REORGANIZATION OF THE CORTICO-SPINAL PATHWAY IN PATIENTS WITH CHRONIC COMPLETE THORACIC SPINAL CORD INJURY: A STUDY OF MOTOR EVOKED POTENTIALS

Der-Sheng Han, MD1, Chih-Ming Li, MD, MS2,3 and Chein-Wei Chang, MD4

From the 1Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital Bei-Hu Branch, Taipei, 2Institute of Biomedical Engineering, National Cheng Kung University, Tainan, 3Department of Physical Medicine and Rehabilitation, Pingtung Hospital, Ministry of Health and 4Department of Physical Medicine and Rehabilitation, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan

OBJECTIVE: To evaluate the change in motor evoked potential parameters following transcranial magnetic stimulation in patients with chronic complete thoracic cord injury.

DESIGN: A cross-sectional study.

SUBJECTS: Eighteen patients with chronic complete thoracic cord injury and 18 age- and sex-matched healthy controls were included in the study. The mean post-injury duration was 13.0 (standard deviation (SD) 6.0) years.

METHODS: The latency, amplitude, central conduction time and peripheral conduction time of motor evoked potentials from bilateral abductor pollicis brevis and first dorsal interosseous muscles following transcranial magnetic stimulation were measured and compared between the patients and healthy controls. The predicting variables for central conduction time, including age, sex, height, illness duration and job activity, were analysed using a simple correlation and stepwise multiple regression model.

RESULTS: The patients with complete thoracic cord injury had longer central conduction time recording of the dominant hand in both abductor pollicis brevis and first dorsal interosseous muscles. The difference in latency approached significance between the patients and controls. There was no statistical difference in amplitude between them. Regression analysis demonstrated that patients who were older, less physically active and with longer illness duration showed prolonged central conduction time.

CONCLUSION: The central conduction time in the dominant hand of chronic complete thoracic cord injury is prolonged. This study revealed motor reorganization of the central nervous system in complete thoracic cord injury. Decreased physical activity and prolonged illness may cause these changes.

Key words: transcranial magnetic stimulation, motor evoked potential, spinal cord injury, reorganization, nerve conduction study.

J Rehabil Med 2008; 40: 208–212

Correspondence address: Chein-Wei Chang, Department of Physical Medicine & Rehabilitation, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan. E-mail: cheinweichang@gmail.com

Submitted March 18, 2007; accepted October 16, 2007

Introduction

Transcranial magnetic stimulation (TMS) is a non-invasive technique for stimulating the motor cortex and is therefore suitable for neurophysiological studies in humans. TMS allows safe and painless assessment of the integrity of the descending motor pathway in the brain and spinal cord (1). Moreover, it can identify the cortical representation of a specific muscle with a time resolution of milliseconds, and has thus been widely and reliably employed in depicting short- and long-term reorganization of cortico-spinal motor output after spinal cord injury (2–8), hemispheric stroke (9, 10), limb amputation (11–13), transient anaesthesia (14) and rehabilitation training (15).

Spinal cord injury (SCI) incurs high mortality and morbidity. Due to the lack of an effective therapy, neurorehabilitation is still the conventional treatment for this debilitating ailment. Since the central nervous system is trainable, the design of more effective rehabilitation protocols, which take advantage of motor reorganization after SCI and do not just compensate for deficits, is an ongoing process in this field (16). Reorganization within the primary motor cortex was observed following SCI, but the pattern is variable. It is affected by many factors, including age of injury (17), location and extent of the lesion, and time since injury (18). The motor evoked potentials (MEP) following TMS of muscles caudal to the lesion after complete SCI are generally absent or increased in latency and threshold due to a block of the cortico-spinal pathway (5, 7, 8, 19). The cortical mapping of muscles rostral to the cord lesion is believed to expand after SCI. However, the change in the evoked potential latency following TMS is controversial, as there have been disparate reports showing no significant alteration (7), shortened central conduction latencies in injured patients (2, 20), and others showing the opposite results (6).

Plasticity of the undamaged cortico-spinal pathway is crucial to neurorehabilitation of those patients. We hypothesized that physical activity and age affect the reorganization process. The aim of this study was to examine the reorganization in patients with paraplegia with complete thoracic cord injury (CTCI) by evaluating the differences in the electrophysiological parameters of MEP elicited by TMS.

Material and Methods

Subjects

Eighteen patients with CTCI (13 men, 5 women) and 18 sex- and age-matched healthy controls were recruited to this study following informed consent and institutional review board approval. The patients were recruited randomly from the member list of a local SCI Association with a mean age of 36.5 (standard devation (SD) 8.2) years and a mean height of 166.2 (SD 7.2) cm. Only patients who had had CTCI for more than one year were included in the study. Overall, the mean duration of CTCI was 13.0 (SD 6.0) years. Seventeen patients were victims of trauma. All patients belonged to the complete type (American Spinal Cord Injury Association Scale A) at the thoracic level. They were free from diabetes, uraemia, epilepsy, neurological deficits in bilateral upper extremities, a history of cranial surgery or skull fracture, and did not have a cardiac pacemaker. The score of job activity was defined as: 0 = no job (or less than 4 h/day), 1 = part-time job (or 4–8 h/day), 2 = full-time job (equal or more than 8 h/day). The healthy controls were matched for age (33.7 (SD 10.9) years), sex, and height (168.8 (SD 7.1) cm). All subjects’ dominant side was on the right. The clinical details are shown in Table I.

Motor evoked potentials study by transcranial magnetic stimulation

Subjects were seated comfortably with their forearms supported on armrests. They were instructed to keep their arms relaxed with the hands and wrists in a neutral position. Magnetic stimulation was delivered with a Magstim 200 magnetic stimulator (Magstim Co., Whitland, Carmarthenshire, UK) through a figure-of-8 coil positioned tangentially to the scalp with the handle pointing backwards and the centre over the point of stimulation. The point of stimulation was 3 cm contra-lateral to the vertex on the interaural line (21). The intensity of magnetic stimulation was 100% of the maximum output of the device. MEPs elicited by TMS were recorded from bilateral abductor pollicis brevis (APB) and first dorsal interosseous (FDI) muscles with surface electrodes in a belly-tendon montage according to the recommendations of the ad hoc International Federation of Clinical Neurophysiology Committee (21). The shortest latency, highest amplitude and largest area of consecutive 5 MEPs in each muscle were recorded with the connected electromyography system (Medelec Synergy, Oxford Instruments, UK), with the amplifier set at a bandpass filter of 16–3000 Hz.

Measurement of central conduction time

The median and ulnar nerves were stimulated by electrical stimulation applied at the level of the wrist. The intensity of stimulation was supramaximal. The skin temperature of the forearm ranged between 32°C and 35°C in all subjects. The shortest latencies of M and F waves were recorded. The central conduction time (CCT) was defined as the difference between the onset latency of MEPs to cortical stimulation and peripheral conduction time (PCT). The PCT is calculated from the latencies of M and F waves, as follows:

CCT = (latency of MEP) – (latency of M wave + latency of F wave – 1)/2 (22).

Statistical analysis

Data are presented as the mean and SD. Patients vs healthy controls and side-to-side comparisons of means were performed with the Mann-Whitney U test and the Wilcoxon signed-rank test, respectively. The univariate correlation analysis between CCT and predicting variables, including age, sex, height, cord injury, illness duration and job activity, was performed. The stepwise multiple regression analysis was then employed to eliminate the co-linearity between variables and to find a regression equation to predict CCT. The level of significance was set at p < 0.05 for all comparisons. Analyses were carried out using the SPSS 10.0 (Statistical Product and Service Solutions Inc., Chicago, IL, USA).

Results

Compared with healthy controls, patients with CTCI had longer CCT in both the APB and the FDI muscles of the dominant hand. The patients with CTCI had longer MEP latencies obtained in the right APB muscles compared with healthy controls only approaching the level of statistical significance (Table II). Comparisons of bilateral values revealed longer PCT from both right APB and FDI muscles than left muscles in healthy controls (p-value = 0.031 for APB and 0.043 for FDI), with no side-to-side difference in patients with CTCI.

The simple correlation between CCT and variables, including sex, age, cord injury, height, illness duration and job activity, was performed first to determine the predicting factors. Age, cord injury and job activity correlated positively with CCT obtained in both APB and FDI muscles of the dominant hands, and the illness duration correlated with CCT obtained only in FDI (Table III). In order to eliminate the effect of co-linearity, we used stepwise multiple regression analysis with CCT as the dependent variable, and sex, age, height, illness duration and job activity as the independent variables. The significant predictors of CCT were age and job activity in APB muscles of the dominant hand (Table IV). The regression equation of CCT in APB muscles of dominant hands = 3.998 + 0.056 × age –0.49 × job activity. The predictors of CCT in FDI muscles of dominant hands were illness duration and age. The equation of CCT in FDI muscles of dominant hands = 3.351 + 0.042 × age + 0.061 × illness duration.

Discussion

The results of this study illustrate that CCT is prolonged in the MEP by TMS in both APB and FDI muscles, as recorded in the dominant hand of patients with chronic CTCI. This lengthened CCT significantly correlated with age and job activity. The CCT predominantly reflects the maximum speed of the activated fibres and a prolonged CCT may suggest an impaired temporospatial summation of cortico-spinal pathway or changes in cortical excitability. Hence, a significant central reorganization of the motor system had probably occurred in chronic CTCI patients. Our results are in accordance with an earlier report, which revealed increased latencies and decreased thresholds on the MEPs rostral to the cord lesion in patients with CTCI (6). Longer latencies in MEP rostral to cord lesion might be due to several factors, including a longer cortico-spinal activation process (6), less efficient synaptic function or changes in the pattern of synaptic connections due to deafferentation (1). Deafferentation results in rapid reorganization of the sensorimotor area targeting the territories proximal to the disconnected region (18). Conversely, enhanced sensory feedback of a body part may increase the representation in the primary motor cortex of that body part (23). However, the mechanisms underlying this injury-induced plasticity cannot be elucidated in our study (24).

We used multiple regression analysis to determine the correlating factors of prolonged CCT. This method eliminates the effect of co-linearity and confounding. The results revealed that the change in CCT is significantly correlated with age and physical activity in APB muscles of the dominant hand, and is significantly correlated with age and duration of illness in FDI muscles of the dominant hand. No such correlation was observed in the non-dominant hand. It is not surprising that CCT, which reflects the conduction speed of the fastest fibres in the cortico-spinal pathway, is correlated with age. According to our regression equation, there is approximately 8% prolongation of the CCT per decade of age. This value is higher than the 3% increase per decade observed in the peripheral conduction studies (25). Some factors, other than increased demyelination or decreased synaptic efficiency due to ageing, may also affect the conduction speed in the cortico-spinal tract.

A previous report by Sanes & Donoghue (23) showed that an increase in motor activity could cause central reorganization with increased cortical representation of specific muscle and increased excitability. Since fast conducting fibres, which are usually larger in diameter, could mediate relative powerful movement, the central conduction time is correlated to physical activity. A study by Samii et al. (26) showed prominent evidence in patients with chronic fatigue syndrome who had a reduction in daily activities to less than 50% of the pre-morbid level for at least 6 months. These patients showed significant lower post-exercise MEP facilitation. Another classic study on proficient Braille readers revealed a significantly larger representation area of the FDI muscle (27). On the other hand, patients with an immobilized ankle joint for a mean duration of 16 weeks had reduced motor cortex area of the inactivated tibialis anterior muscle. The reduced area correlated with the duration of immobilization. These changes could be reversed by voluntary ankle movement (28). Thus, the parameters of MEP by TMS may be affected by both physical activity and inactivity. The daily physical activity is generally decreased and largely from the upper extremity in CTCI patients. All of the patients used self-propelled manual wheelchairs. The difference in the level of physical activity came largely from their employment. This is why employment activity was chosen as a surrogate of physical activity.

The time frame is also another key factor to organization. The central nervous system changes after injury can be induced not only in the short-term but also in the long-term (18). Rapid organization, occurring within minutes, can be observed after transient deafferentation (29). Motor reorganization following stroke can also occur after years of onset (30). It is reasonable to assume that duration of a condition contributes to the extent of reorganization. However, our analysis does not determine why only FDI was affected by illness duration.

In the present study, healthy controls had longer PCT in the MEPs from APB and FDI muscles in the dominant hands. The PCT, a parameter deduced from M and F wave latencies, revealed the conduction time of the fastest fibres between the alpha motor neuron and innervated muscle fibre. In a study of healthy individuals, longer latency, smaller amplitude, and slower distal conduction velocity of the sensory nerve were observed in right median and ulnar nerves (31). A similar result was obtained from another study on asymptomatic workers (32). This prolongation of conduction time might result from accumulation of multiple microtraumas to axons during physical activity. However, further study on the correlation of physical activity and the changes in PCT is needed in order to elucidate this mechanism.

A relatively small sample size for multiple regression analysis in the present study may decrease the power of test. However, the limited number of cases in this study was sufficient to achieve positive results. In the future, we will recruit bed-ridden patients who perform less physical activity than the healthy population, in order to verify a prolonged CCT and latency. Furthermore, the parameters of cortical excitability should be included in future studies in order to determine whether reorganization occurs at the level of the brain or the spinal cord (33).

In conclusion, this study verified the prolonged CCT of MEP by TMS in the APB and FDI muscles of dominant hands in patients with chronic CTCI. The prolongation was significantly related to older age, less physical activity and increased duration of CTCI. It further implied that decreased physical activity could result in reorganization in patients with chronic CTCI.

Acknowledgements

We thank all the CTCI patients and healthy controls for their participation in this study. This study was partly sponsored by the National Science Council, Taiwan.

REFERENCES

1. Zanette G, Tinazzi M, Bonato C, di Summa A, Manganotti P, Polo A, et al. Reversible changes of motor cortical outputs following immobilization of the upper limb. Electroencephologr Clin Neurophysiol 1997; 105: 269–279.

2. Topka H, Cohen LG, Cole RA, Hallett M. Reorganization of corticospinal pathways following spinal cord injury. Neurology 1991; 41: 1276–1283.

3. Thomas SL, Gorassini MA. Increases in corticospinal tract function by treadmill training after incomplete spinal cord injury. J Neurophysiol 2005; 94: 2844–2855.

4. Smith HC, Savic G, Frankel HL, Ellaway PH, Maskill DW, Jamous MA, et al. Corticospinal function studied over time following incomplete spinal cord injury. Spinal Cord 2000; 38: 292–300.

5. Davey NJ, Smith HC, Wells E, Maskill DW, Savic G, Ellaway PH, et al. Responses of thenar muscles to transcranial magnetic stimulation of the motor cortex in patients with incomplete spinal cord injury. J Neurol Neurosurg Psychiatry 1998; 65: 80–87.

6. Cariga P, Catley M, Nowicky AV, Savic G, Ellaway PH, Davey NJ. Segmental recording of cortical motor evoked potentials from thoracic paravertebral myotomes in complete spinal cord injury. Spine 2002; 27: 1438–1443.

7. Brouwer B, Hopkins-Rosseel DH. Motor cortical mapping of proximal upper extremity muscles following spinal cord injury. Spinal Cord 1997; 35: 205–212.

8. Alexeeva N, Broton JG, Calancie B. Latency of changes in spinal motoneuron excitability evoked by transcranial magnetic brain stimulation in spinal cord injured individuals. Eletroencephalogr Clin Neurophysiol 1998; 109: 297–303.

9. Leocani L, Comi G. Electrophysiological studies of brain plasticity of the motor system. Neurol Sci 2006; 27 Suppl: S27–S29.

10. Cicinelli P, Traversa R, Rossini PM. Post-stroke reorganization of brain motor output to the hand: a 2-4 month follow-up with focal magnetic transcranial stimulation. Electroencephologr Clin Neurophysiol 1997; 105: 438–450.

11. Roricht S, Meyer BU, Niehaus L, Brandt SA. Long-term reorganization of motor cortex outputs after arm amputation. Neurology 1999; 53: 106–111.

12. Pascual-Leone A, Peris M, Tormos JM, Pascual AP, Catala MD. Reorganization of human cortical motor output maps following traumatic forearm amputation. Neuro Report 1996; 7: 2068–2070.

13. Cohen LG, Bandinelli S, Findley TW, Hallett M. Motor reorganization after upper limb amputation in man. Brain 1991; 114: 615–627.

14. McNulty PA, Macefield VG, Taylor JL, Hallett M. Cortically evoked neural volleys to the human hand are increased during ischemic block of the forearm. J Physiol 2002; 538: 279–288.

15. Papathanasiou I, Filipovic SR, Whurr R, Jahanshahi M. Plasticity of motor cortex excitability induced by rehabilitation therapy for writing. Neurology 2003; 161: 977–980.

16. Behrman AL, Bowden MG, Nair PM. Neuroplasticity after spinal cord injury and training: an emerging paradigm shift in rehabilitation and walking recovery. Phys Ther 2006; 86: 1406–1425.

17. Benecke R, Meyer BU, Freud HJ. Reorganization of descending motor pathways in patients after hemispherectomy and severe hemispheric lesions demonstrated by magnetic brain stimulation. Exp Brain Res 1991; 83: 419–426.

18. Chen R, Cohen LG, Hallett M. Nervous system reorganization following injury. Neuroscience 2002; 111: 761–773.

19. Calancie B, Alexeeva N, Broton JG, Suys S, Hall A, Klose KJ. Distribution and latency of muscle responses to transcranial magnetic stimulation of motor cortex after spinal cord injury in humans. J Neurotrauma 1999; 16: 49–67.

20. Levy WJJ, Amassian VE, Traad M, Cadwell J. Focal magnetic coil stimulation reveals motor cortical system reorganized in humans after traumatic quadriplegia. Brain Res 1990; 510: 130–134.

21. Rossini PM, Barker AT, Berardelli A, Caramia MD, Caruso G, Cracco RQ, et al. Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee. Electroencephologr Clin Neurophysiol 1994; 91: 79–92.

22. Chang CW, Lin SM. Measurement of motor conduction in the thoracolumbar cord. Spine 1996; 21: 485–491.

23. Sanes JN, Donoghue JP. Plasticity and primary motor cortex. Annu Rev Neurosci 2000; 23: 393–415.

24. Muir GD, Steeves JD. Sensorimotor stimulation to improve locomotor recovery after spinal cord injury. Trends Neurosci 1997; 20: 72–77.

25. Introduction to nerve conduction studies. In: Sethi RK, Thompson LL, editors, The electromyographer’s handbook. Boston: Little and Brown Co.; 1989, p. 1–21.

26. Samii A, Wassermann EM, Ikoma K, Mercuri B, George MS, O’Fallon A, et al. Decreased postexercise facilitation of motor evoked potentials in patients with chronic fatigue syndrome or depression. Neurology 1996; 47: 1410–1414.

27. Pascual-Leone A, Cammarota A, Wassermann EM, Brasil-Neto JP, Cohen LG, Hallett M. Modulation of motor cortical outputs to the reading hand of Braille readers. Ann Neurol 1993; 34: 33–37.

28. Liepert J, Tegenthoff M, Malin JP. Changes of cortical motor area size during immobilization. Eletroencephalogr Clin Neurophysiol 1995; 97: 382–386.

29. Metzler J, Marks P. Functional changes in cat somatic sensory-motor cortex during short-term reversible epidural blocks. Brain Res 1979; 177; 379–383.

30. Lee RG, van Donkelaar P. Mechanisms underlying functional recovery following stroke. Can J Neurol Sci 1995; 22: 257–263.

31. Bromberg MB, Jaros L. Symmetry of normal motor and sensory nerve conduction measurements. Muscle Nerve 1998; 21: 498–503.

32. Werner RA, Franzblau A. Hand dominance effect on median and ulnar sensory evoked amplitude and latency in asymptomatic workers. Arch Phys Med Rehabil 1996; 77: 473–476.

33. Talelli P, Greenwood RJ, Rothwell JC. Arm function after stroke: neurophysiological correlates and recovery mechanisms assessed by transcranial magnetic stimulation. Clin Neurophysiol 2006; 117: 1641–1659.