Modulation of motor cortex excitability after upper limb immobilization

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Abstract

Objective

To examine the mechanisms of disuse-induced plasticity following long-term limb immobilization.

Methods

We studied 9 subjects, who underwent left upper limb immobilization for unilateral wrist fractures. All subjects were examined immediately after splint removal. Cortical motor maps, resting motor threshold (RMT), motor evoked potential (MEP) latency and MEP recruitment curves were studied from abductor pollicis brevis (APB) and flexor carpi radialis (FCR) muscles with single pulse transcranial magnetic stimulation (TMS). Paired pulse TMS was used to study intracortical inhibition and facilitation. Compound muscle action potentials (CMAPs) and F waves were obtained after median nerve stimulation. In 4/9 subjects the recording was repeated after 35–41 days.

Results

CMAP amplitude and RMT were reduced in APB muscle on the immobilized sides in comparison to the non-immobilized sides and controls after splint removal. CMAP amplitude and RMT were unchanged in FCR muscle. MEP latency and F waves were unchanged. MEP recruitment was significantly greater on the immobilized side at rest, but the asymmetry disappeared during voluntary muscle contraction. Paired pulse TMS showed an imbalance between inhibitory and excitatory networks, with a prevalence of excitation on the immobilized sides. A slight, non-significant change in the strength of corticospinal projections to the non-immobilized sides was found. TMS parameters were not correlated with hand dexterity. These abnormalities were largely normalized at the time of retesting in the four patients who were followed-up.

Conclusions

Hyperexcitability occurs within the representation of single muscles, associated with changes in RMT and with an imbalance between intracortical inhibition and facilitation. These findings may be related to changes in the sensory input from the immobilized upper limb and/or in the discharge properties of the motor units.

Significance

Different mechanisms may contribute to the reversible neuroplastic changes, which occur in response to long-term immobilization of the upper-limbs.

Introduction

Evidence from animal and human experiments suggests that neuroplastic changes may occur in sensorimotor areas of the adult nervous system following modification of somatic afferences or of motor output (Jones, 2000, Sanes and Donoghue, 2000). Learning new motor skills (Pascual-Leone et al., 1995) and performing skilled motor activities (Elbert et al., 1995) result in an expansion of the representation of the muscles involved in the task. Complete long term sensorimotor deafferentation, as in the case of limb amputation (Chen et al., 1998, Cohen et al., 1991, Kew et al., 1994, Ridding and Rothwell, 1997, Wu and Kaas, 1999) and peripheral nerve lesions (Rijntjes et al., 1997, Tinazzi et al., 1998), as well as short term deafferentation secondary to ischemic nerve block (Brasil-Neto et al., 1993, Ridding and Rothwell, 1997, Ziemann et al., 1998a, Ziemann et al., 1998b), result in an expansion of the surrounding representations.

While a great deal of experimental evidence has been gathered on neuroplasticity following sensorimotor deafferentation, little is known about the changes taking place after limb disuse. This condition is associated with sensorimotor restriction, which is functionally different from the complete deafferentation following nerve lesions or limb amputation. Animal studies suggest that sensory impoverishment may determine changes in the organization and size of cortical receptive fields in the somatosensory cortex (Coq and Xerri, 1999, Langlet et al., 1999). The vast majority of studies on the effects of long term immobilization in humans have examined changes in the contractile properties of skeletal muscle (Desaphy et al., 2001, Seki et al., 2001b) or motor units (Seki et al., 2001a). Only two reports to date have documented central motor changes in neurologically normal subjects who wore splints for more than four weeks because of fractures of the wrist (Zanette et al., 1997) or the leg (Liepert et al., 1995). These two transcranial magnetic stimulation (TMS) studies yielded conflicting results, because the latter found a reduction in the motor maps of immobilized muscles, while the former reported maps of normal area, but greater responses to TMS. Data from stroke patients, treated with constraint-induced therapy (Taub et al., 2002) are able to add little information on the topic, because motor stroke per se is capable of inducing very extensive bilateral cortical reorganization (Liepert et al., 2000).

The experimental model of limb disuse offers a unique opportunity to evaluate the changes taking place within the representation of the immobilized body parts. Most of the studies on neuroplasticity have been conducted on surviving body parts or nerves and can provide only indirect information on the changes occurring in the deprived cortical areas. To date there has been only one report evaluating the functional correlates of somatosensory reorganization within the representation of injured nerves (Moore and Schady, 2000).

In an attempt to better understand the mechanisms of motor changes after long term sensorimotor restriction, we applied TMS to nine patients, whose left upper limbs were immobilized for wrist fractures. The study was aimed at elucidating different points. The first was to evaluate the contribution of the motor cortex in the generation of motor hyperexcitability. The second was to understand whether the changes in motor maps represent true representational plasticity or the presence of a different level of ‘rest’ of the corticospinal system (Siebner and Rothwell, 2003). The third point was to test if any change took place in the representation of the unrestricted limb. Finally we were interested in establishing a correlation between indices of motor excitability and hand function. It is common experience that hand movements are clumsy after splint removal. Even though mechanical factors, such as stiffness of joint and muscle and the lack of motor practice play a role in worsening hand dexterity, cortical changes may contribute to the clumsiness, due to the importance of the motor cortex in fine hand movements. To these aims, we studied resting motor threshold (RMT) in response to TMS, motor cortical maps, TMS recruitment curves, intracortical inhibition (ICI) and facilitation (ICF) and F waves in our patients. In this experimental setting we could not obtain baseline (prior to fracture) data for the patients, thus we compared immobilized vs normal sides of patients and patients vs normal controls. The possible correlation between the abnormalities and hand dexterity was studied. Patients were re-tested 5–6 weeks later to understand to which extent the changes were reversible.

Section snippets

Subjects

We studied 9 patients (4 males, 5 females), aged 18–52 years (mean age 36.9±11.7 years), who wore splints for traumatic fractures of the left wrist. None of them underwent surgical treatment of the fracture. None of the patients had any history of neurological disease. The mean duration of immobilization was 37.4±4.4 days (range 30–45 days). The splints immobilized the wrist, elbow and metacarpo-phalangeal joints and the upper limb was fixed in a mid-range flexion-extension position. There was

Results

ANOVA showed a significant effect of the side on manual dexterity [F(3, 44)=156.7, P<0.001]. No differences were found between the right (14.5±3.2 s) and left sides (15.6±4.2 s) of normal controls and the free sides of patients (15.1±4.5 s). The patients took significantly longer to complete the test on the immobilized side (34.4±5.7 s; P<0.001).

Significant reductions in CMAP amplitude [F (3, 44)=4.8, P<0.01; patients' immobilized sides vs controls' left sides, P=0.02; patients' immobilized vs

Discussion

This is the first report elucidating the mechanisms underlying motor reorganization in the representation of muscles undergoing sensorimotor restriction related to upper limb immobilization. The area and CoG of motor maps of immobilized muscles at rest did not change in our patients. Rather we found larger map volumes and steeper MEP recruitment curves at rest on the immobilized sides. MEP recruitment asymmetries disappeared during voluntary contraction. Imbalance between ICI and ICF, resulting

Acknowledgments

The authors wish to thank Mr Dino Volpato for his technical assistance, Dr Antonio Forgione for his help with the experimental recordings and Dr Nicos Giotakis for patient referral.

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