Tremor in the human hand following peripheral nerve transection and reinnervation

Brain Research 989 (2003) 238–245 www.elsevier.com / locate / brainres

Research report

Tremor in the human hand following peripheral nerve transection and reinnervation Frank A. Proudlock a , Jon Scott b , * a

b

Department of Ophthalmology, Leicester Royal Infirmary, Leicester, UK Department of Pre-Clinical Sciences, University of Leicester, P.O. Box 138, Leicester LE1 9 HN, UK Accepted 23 July 2003

Abstract Slow movements and position holding by the digits are both characterised by 8–10 Hz tremor which appears to be centrally generated. Denervation and subsequent reinnervation lead to significant alterations in peripheral connectivity and reflex organisation. We have tested the hypothesis that 8–10 Hz tremor is present in the digits of subjects following a complete nerve lesion. The frequency content of abduction and adduction movements was recorded in 12 index fingers and nine little fingers reinnervated subsequent to a complete ulnar nerve transection. An optical position laser transducer was used to measure digital movements, minimising mechanical interference to the system. Concurrently, surface electromyograms (EMG) were also recorded from first dorsal interosseus muscles (1DI) and abductor digiti minimi brevis (ADMB) muscles for index and little fingers, respectively. The maximal voluntary contraction (MVC) of the reinnervated muscles varied from 5.9% to 100% of those of the unimpaired, contralateral hands. The subjects performed abduction–adduction movements of the index and little fingers and a position holding task. Significant peaks in PSD curves of acceleration and rectified integrated EMG traces were identified. Tremor in the 8–10 Hz range was evident in both the acceleration and EMG signals for the majority of digits during both the slow movement and position holding tasks. These findings demonstrate the robust nature of these 8–10 Hz oscillations, even following the significant changes in peripheral connectivity of muscle and nerve resulting from nerve transection and reinnervation.  2003 Elsevier B.V. All rights reserved. Theme: Development and regeneration Topic: Motor systems Keywords: Tremor; Peripheral nerve injury; Reinnervation; Regeneration; Plasticity

1. Introduction Slow movements performed by the digits are not entirely smooth but are characterised by 8–10 Hz tremor, manifest as a localised peak in the power spectral density (PSD) function of velocity and acceleration traces [35,36,41]. This pulsatile output is not generated by the stretch reflex [41] but appears to be centrally generated since coherent 10 Hz oscillations are evident in both the eye and digit when performing a related task [24,25]. Although smaller in amplitude, similar frequencies of tremor are also evident in the acceleration records of digits *Corresponding author. Tel.: 144-116-252-3083; fax: 144-116-2525072. E-mail address: [email protected] (J. Scott). 0006-8993 / 03 / $ – see front matter  2003 Elsevier B.V. All rights reserved. doi:10.1016 / S0006-8993(03)03377-8

during position holding [15,23]. This tremor has also been linked to a centrally driven oscillation, although the degree to which peripheral mechanical reflexes and motor unit firing properties also contribute is currently being debated [7,14,28] (see Ref. [24] for review). There has been much recent interest concerning whether the central generation of these oscillations in such diverse systems as the hand and the eye, may provide a vital role in synchronisation of movement [8,25,36,40]. Peripheral nerve trauma initially results in widespread sensory and motor loss due to axonal degeneration distal to the site of injury and consequent denervation of motor end plates and sensory receptors as well as re-organisation of central connections (reviewed in Ref. [13]). Although the peripheral nervous system has potent regenerative capacities due to the ability of axons to sprout and re-grow along

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remaining endoneurial tubes [2,16], many studies have demonstrated that poor recovery results from factors such as degeneration of target structures during denervation, unsuccessful reestablishment of connections and mislocation of axons to different target structures [1,5,21,22,30,44]. We have tested the hypothesis that 8–10 Hz oscillations are evident during position holding and slow movement tasks in the digits subsequent to reinnervation. Since reinnervation results in profound changes in peripheral connectivity, for example, greatly reduced response of muscle stretch receptors [1,17] and enlarged motor unit size [3,6,12], the question is particularly interesting in delineating between peripheral effects, such as the peripheral reflexes and motor unit properties, and a centrally generated oscillation. Fig. 1. Set-up used to record digital movements and surface EMG (see text for explanation).

2. Materials and methods

2.2. Tremor and EMG recording 2.1. Subjects The study received approval from the University of Leicester Hospitals Trust Ethics Committee and with informed written consent from the participants after verbal and written explanation of the nature and possible consequences of the study. The study was performed in accordance with tenets of the Declaration of Helsinki. Twenty-one reinnervated digits (12 index and nine little fingers) were recorded from 12 subjects who had suffered complete ulnar nerve lesioning. The subjects comprised 11 males and one female with a mean age of 41.1 years (S.D.513.0). Further details of the subjects are given in Table 1. Post-traumatic periods varied widely from 7 months up to 17 years. Apart from one subject (subject 7), injuries were caused by a glass or knife lesion and were followed by microsurgical repair. The normal hands of the subjects were used as controls.

An optical displacement laser transducer with a range of 10 mm and a resolution of 3 mm (model: LD 1605-20, Micro-epsilon, Messtechnik, Germany) was used to record movements of the index and little fingers (Fig. 1). The laser was shone onto a small white adhesive backed card (15 mm315 mm) attached to the digit at a distance of 57 mm from the joint centre of rotation (at which distance, displacement in millimetres equates to the angle in degrees). Digits were splinted across the interphalangeal joints. The hand and arm were firmly clamped using a moulded hand clamp and a cushioned arm splint arrangement. The optical laser transducer performed a low pass filtering operation (bandwidth51 kHz) when measuring displacement. Surface EMGs were recorded from first dorsal interosseus muscles (1DI) and abductor digiti minimi brevis (ADMB) muscles using tab electrodes cut down to 11

Table 1 Subject details Subject

Injury

Age

Dominant hand

Injured hand

Post-traumatic period (years)

% MVC of impaired hand Index

Little

1 2 3 4 5 6 7 8 9 10 11 12

Ulnar Ulnar Ulnar Ulnar Ulnar Ulnar Ulnar Ulnar Ulnar & Median Ulnar & Median Ulnar & Median Ulnar & Median

31 33 32 38 32 70 54 53 41 24 36 49

Right Left Right Right Right Right Right Right Right Right Right Right

Left Left Right Right Right Left Right Left Right Left Left Left

4.0 1.6 6.0 2.4 6.2 16.8 not known 6.6 5.6 3.6 0.6 9.1

81.2 53.6 29.4 82.0 100.0 53.8 18.2 69.6 22.7 12.5 5.9 20.0

42.2 54.5 35.3 100.0 46.1 12.5 83.3 45.5 0.0 19.0 12.5 35.7

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mm318 mm (Biotabs, Medical & Surgical Bio-adhesives, UK). The electrodes were typically positioned with the positive electrode positioned over the belly of the muscle and the negative electrode towards the proximal tendon, approximating to a monopolar recording. Resistances between electrodes were recorded before and after trials to ensure they were below 20 kV over the course of recording. Both digit position and EMG data were recorded using a 14011 digital interface operating under Spike2.21 for Windows  software (Cambridge Electronic Design, UK).

2.3. Maximal voluntary contraction measurement A dynamometer was constructed for measuring the maximum voluntary contraction (MVC) of the 1DI and ADMB muscles. The gauge consisted of foil strain gauges bonded to flattened surfaces of an 8 mm370 mm steel bar. Force was applied by the digit through a rigid nylon loop fixed to the end of the bar. The hand gripped a 40 mm nylon grip with the hypothenar eminence resting on a perspex platform and the index or little finger was extended to apply force against the gauge. The MVC was evaluated as the maximum level attained during three brief attempts at applying the maximum force against the dynamometer. An estimate of the percentage loss of muscle strength was derived from:

performed an abduction and adduction move using visual feedback followed by an abduction and adduction move from memory. An audible cue was provided 300 ms before each abduction and adduction target movement (both visual and non-visual) to assist in timing the movement. The subject repeated this process for a period of 3 min, resulting in 58 ramp movements in all (29 abduction moves and 29 adduction moves). During this task, only the abduction and adduction moves were analysed; the 1.5-s hold period was not included (cf. Fig. 2). Only trials where the subject was able to perform slow abduction and adduction ramp movements exceeding a 1-s time course were included. Accordingly, four of the 12 nerve-lesioned subjects could not perform the slow ramp movements with the 1DI and five were unable to do so with the ADMB, in which case the position holding was the only active task recorded. Resting tremor was also recorded for 60 s during a period of no EMG activity. This was used to measure background levels of mechanical or electrical noise.

2.5. Analysis For the position holding task, finite fast Fourier trans-

MVC of impaired hand ]]]]]]] 3 100%. MVC of normal hand Handedness could lead to biasing of these estimates, however for six of the subjects the dominant hand had been injured and for the other six, it was the non-dominant.

2.4. Protocol Feedback of the digit position was provided through a cathode ray tube display (100 mm380 mm) on which a target cue was displayed as a wide, low luminance line (5 mm wide) and the digit position as a narrow high luminance line (1.5 mm wide). The subject was requested to perform two tasks, where possible.

1. A position holding task in which the subject held the digit in an abducted position, 108 away from the resting position. Position holding was performed with and without visual feedback, each for a 40-s period. This process was repeated, generating 80 s of data with visual feedback and 80 s of data without. 2. A slow movement task in which the subject tracked a target equivalent to alternate, 7.58 amplitude and 58 s 21 velocity, abduction and adduction ramp moves, separated by a 1.5-s hold period. Each abduction / adduction ramp movement lasted 1.5 s. The subject

Fig. 2. Derivation of the tremor measurements during ramp movements. The figure shows the abduction and adduction ramp moves performed by the control index finger of a subject during visual and non-visual feedback. The linear regression was calculated over the steady-state ramp move in the displacement trace and then subtracted from the displacement to give the ‘flattened’ tremor. Tremor analysis was only carried out during the periods indicated by the grey bands.

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forms were derived from 1-s blocks of the position and rectified EMG time traces, subsequent to the application of a raised cosine (Hanning) window. These were squared and averaged for the 80 s of abduction data and adduction data to produce a PSD curve with a frequency resolution of 1 Hz. For the slow movement task, cursors were positioned semi-automatically over offline recordings of the tremor and velocity records at points 200 and 1400 ms after the ramp movement commenced (500 and 1700 ms after the audible cue, Fig. 2). The first cursor could be repositioned at the beginning of the abduction / adduction movement if the subject made a movement earlier or later. The second cursor would automatically reposition itself 1200 ms later. The position trace was flattened between the cursors by subtracting the best-fit regression line of the data from the trace (Fig. 2). One-second blocks of data between the cursors were used to derive finite fast Fourier transforms of the position and rectified EMG time data, subsequent to the application of a raised cosine (Hanning) window. These were squared and averaged to produce PSD curves. Derivation of velocity and acceleration PSD curves was performed in the frequency domain by multiplying the data by a weighting function (frequency 2 in radians). A significant peak within the range of 7–11 Hz was identified by calculating the upper confidence level of two standard deviations of the PSD curve using the x 2 distribution [34]. If the PSD curve at the peak was raised above the curve of the confidence level of the frequencies on either side then it was judged to be significant.

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Fig. 3. The upper traces show raw records of the target signal, digit position, velocity and EMG during position holding by subject 12 for a 2-s period. Averaged PSD curves of acceleration and rectified EMG traces for the control and impaired index fingers and 1DI muscles are also shown.

3. Results Reinnervation of 1DI and ADMB muscles following peripheral nerve lesioning resulted in varied levels of recovery of muscle strengths with percentages of MVC of impaired hands ranging from 5.9% to 100% of muscle strengths in the control hand (Table 1). The majority of MVCs from reinnervated muscles were less than half those recorded from the contralateral hand (50% of 1DI muscles and 82% of ADMB muscles were below 50% MVC). The mean reduction in MVC was 45.7% for the 1DI muscle and 36.7% for the ADMB muscle. Reduced MVCs were evident even after long periods of recovery (for example subject 6, Table 1). The mean (6S.D.) MVCs for the control 1DI and ADMB muscles were 22.3N (67.8N) and 14.6 (65.8N), respectively. Reinnervated muscles showed apparent changes in motor unit firing patterns, in comparison to the control hand. For example, Fig. 3 shows records of a poorly reinnervated muscle during a position holding task (subject 12) compared to the control hand. Enlarged potentials in the EMG of the reinnervated hand correspond to discontinuities in the position trace, in contrast to the control hand where the EMG potentials are smaller and the

resultant tremor is less. Although the strength of the muscle was only 20% of that of the contralateral hand, 8–10 Hz oscillations are evident in the position and velocity traces of the reinnervated muscle and also in the average PSD curve of both the acceleration and rectified EMG traces as confirmed by statistical analysis. Enlarged potentials and the presence of 8–10 Hz oscillations were also a consistent finding in stronger muscles. Fig. 4 shows surface EMG traces from 1DI muscles of impaired and control hands in subject 5 during a single abduction move of the index finger where the strength of the reinnervated muscle was equivalent to that of the control hand. The EMG trace also shows the presence of large potentials occurring at 9–10 Hz in the impaired muscle. This was confirmed with the presence of a statistically significant peak in the 8–10 Hz range in the PSD of both acceleration and rectified EMG traces for this subject. A peak was also consistently present in the acceleration and EMG PSD curve at the first harmonic, i.e. 18–20 Hz. Such large amplitude potentials were never recorded from the control subjects during position holding (Fig. 3) and only occasionally during the ramp tests at the end of

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hand. Consequently, a peak is evident at |8–10 Hz in the PSD curve of both acceleration and EMG traces averaged across the test. The frequency of occurrence of 8–10 Hz tremor (with a peak between 7 and 11 Hz) in acceleration and EMG PSD is listed as percentages for controls and nerve lesioned subjects in Table 2. Overall, 8–10 Hz tremor was more obvious in acceleration PSD compared to EMG PSD and also percentages were higher in the index finger compared to the little finger. The percentage of subjects manifesting oscillations in the 8–10 Hz range was not appreciably different in reinnervated hands compared to controls in any category. Averaged PSD curves of acceleration traces during position holding (160 s of data per subject) and slow abduction movements (29 moves per subject) for control and reinnervated subjects are shown in Fig. 5. An 8–10 Hz peak can be distinguished in both the index and little fingers during position holding and slow movements. The 8–10 Hz peak was larger in amplitude in the index finger compared to the little finger. This was true in the control and reinnervated muscle and also during both the position holding and slow movement task (Fig. 5). The areas under the PSD curves were less during the position holding task compared to the slow movement task as indicated by the y-axis range. Also, the 8–10 Hz peak was smaller in relation to higher frequencies (e.g. 15 and 45 Hz) during the position holding task compared to the slow movement task. There was no difference between PSD functions for visual and non-visual tasks except for the presence of a peak at |1–2 Hz during the visual feedback, presumably due to the visual feedback loop. PSD functions between 0 and 45 Hz were less than an order of magnitude of the position holding task and less than two orders of magnitude of the slow movement task. The area under the PSD curve between 8 and 10 Hz was measured and correlated to the muscle strength ((MVC of impaired hand / MVC of control hand)3100%) of reinnervated muscles using the general linear model. There were no significant correlations for the index and little fingers during either the position holding or slow movement tasks.

Fig. 4. Raw records of the target signal, digit position, velocity and EMG during a slow abduction movement by subject 5 during a 2-s period of the slow movement task. Averaged PSD curves of acceleration and rectified EMG traces from the control and impaired index fingers and 1DI muscles are shown below. The dashed lines indicate the association between the EMG potentials and the subsequent peaks in the velocity record.

the abduction movement (Fig. 4). In the original time traces (Figs. 3 and 4) these potentials are visibly phase locked with relatively large oscillations as seen in the velocity profile, where the amplitude of the oscillations appears markedly enlarged by comparison with the control

Table 2 Proportions of subjects displaying tremor during the position holding and movement tasks Digit

Controls

Index Little

Lesioned

Index Little

Slow movements n Accel. EMG Accel. EMG Accel. EMG Accel. EMG

12 12 9 9 8 8 4 4

Position holding Visual abduction

Non-Visual adduction

n abduction

Visual adduction

Non-Visual

83.3 50.0 77.8 55.6 87.5 62.5 75.0 50.0

83.3 50.0 66.7 77.8 75.0 87.5 75.0 75.0

83.3 50.0 44.4 33.3 87.5 75.0 75.0 25.0

91.7 75.0 55.6 44.4 62.5 12.5 50.0 25.0

12 12 9 9 12 12 9 9

100.0 91.7 94.4 100.0 91.7 91.7 94.4 94.4

100.0 91.7 94.4 94.4 87.5 91.7 94.4 94.4

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Fig. 5. Averaged PSD curves for position holding and slow abduction movements for the index and little fingers of control hands (left hand graphs) and reinnervated hands.

4. Discussion These results demonstrate that 8–10 Hz tremor is present following complete ulnar nerve transection and subsequent reinnervation of intrinsic hand muscles during both position holding and slow movement tasks. In the light of knowledge that has accrued over recent years regarding the profound effect of denervation and reinnervation upon muscle structure, sensory feedback, peripheral and central connectivity and reflexes, and motor unit size and distribution, these findings demonstrate the robust nature of 8–10 Hz output subsequent to dramatic alterations in peripheral circuitry. The frequency of occurrence of 8–10 Hz oscillations in reinnervated muscles did not appear to be influenced to any significant degree by a loss in muscle strength. Reduced MVCs were recorded in the majority of reinnervated muscles even after long periods of recovery. Muscle atrophy following lengthy denervation periods has been shown to result in a permanent loss of muscle mass and

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force production even subsequent to full reinnervation [10,11,19]. Possibly one of the greatest hindrances to successful motor recovery and improvement in muscle strength is due to inappropriate reinnervation, caused by axons entering foreign tissue (neuroma formation) or reaching incorrect target structures (axonal mislocation). Although epineural and perineural primary repairs were performed on all the subjects, reducing inappropriate reinnervation [29,33], the chance of axonal mislocation of intrinsic hand muscles by the ulnar nerve is particularly high due to the large numbers of cutaneous fibres contained in the nerve [1]. Consequently, the loss in muscle strength may be a strong indicator of abnormal peripheral connections to both motor and sensory muscle structures in the muscle [1,17,31,32]. It is of note that muscle sense organs show reduced responsiveness to stretch when reinnervated [1,17], particularly if inappropriately innervated by cutaneous afferents [22]. Kinaesthetic feedback is essential for the fine control of movement; such as performed by the digits, and impairments in proprioceptive feedback may have contributed to the inability of some nerve lesioned subjects to perform slow ramp movements. The recorded MVCs indicated that the majority of subjects should have had sufficient strength to perform the ramps, since the force required to abduct a digit against gravity is minimal. However, four of the subjects appeared unable to do so with the index finger and five subjects with the little finger. It is also interesting to note that the same subjects often showed marked 8–10 Hz tremor during a position holding task (Fig. 4). The present findings support the view that Ia afferent feedback is unnecessary for the generation of 8–10 Hz tremor during position holding and slow movement tasks. These observations are corroborated by the findings of Wessberg and Vallbo [41] who showed that spindle output during slow movements, although correlated to pulsatile output, is insufficient to generate the 8–10 Hz oscillations. They suggest, therefore, that the 8–10 Hz output is a centrally generated phenomenon. Surface EMG recordings of reinnervated 1DI and ADMB muscles during position holding and slow movement showed large amplitude potentials that were not apparent in the records from the uninjured hands. It is possible that these potentials represent synchronous activation of groups of motor units, however, a more probable explanation is that these represent the action potentials arising from single, enlarged motor units. During the denervation–reinnervation process, a significant proportion of motor neurons fail to reinnervate the muscle fibres. As a consequence, the muscle is reinnervated by relatively few motor axons and the motor units thus formed may be significantly larger [3,6,12]. The existence of fewer but enlarged motor units will compromise the wide range of motor unit sizes and firing frequencies required for smooth force build up and the generation of fine movements. The effects of peripheral nerve lesions and subsequent

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reinnervation are far reaching and have been shown to elicit changes in motor neuron arborisation patterns [20,26,43] and excitability [18,37] in the spinal cord. Also, cortical hand representations are highly abnormal following reinnervation where larger and often multiply represented receptive fields have a disordered and fractured somatotopic arrangement [9,27,38]. Recruitment order of motor units is maintained following reinnervation [4], although reinnervation has been shown to interfere with agonist and antagonist coordination [39]. Certain authors have emphasized the importance of such agonist–antagonist interactions in producing the acceleration and deceleration phases that generate the individual discontinuities of the pulsatile output [35,36]. Interestingly, reinnervation appears to accentuate these discontinuities presumably because enlarged motor units now contribute to the agonist–antagonist interaction, which still remain phase locked in character. The robust quality of this 8–10 Hz signal following dramatic alterations in peripheral connectivity has been demonstrated from its presence during both position holding and slow movement tasks by reinnervated muscle, irrespective of the relative strength of the muscle and the period of recovery. This supports the evidence that these 8–10 Hz tremors are of central origin [7,28,42]. Furthermore, the tremors are clearly not diminished by significant alterations in spinal connectivity and afferent feedback.

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