, 1979) and presumably the slow conducting corticospinal neurons; the mean fibre size of the pyramidal tract in man is merely 1·03 µm (Heffner & Masterton, 1975). Rather than initiating and driving the reactive grip responses in a moment-to-moment manner, we believe that descending cortical signals are essential in setting the various subcortical networks to operate according to the requirements imposed by the task and the context (cf. 'motor set', Tanji & Evarts, 1976).
Non-operating hand
Previous studies have revealed that 85 % of XKS individuals show mirror movements during self-paced manual tasks (Quinton et al. 1996). The present findings demonstrate that such subjects can also show reflex force mirroring; our control subjects only rarely showed reflex force mirroring. We have argued above that the fast conducting corticospinal system is not involved in the response to grip perturbation in the XKS subjects. Thus, it is unlikely that their reflex mirroring resulted from activity in the ipsilateral corticospinal projection as suggested by Mayston et al. (1997) when discussing the origin of mirrored activity during voluntary movements. If activity in the fast conducting ipsilateral corticospinal projection was responsible for the mirroring, then reflex force mirroring should have been stronger in subjects K1 and K2, who show predominantly ipsilateral projections, than in subject K8, who has a largely symmetrically organized corticospinal projection. Instead, the mirroring with K1 and K2 was substantially weaker than that observed with K8.
The pathways involved in the reflex mirroring of the XKS subjects in the present study may also have contributed to the mirroring in XKS subjects observed during self-paced manual actions (Kallmann et al. 1944; Mayston et al. 1997). Aberrant pathways may exist in XKS due to faulty axonal guidance resulting from a defect in the XKS gene product. This gene product is normally present at about the time the cerebellar commissures are forming (fetal day 57; O'Rahilly & Müller, 1994), therefore aberrant commissural projections could be present. Furthermore, erroneous terminations at the bulbar networks of corticobulbar connections cannot be excluded; this may cause mirroring due to an impaired descending programming of subcortical networks. Indeed, the overall great bilateral organization at the bulbar level provides an attractive anatomical substrate for explaining mirroring. Reticulospinal fibres descend bilaterally in the human spinal cord (Nathan et al. 1996) and ascending projections that carry cutaneous mechanoreceptive information from forelimbs project bilaterally to the pontomedullary reticular formation in the monkey (Haber et al. 1982). Although no information is available regarding the time of formation of descending projections at the bulbar level, aberrant projections, including reticulospinal projections, could exist in our XKS subjects.
In conclusion, our findings based on XKS subjects provide evidence that (i) there is a difference in the efferent pathways of cutaneomuscular reflex responses elicited following electrical stimulation of the digital nerves and somatosensory driven grip responses elicited following load perturbation, and that (ii) reactive control of precision grip in subjects with XKS, which is indistinguishable from that observed in normal subjects, is not mediated via the fast corticospinal projection but is likely to rely on fast subcortical pathways.
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This study was supported by the Swedish Medical Research Council (project 08667) and the Göran Gustafsson Foundation for Research in Natural Sciences and Medicine. The Wellcome Trust supported M.J.M. We specially thank Mr A. Bäckström for technical assistance.
Corresponding author
L. M. Harrison: Department of Physiology, University College London, Gower Street, London WC1E 6BT, UK.
Email: linda.harrison{at}ucl.ac.uk
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