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J Appl Physiol 105: 868-878, 2008. First published July 17, 2008; doi:10.1152/japplphysiol.90530.2008
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Neuromuscular plasticity during and following 3 wk of human forearm cast immobilization

Brian C. Clark,1 Lailah C. Issac,1 Jason L. Lane,1 Leatha A. Damron,2 and Richard L. Hoffman1

1Department of Biomedical Sciences, Institute for Neuromusculoskeletal Research, Ohio University, Athens, Ohio; and 2Department of Physical Therapy, SUNY Upstate Medical University, Syracuse, New York

Submitted 16 April 2008 ; accepted in final form 16 July 2008


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Prolonged reductions in muscle activity results in alterations in neuromuscular properties; however, the time course of adaptations is not fully understood, and many of the specific adaptations have not been identified. This study evaluated the temporal evolution of adaptations in neuromuscular properties during and following 3 wk of immobilization. We utilized a combination of techniques involving nerve stimulation and transcranial magnetic stimulation to assess changes in central activation of muscle, along with spinal (H reflex) and corticospinal excitability [i.e., motor-evoked potential (MEP) amplitude, silent period (SP)] and contractile properties in 10 healthy humans undergoing 3 wk of forearm immobilization and 9 control subjects. Immobilization induced deficits in central activation (85 ± 3 to 67 ± 7% ) that returned to baseline levels 1 wk after cast removal. The flexor carpii radialis MEP amplitude increased greater than twofold after the first week of immobilization and remained elevated throughout immobilization and 1 wk after cast removal. Additionally, we observed a prolongation of the SP 1 wk after cast removal compared with baseline (78.5 ± 7.1 to 98.2 ± 8.7 ms). The contractile properties were also altered, since the rate of evoked force relaxation was slower following immobilization (–14.5 ± 1.4 to –11.3 ± 1.0% peak force/ms), and remained depressed 1 wk after cast removal (–10.5 ± 0.8% peak force/ms). These observations detail the time course of adaptations in corticospinal and contractile properties associated with disuse and illustrate the profound effect of immobilization on the human neuromuscular system as evidenced by the alterations in corticospinal excitability persisting 1 wk following cast removal.

electromyogram; motor cortex; motor-evoked potential; muscle; disuse

PROLONGED REDUCTIONS IN SENSORIMOTOR ACTIVITY, such as that associated with bed rest, limb unweighting, and cast immobilization, result in drastic reductions in muscle mass, strength, and motor performance. Although disuse atrophy has fascinated physiologists for well over 150 yr (46) and the molecular pathways of disuse atrophy have received widespread scientific attention (44, 69), much less is known regarding the associated alterations in neural properties (11), despite deficits in central activation of skeletal muscle explaining ~50% of the variability in the loss of strength following prolonged unweighting (8). To what extent reductions in sensorimotor activity alter corticospinal organization and function is poorly understood, despite the need for the identification of the responses and mechanisms of plasticity being needed to help establish therapeutic theories by which to approach motor function and neurorehabilitation.

Immobilization has previously been shown to substantially alter the behavioral and functional properties of motor units. For example, Seki et al. (51) recently reported that a week of hand immobilization reduced the mean firing rate of the first dorsal interosseous during a maximal contraction (51), and Lundbye-Jensen and Nielsen (38) recently reported reduced coupling between motor cortex and spinal motoneuron activity following 1 wk of immobilization as assessed by corticomuscular (EEG-EMG) coherence. These findings of immobilization altering neural properties are consistent with other studies suggesting deficits in motor unit activation with cast immobilization (13, 32), based on their comparisons of forces from voluntary and electrically evoked contractions. Although these findings indicate that maladaptive changes occur in motor function with immobilization, and despite the suggestion that the strength loss observed during the early phases of disuse (i.e., 1–2 wk) is related to neural, rather than contractile, disturbances (11), few systematic investigations have been conducted to evaluate the neuroplastic time course with immobilization and to identify the neurophysiological adaptations.

The technological advancements made over the last couple of decades now allow for detailed and sophisticated in vivo investigations of the human neuromuscular system. For example, transcranial magnetic stimulation (TMS) can be used to transsynaptically activate the motor cortex via electromagnetic induction and permit the study of cortical reorganization. A variety of different measures can be obtained from responses evoked by TMS, such as motor threshold (MT), motor-evoked potential (MEP) amplitude, and the corticospinal silent period (SP). These measures reflect different aspects of corticospinal excitability, with MT primarily related to the electrical susceptibility of the axons on which the stimulus acts, MEP amplitude primarily reflecting corticospinal excitability, and the SP duration measuring inhibitory mechanisms (39).

Several recent investigations have evaluated changes in corticospinal excitability following immobilization, with largely discrepant results ranging from hyperexcitability (66), to no acute effect (31, 50), to hypoexcitability (17) being reported. Although several potential between-study differences may explain these divergent results, it is likely that differences in the cast immobilization protocol duration and the health/injury status of the study populations play a major role. For example, the majority of these studies utilized patients undergoing immobilization due to bone fractures, whereby confounders of pain and inflammation are likely to also modulate central nervous system plasticity (19, 47). The purpose of the present study was to determine the effect and time course of adaptations of 3 wk of hand-forearm cast immobilization on neuromuscular strength and central activation failure, corticospinal excitability and inhibition, spinal excitability, and evoked muscle contractile properties. Additionally, we were interested in the recovery from the immobilization stimuli and evaluated the long-lasting effects on the aforementioned properties. We hypothesized that corticospinal excitability during an active muscle contraction would decrease with immobilization (i.e., prolonged SP and/or reduced MEP amplitude) and that pronounced adaptations would occur after only 1 wk of immobilization.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Design

Ten healthy subjects completed 3 wk of forearm cast immobilization (5 women, 5 men; 21.9 ± 0.5 yr; 169.4 ± 3.2 cm, 77.7 ± 5.0 kg), and nine healthy subjects served as a control group (5 women, 4 men; 24.1 ± 1.50 yr, 171.9 ± 3.2 cm, and 70.0 ± 3.8 kg). The study was approved by the Ohio University Institutional Review Board, and subjects were excluded if they were taking medications or had any known neuromusculoskeletal limitations. Both subject groups had the neuromuscular function of their nondominant arm tested at baseline, which included obtaining measures of resting and active MT, resting MEP amplitude, duration of the SP, H reflex, muscle strength, central activation failure, electrically evoked potentiated muscle peak force, and the rates of evoked force development and relaxation. Subjects were asked not to consume alcohol (abstain for 24 h) or caffeine (abstain for 4 h) before the testing sessions. Testing sessions were performed at the same time of day for each subject. The control subjects were tested again after 3 wk with no intervening activity or procedures (Fig. 1A). At the conclusion of the baseline testing session, the immobilization subjects were fitted with a rigid wrist-hand platform splint (immobilization of the fingers and wrist) with a splint liner on the nondominant forearm, and an arm sling was provided for subject comfort (Fig. 1B) (model 1101-1103, Orthomerica, Orlando, FL). Splints were removed once a week for testing, and 1–2 additional times/wk under laboratory supervision to wash the arm and inspect the limb for complications. After 7, 14, and 21 days of immobilization and 7 days after cast removal, the aforementioned testing session was repeated (Fig. 1A).


Figure 1
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  		Fig. 1. Study design. A: subjects in the experimental group (n = 10) had their nondominant forearm cast immobilized for 3 wk. Their corticospinal function was assessed weekly during the immobilization period and 1 wk after the removal of the cast. Subjects in the control group had their corticospinal function assessed on two separate occasions separated by 3 wk. During each testing session, resting and active motor threshold, motor-evoked potential amplitude, the duration of the silent period, spinal reflex excitability (Hmax/Mmax) and muscular strength were determined. Central activation of the wrist flexors was determined on days 0 and 21. B: schematic of the rigid wrist-hand platform splint used to immobilize the wrist and fingers.

 
Experimental Setup

Electrical recordings.   Electrical signals were recorded from the non-dominant flexor carpi radialis (FCR) using bipolar surface electrodes located longitudinally over the muscle on shaved and cleaned skin with a reference electrode just distal to the medial epicondyle (Ag-AgCl, 8-mm diameter, EL258, interelectrode distance of 25 mm; Biopac Systems, Goleta, CA). The electromyogram (EMG) signals were amplified (500–1,000x), band-pass filtered (10–500 Hz), and sampled at a high sampling rate to obtain high temporal resolution recordings (100 kHz) (MP150, BioPac Systems). Electrode placement was marked with indelible ink for repositioning during subsequent testing sessions.

Mechanical recordings.   To quantify wrist flexion forces subjects were seated with the elbow at 90°, the hand pronated, and the forearm supported and restricted while the head rested on a pad (Fig. 2A) (Biodex System 4, Biodex Medical Systems, Shirley, NY). The wrist joint's axis of rotation was aligned with the axis of rotation of a torque motor to which a lever arm was attached. The signal was scaled to maximize its resolution (208.7 mV per N-M; Biodex Researchers Tool Kit Software), smoothed over a 10-point running average, and sampled at 625 Hz (MP150, BioPac Systems). Subjects received visual feedback of all exerted forces on a 53-cm computer monitor located 1 m directly in front of them.


Figure 2
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  		Fig. 2. The experimental setup for recording mechanical forces (A) and changes in wrist flexion strength during and following forearm cast immobilization (B) (filled symbols, immobilization group; open symbols, control group). As expected, strength decreased significantly with immobilization (P < 0.01), with a 27% decrease after 1 wk (*P = 0.01), a 31% decrease after 2 wk (*P < 0.01), and a 41% decrease after 3 wk of immobilization (*P < 0.01). One week after the resumption of normal activity (recovery), muscular strength returned back to baseline levels. No changes were observed in the control subjects. Stim, stimulation.

 
TMS.   Single-pulse, monophasic waveform magnetic stimuli were delivered using a Magstim 2002 (The Magstim, Whitland, England) magnetic stimulator with a 70-mm figure-of-eight focal coil positioned tangential to the scalp with the handle pointing backward and laterally at 45° from the midline (5). In this position, the induced current flows in a lateral-posterior to medial-anterior direction in the brain, approximately perpendicular to the orientation of the central sulcus, and predominantly activates corticospinal neurons transsynaptically (58). The stimulation location that elicited the largest p-p amplitude of the FCR MEP was identified and marked on a lycra cap for coil placement for all measured outcome variables described below. This procedure was repeated for each testing session.

Electrical stimulation.   Electrical stimulation was delivered to the median nerve in the bicipital groove at the optimal stimulation site identified with a probe (F-BSE1, Astro-Med, West Warwick, MA). Subsequently, stimulation was delivered via surface electrodes with an 8-mm cathode (EL258, Biopac Systems,) and a 35-mm anode located above the cathode (Nikomed Trace 1). The electrical stimuli consisted of 1-ms rectangular pulses (Grass S88, Astro-Med, West Warwick, MA).

Outcome Variables

We assessed a variety of outcome variables in two subject groups at different time points. For subjects in the control group, we obtained measures on two separate days separated by 3 wk. For subjects in the immobilization group, we obtained measures before (baseline), once a week during a 3-wk-long immobilization period, and 1 wk after the cast was removed (recovery) to gain insight into the reorganization of the corticospinal pathways and functional alterations of the neuromuscular system. In an attempt to minimize the potential for the testing sessions to serve as an exercise stimulus, we did not assess central activation failure during the testing sessions on the first and second weeks of immobilization, since this assessment requires several additional maximal voluntary contractions. As such, central activation and the evoked force parameters (peak force and rates of force development and relaxation) were only obtained at baseline, immediately after 3 wk of immobilization, and 1 wk after cast removal.

Maximal voluntary contraction force.   To assess maximal wrist flexion strength, subjects performed a minimum of three maximal voluntary contractions (MVCs) with a 1- to 2-min rest period between each contraction. During testing, strong verbal encouragement was provided by the investigators, visual force feedback was shown, and the highest net value was considered the MVC force.

Central activation of muscle.   To determine what percentage of the total force-generating capacity of the wrist flexors can be produced voluntarily, a combination of voluntary and electrically stimulated contractions were performed following the commonly utilized interpolated twitch technique (40). Briefly, a supramaximal electrical stimulus (100-Hz doublet) was delivered to the median nerve while the subject performed a MVC (Fig. 3A). The increase in force following the stimulation was expressed relative to a potentiated stimulus response obtained immediately after the MVC, and the percentage of the muscle voluntary activated was calculated {%central activation = [1 – (evoked force during MVC/PAP evoked force)] x 100}, where PAP is postactivation potentiation.


Figure 3
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  		Fig. 3. Deficits in central neural activation following cast immobilization and the slowing in contractile properties. A: representative force trace during a maximal voluntary wrist flexion contraction (MVC) coupled with a superimposed electrical stimulus (100-Hz doublet) during and following the MVC. The trace obtained before immobilization (top) yielded little increase in force when the stimulation was applied during the MVC, whereas following immobilization (bottom) a substantial increase in force is observed, suggesting an inability to voluntarily achieve maximal muscle activation. B: changes in the average central activation in subjects undergoing 3 wk of forearm cast immobilization (filled symbols) and control subjects (open symbols). A deficit in central activation of the musculature was observed following 3 wk of immobilization (cast removal) compared with baseline (*P = 0.03) and 1 wk after cast removal (recovery; *P = 0.04). No changes were observed in the control subjects. C: changes in the rates of evoked force development and relaxation before (baseline), following 3 wk of immobilization (cast removal), and 1 wk after cast removal (recovery). A slowing in the rate of force relaxation was observed following cast removal (P = 0.05) and recovery compared with baseline (*P = 0.03). The rate of force development did not slow significantly, although a modest effect size (ES) was observed ({dagger}P = 0.06).

 
Muscle contractile properties.   To identify changes in the functional properties of the wrist flexor muscles, we evaluated the force-time curves evoked from an electrical doublet (100 Hz) delivered ~1 s following a 5-s MVC (postactivation potentiated doublet) (Fig. 3A). Two trials were performed and averaged for calculating peak force, the relative rate of evoked force development between 10 and 90% of peak force (+dF/dt), and the relative rate of force relaxation between 90 and 50% of peak force (–dF/dt).

H reflexes and maximal compound muscle fiber action potential.   To determine whether immobilization induced changes in spinal excitability, we measured the amplitude of the H reflex. The H reflex is a spinal reflex response resultant from submaximal electrical stimulation of sensory nerve fibers that project back on and excite the {alpha}-motorneurons (68). We normalized the evoked H waves to the maximal compound muscle fiber action potential (Mmax) to control for potential changes in muscle cell membrane properties associated with immobilization.

Before eliciting the FCR H reflex, the maximal p-p amplitude of the M wave (Mmax) was determined with supramaximal electrical stimulation as we have previously described (6, 8). Subsequently the FCR H-reflex was elicited between seconds 3 and 4 of a 5-s steady isometric wrist flexion contraction at 15% MVC in which subjects matched a target force line located on a monitor, and a recruitment curve was developed by gradually increasing the stimulation intensity. The 15% contraction intensity was based on the MVC obtained on each testing day; thus the contraction intensity was set at the same relative intensity over repeat sessions. To minimize fatigue, 10–20 s separated each contraction trial, and ~40–60 pulses at varying intensities were delivered, with the majority of these stimuli being at an intensity surrounding maximal p-p amplitude of the H wave. The H waves were identified by criteria previously proposed (41), and the three highest H waves observed were averaged to represent the Hmax and normalized to the Mmax ([Hmax/Mmax] x 100).

Resting and active MT.   To determine whether immobilization induced changes in the orientation, density, and electrical susceptibility of the cortical neurons, we measured resting MT. Alterations in resting MT can reflect changes at a variety of levels [i.e., the neural membrane, axonal electronic properties, the structure and number of excitatory projections onto the primary motor cortex, or upregulation of receptors in this region (39)] and hence represents a global assessment of the membrane excitability of pyramidal neurons (39, 70). We also measured changes in the active MT. Voluntary contraction results in a reduction in MT compared with resting conditions, which is thought to be indicative of the magnitude of voluntary motor drive to the corticomuscular pathway (56).

MTs were determined while subjects were seated in the dynamometer (Fig. 2A) by delivering single-pulse TMS (minimum of 10 s between pulses) at gradually increasing stimulation intensities. Stimulation began at intensities well below threshold and was increased in 1% increments until the TMS intensity that induced suprathreshold MEPs was observed. Resting MT was defined as the lowest intensity of stimulation required to evoke MEPs with a p-p amplitude of ≥50 µV in at least 5 of 10 trials. During this assessment, the muscle was completely relaxed as monitored by the EMG signal. During the active MT assessment, subjects performed an isometric wrist flexion contraction at a target force of 15% MVC. Before the active MT determination began, subjects performed a minimum of six trials during which the interference/background EMG associated with the target force level was recorded. The maximum peak-to-peak amplitude associated with the voluntary contraction trials were averaged and considered the maximum EMG activity during a 15% of maximum contraction, and the active MT was subsequently defined as the lowest TMS intensity required to evoke MEPs with a peak-to-peak amplitude greater than or equal to two times that present in at least 5 of 10 of these voluntary trials. We chose to quantify threshold in this manner rather than using an absolute voltage (i.e., 300 µV) in an attempt to minimize the influence of the numerous well known factors that influence the amplitude of the voluntary signal, which are likely to have been altered with repeat measurements (18). MTs are reported as a percentage of the maximal TMS stimulator output.

MEP amplitude and the SP.   To determine whether immobilization induced changes in corticospinal excitability, we measured the amplitude of the MEP at rest. When TMS is applied to the motor cortex at an intensity above MT, high-frequency indirect waves (I waves) are elicited in the corticospinal tract (12), which are modifiable by many mechanisms including neurotransmitters (i.e., glutatmate, GABA), modulators of neurotransmission (i.e., acetylcholine, norepinephrine, and dopamine) (70), and interneurones contacted by corticospinal tract cells (29) with the actual efficacy of the corticomotoneuronal synapse itself demonstrating some activity-dependent changes (21) all functioning to influence the amplitude of the MEP. To assess changes in immobilization-induced inhibitory effects, we measured the duration of the SP. There are several mechanisms thought to contribute to the SP, with spinal inhibitory mechanisms thought to be active in the early part and the latter part being specifically cortical in its origin and most likely mediated by GABAergic and dopaminergic cortical inhibitory mechanisms (5, 20, 30, 73).

To assess changes in MEP amplitude at rest (Fig. 5A), single pulses were delivered at 130% of resting MT. The p-p amplitude of the MEPs were calculated and averaged over 7 trials and normalized to the Mmax and multiplied by 100 ([MEP/Mmax] x 100). Additionally, we applied seven trials of suprathreshold stimulation (130% of active MT) during tonic voluntary contractions at 15% MVC from which we quantified and averaged the duration of the SP (Fig. 6A). We chose this stimulus intensity based on our previous findings of the SP evoked at this intensity being more reliable than lower intensities (i.e., displaying less systematic bias) (10). These SP analyses were performed by a single, blinded investigator visually defining the SP onset as the initial deflection (positive or negative) of the MEP, and the SP offset as the return of the interference EMG was defined as the first positive of negative deflection of the EMG signal associated with the resumption of voluntary EMG activity. We previously reported that this quantification method displays high interrater reliability (r = 0.97) and a week-to-week coefficient of variation among healthy subjects of ~12% (10).


Figure 5
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  		Fig. 5. Increase in resting motor evoked potential (MEP) amplitude during and following immobilization. A: representative EMG traces of the resting MEPs evoked with a stimulus intensity of 30% above motor threshold for one subject at baseline (solid trace) and after 3 wk of cast immobilization (shaded trace). B: changes in the resting MEP amplitude in subjects undergoing 3 wk of forearm cast immobilization (hatched bars) and after 1 wk of the restoration of activity via cast removal (shaded bar). A time main effect was observed (P = 0.03; ES = 0.25) with post hoc testing indicating the MEP amplitude was significantly larger than the baseline values after 1 wk (day 7; *P < 0.01), 2 wk (day 14; *P = 0.02), and 3 wk (day 21; *P < 0.01) of immobilization, and the elevated MEP amplitude persisted 1 wk after the cast was removed (day 28; *P = 0.01). No changes were observed in the control subjects.

 

Figure 6
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  		Fig. 6. Prolongation of the silent period (SP) exists 1 wk following 3 wk of forearm cast immobilization. A: representative EMG traces for one subject at baseline (black bottom trace), immediately following 3 wk of cast immobilization (medium gray middle trace) and following 1 wk of recovery from the immobilization period (light gray upper trace). Note the return of the voluntary EMG signal occurring progressively later during the recovery condition. B: average changes in the SP in subjects undergoing 3 wk of forearm cast immobilization (hatched bars) and after 1 wk of the restoration of activity via cast removal (gray bar). A time main effect was observed (P = 0.05; ES = 0.22) with post hoc testing indicating the SP duration was significantly longer 1 wk after the cast was removed (day 28) compared with baseline (day 0; *P = 0.03) and 1 wk of immobilization (day 7; *P = 0.01). A prolonged mean SP duration was observed immediately after 3 wk of immobilization (day 21), but this change did not reach statistical significance ({dagger}P = 0.10). No changes were observed in the control subjects. C: no changes were observed in the active MEP amplitude in the immobilization group (P = 0.55) or the control group (P = 0.99).

 
Statistics

Repeated-measures analysis of variance procedures followed by least significant difference post hoc tests were utilized to determine changes over time. Immobilization group data and control group data were analyzed separately. The control group data were used to assess repeatability of the experimental measures, and the immobilization group data were used to determine the time course of adaptations to immobilization. For all analyses, a preset {alpha}-level of significance equal to 0.05 was required for statistical significance. The SPSS statistical package (version 14.0, Chicago, IL) was used for data analysis. Data are presented as means ± SE. Additionally, to further aid in interpretation, we also report the effect size (ES; partial {eta}2), which represents the proportion of total variation attributable to a given factor when partialing out other factors from the total nonerror variation.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Muscular Strength and Central Activation

As would be expected with limb immobilization (15, 51–53, 65), we observed a reduction in wrist flexion strength (Fig. 2B; P < 0.01; ES = 0.43), with a 27% reduction in MVC force already observed after the first week of immobilization (P = 0.01), which remained lower than baseline levels during the second and third weeks (total reductions of 31 and 41%; P ≤ 0.01) and returned back to baseline levels 1 wk after the cast was removed (P = 0.14). Strength did not change in the control group (Fig. 2B; P = 0.24; ES = 0.17).

Following 3 wk of immobilization, a significant reduction in central activation was observed (Fig. 3; P = 0.01; ES = 0.38), with the maximality of muscle activation decreasing from 85.6 ± 3.4% at baseline to 66.7 ± 6.8% after immobilization (P = 0.03). This observed neural deficit in activation had returned to baseline levels a week after the cast was removed. Central activation did not change in the control group (Fig. 3; P = 0.81; ES = 0.01).

Muscle Contractile Properties

Evoked potentiated peak force did not change over time in the immobilization or control groups (immobilization group, baseline: 1.72 ± 0.27 N·m; 3 wk of immobilization: 1.56 ± 0.30 N·m; 1 wk after cast removal: 2.00 ± 0.40 N·m; P = 0.51; ES = 0.07) (control group: 2.28 ± 0.29 vs. 2.12 ± 0.21 N·m; P = 0.63; ES = 0.03). The +dF/dt did not significantly change with immobilization (P = 0.06), although a modest ES was observed for a slight slowing in the relative rate of force development (ES = 0.26) (Fig. 3C). The +dF/dt did not change in the control group (15.47 ± 0.65 vs. 15.78 ± 1.11% peak force/ms) (P = 0.77; ES = 0.01). Immobilization resulted in a slowing in the rate of evoked force development following immobilization that remained depressed 1 wk after cast removal compared with baseline (P = 0.01; ES = 0.38) (Fig. 3C). The –dF/dt did not change in the control group (–12.97 ± 2.02 vs. –14.05 ± 2.00% peak force/ms) (P = 0.59; ES = 0.04).

Spinal Reflex Excitability

Hmax/Mmax excitability did not change over time in the immobilization or control groups (immobilization group: baseline: 38.2 ± 4.9%; 1, 2, and 3 wk of immobilization: 47.3 ± 7.7, 38.8 ± 7.2, 38.2 ± 4.5%, respectively; 1 wk after cast removal: 35.8+4.6%; P = 0.42; ES = 0.10) (control group: 60.1 ± 6.1 vs. 64.6 ± 6.0%; P = 0.60; ES = 0.04). Additionally, the Mmax did not change over time in the immobilization or control groups (immobilization group: baseline: 6.0 ± 1.1 mV; 1, 2, and 3 wk of immobilization: 5.2 ± 0.9, 5.4 ± 1.1, 5.3 ± 0.8 mV, respectively; 1 wk after cast removal: 5.9 ± 1.3 mV; P = 0.31; ES = 0.12) (control group: 6.29 ± 0.68 vs. 5.84 ± 0.49 mV; P = 0.63; ES = 0.03).

Resting and Active MT

Resting MT did not change with immobilization (Fig. 4A; P = 0.77; ES = 0.05); however, active MT exhibited a temporal adaptation (Fig. 4B; P = 0.04; ES = 0.23), with a relative decrease of ~12% in active MT occurring after the first week of immobilization compared with baseline and all other time points (Fig. 4B; P = 0.04). Neither resting nor active MT changed in the control group (Fig. 4; RMT: P = 0.56; ES = 0.04; AMT: P = 0.91; ES < 0.01).


Figure 4
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  		Fig. 4. Changes in resting (A) and active (B) motor threshold (MT) in subjects undergoing 3 wk of forearm cast immobilization (filled symbols) and control subjects (open symbols). Resting MT was unaltered with immobilization (P = 0.77; ES = 0.05). A time main effect was observed for active MT (P = 0.04; ES = 0.23), with post hoc testing indicating a significant reduction after 1 wk of immobilization (day 7) compared with all other time points (*P = 0.04).

 
MEP Amplitude and the Cortical SP

Immobilization resulted in an increase in the resting MEP amplitude (Fig. 5; P = 0.03; ES = 0.25). A greater than twofold increase was observed after as little as 1 wk of immobilization (P < 0.01) and remained elevated slightly above this level throughout the immobilization period as well as 1 wk after cast removal (P < 0.02). Resting MEP amplitude did not change in the control group (5.1 ± 1.3 vs. 6.9 ± 2.5%; P = 0.43; ES = 0.08).

Immobilization resulted in prolongation of the SP duration (P = 0.05; ES = 0.22), with a significant 20% increase in duration being observed 1 wk after the cast was removed compared with values at baseline (P = 0.03) and after 1 wk of immobilization (P = 0.01) (Fig. 6). A similar mean prolongation (18%) in the SP was observed after 3 wk of immobilization compared with baseline; however, this difference failed to reach statistical significance (P = 0.10). The SP duration did not change in the control group (96.9 ± 7.4 vs. 98.3 ± 8.0 ms) (P = 0.87; ES = 0.00). It should be noted that the active MEP amplitudes preceeding the SP did not change with immobilization (P = 0.55; ES = 0.08) (Fig. 6), nor did statistically covarying for the active MEP amplitude alter the results, and as such it does not appear that any alterations in active MEP amplitude with immobilization would have contributed to the lengthening of the SP. Active MEP amplitude did not change in the control group (33.9 ± 4.8 vs. 34.0 ± 6.2%; P = 0.99; ES = 0.00).


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study evaluated the temporal evolution of neuromuscular adaptations to limb immobilization with a special emphasis on corticospinal plasticity. Among the most novel findings are our observations of limb immobilization causing temporally progressive alterations in corticospinal excitability that are reflected primarily in the characteristics of MEPs and that persist for up to a week following cast removal (Figs. 4–6). Most notably, we observed that, under resting conditions, MEP amplitude increased after as little as 1 wk of forearm immobilization and remained elevated for the duration of the limb immobilization protocol as well as 1 wk after cast removal (Fig. 5). Additionally, we observed that, during a voluntary contraction, the SP became prolonged 1 wk after cast removal (Fig. 6) with no change in the active MEP amplitude, which suggests an increase in corticospinal inhibition during a voluntary submaximal muscle contraction. Other significant findings in the present study are limb immobilization causing deficits in central activation of muscle (Fig. 3B) and a slowing in muscle contractile properties that remain depressed 1 wk after cast removal (Fig. 3C).

Several of these findings are in contrast to our initial hypothesis, which was that corticospinal excitability during an active muscle contraction would decrease with immobilization and that the most pronounced adaptations would occur after 1 wk of immobilization. For example, the prolongation of the SP gradually increased over the 3-wk immobilization period and remained elevated 1 wk after cast removal. As such, this adaptation did not follow the same time course of changes in strength and central activation, as both were returned toward baseline levels 1 wk after cast removal, which raises the question of the functional implication of the immobilization-induced alterations.

There are several plausible mechanisms explaining our finding of an increased size of the motor response (MEP amplitude) during and following immobilization at rest. For example, it could be resultant of a change in the motor map area or an increase in the excitability of a given projection area as neurotransmitters are well known to affect MEP size due to the complex modulating effects of dopamine, norepinephrine, serotonin, and acetylcholine on inhibitory and excitatory synaptic transmission in neocortical neural networks (70), both of which have been observed to occur under conditions of deafferentation in animals (3, 43). It could also be modulated by changes in the excitability of interneurones contacted by corticospinal tract cells, as the corticospinal pathway has been shown to converge on the interneurones of reciprocal and nonreciprocal motoneurones (29). Additionally, the actual efficacy of the corticomotoneuronal synapse itself shows large activity-dependent changes following voluntary activity, since sustained fatiguing MVCs have been reported to depress MEP amplitude in response to corticospinal stimulation (21). We also observed a prolongation of the SP, which has been suggested to be regulated by long-lasting cortical inhibition, mainly GABAB receptors (33). Thus our observation of increases in MEP amplitude at rest during and following immobilization suggests increased excitability of the corticospinal pathway, whereas a lengthened SP following immobilization during contraction suggests increased inhibition. It is difficult to say whether these neuroplastic changes are beneficial, maladaptive, or a relative combination of the two. However, because these two antipodal adaptations differ temporally, it appears that they are mediated by different mechanisms, with the corresponding changes following immobilization perhaps serving antagonistically to achieve a relative balance between excitatory and inhibitory balance. However, it is also possible that the differential adaptations are due to the conditions under which they are obtained (resting vs. active contraction), since task-specific adaptations have been observed for changes in spinal excitability following resistance exercise training (the opposite paradigm of disuse) (1). Additionally, it is possible that the scaling of the target force relative to MVC, vs. an absolute force, may explain these findings since the absolute force would have decreased during immobilization due to the corresponding loss of strength. It has previously been reported that alterations in synergistic muscle activity occur following disuse (45, 54, 64), although our laboratory has not observed this phenomenon during a submaximal task expressed relative to maximal strength following unweighting (9). However, if changes in synergistic activity did occur in the present study, the utilization of a target, vs. a target EMG level, may be a limitation of the present study.

We did not observe a significant change in spinal reflex excitability, which is inconsistent with our previous work reporting an increased soleus H reflex following 4 wk of lower limb suspension (8). It is difficult to know what explains this discrepant finding, but it is possible that it is related to the disuse model (limb suspension vs. immobilization), the muscle groups tested (soleus vs. FCR), or the experimental conditions the H reflexes were elicited under, since we elicited H reflexes at rest during our limb suspension work, whereas in the current study they were evoked during a voluntary muscle contraction, although recent work from Lundbye-Jensen and Nielsen reported increased excitability of the FCR H-reflex pathway under both resting and active (10% MVC) conditions following 1 wk of forearm immobilization (38). However, when we closely compare the results from this study to the present one, it appears that the increase in the Hmax/Mmax after 1 wk of immobilization is relatively similar. For example, they report a mean increase from ~33% at baseline to 44% (absolute increase of 11%) after 1 wk of immobilization, whereas we observed a mean change from ~38 to 47% (absolute increase of 9%). As such, although we did not observe a significant change in the H reflex with immobilization, it appears there was a trend for an acute increase after 1 wk of immobilization that returned toward baseline during the latter weeks. It is interesting that the mean baseline values between our immobilization and control groups were substantially different, for which is difficult to understand. It should be noted that the subjects in the immobilization group exhibited baseline values similar to that reported by others using a comparable protocol (38). We do not believe the mean baseline differences are due to a systematic bias between subject groups since the subjects were similar in other parameters, but rather we believe what is a more important issue than subtle baseline differences between groups is that the individuals in the control group did not change over time.

We did not observe a change in the resting MT (Fig. 4), indicating that immobilization did not cause an alteration in the overall membrane excitability of pyramidal neurons (39, 70). Interestingly, we did detect a significant, reduction in the active MT after 1 wk of immobilization (Fig. 4). Although we did not observe any significant changes in the H reflex with immobilization, there was a tendency for a mean increase in the active H reflex after 1 wk of immobilization, which returned to baseline during subsequent weeks. As such, it is possible that our observed reduction in active MT is explained by temporal changes in spinal reflex excitability; however, because we did not obtain H-reflex measures at rest, it is difficult to determine this. Additionally, although differences between resting and active MT are not fully understood, it could also be due to the magnitude of voluntary motor drive (56). Immobilization has been shown to reduce the coupling between descending motor cortex commend and {alpha}-motoneuron activity (38), and it is possible that this finding is related to a change in corticomuscular coherence. It has also been suggested that voluntary drive suppresses the activity of intracortical inhibitory neurons (49), which could also explain this finding.

Another interesting finding of the present study, which is consistent with previous findings (32, 55), is that immobilization resulted in a decreased ability of the nervous system to fully activate the target musculature. It is well known that neural deficits in muscle activation are explained by two primary mechanisms with either not all the motor units being recruited and/or suboptimal rate coding (i.e., maximal motor unit discharge rate, doublet discharge, etc.) (14). The motoneuron and its behavior are the "final common pathway" for motor commands, and the motoneuron pool is influenced by numerous factors, such as dendritic synaptic input current from peripheral and supraspinal sources (26, 27). It was recently shown that 1 wk of hand immobilization decreased the mean firing rate of the first dorsal interosseous during a maximal contraction from 39 to 33 (51). Thus it seems likely that our observation of a decreased central activation is explained, at least in part, by a suboptimal motor unit firing rate. It is not apparent what the functional impact of the immobilization-induced cortical reorganization is on the motor unit properties, and future work is needed to determine the effect of these adaptations on motoneuron behavior as well as on functional properties such as muscular strength and motor control.

This is not the first study to evaluate corticospinal adaptations to cast immobilization (17, 28, 31, 37, 38, 50, 66, 67), and other pertinent models such as deafferentation have explored similar questions (19, 22, 48, 59, 60, 71, 72). Among the cast-immobilization studies, largely discrepant results have been reported on the acute effects of cortical excitability. Several potential explanations may explain these divergent results such as differences in the muscle groups being evaluated, as well as differences in the experimental designs of the reported studies, since the majority of these utilized patients undergoing immobilization due to bone fractures whereby confounds of pain and inflammation are likely to also modulate central nervous system plasticity (19, 47). Among the studies using an experimental casting approach controlling for pain influences, incongruent findings still exist since 10 days of lower leg immobilization were reported to not alter corticospinal excitability immediately after cast removal but rather to facilitate it 24 h later and then return to baseline 48 h after cast removal (50), whereas 4 days of finger immobilization focally reduced excitability with a return to baseline 3 days after cast removal (17). Most recently, a 1-wk forearm immobilization protocol reported an increase in the H-reflex excitability without any concomitant changes in MEPs (38). It is likely that these discrepant findings are related to differences in the muscle groups evaluated, the duration of immobilization, and the conditions under which the measures were obtained (rest vs. active) since we observed an increase in MEP amplitude at rest but not during an active contraction.

With respect to the immobilization-induced adaptations in the muscle contractile properties, we observed a slowing in the rate of force relaxation, which remained for at least 1 wk following cast removal. There is wide discrepancy in the literature regarding changes in relaxation properties with disuse, with some reports suggesting a slowing (15, 57) and others reporting no change (7, 24, 52). Although it is difficult to definitely determine from our data the mechanism explaining our observed reduction in the rate of relaxation, it is likely that it is related to a slowing in the rate of cross-bridge detachment and/or calcium reuptake (2, 4, 23, 61–63). With respect to the rate of force development, we did not observe a significant change following immobilization; however, we did observe a modest ES. As such, we must caution of the possibility of our findings containing a type II statistical error (error of failing to observe a difference when in truth there is one). Previous studies examining contractile force development properties following prolonged disuse have reported both a slowing in force development and/or prolonged time to peak tension (7, 13, 34), as well as no change (15, 52). There are several mechanisms regulating contractile force development that may explain disuse-induced alterations such as fiber-type composition (25), tendon stiffness (35), and the amount and rate of sarcoplasmic reticulum Ca2+ release (16, 36, 42). We did not observe any change in the maximal force of a postactivation potentiated-evoked contraction, which is consistent with our earlier findings (7). However, we should note that we have previously reported a reduction in resting muscle force but a maintenance of potentiated muscle force; thus it is possible that we would have observed differential outcomes if resting force production had been assessed.

In summary, we observed an increase in the amplitude of MEPs with 3 wk of forearm cast immobilization, whereby the MEP increased under resting conditions within 7 days of immobilization and remained elevated throughout the course of the study, including 1 wk after the restoration of sensorimotor activity (cast removal), suggesting motor cortical hyperexcitability since no change in the excitability of the spinal reflexes were observed. Additionally, we observed that 1 wk after cast removal the SP was prolonged, indicating increased inhibition during an active contraction. We also observed pronounced deficits in central activation of the wrist flexor muscles immediately after 3 wk of immobilization and a slowing in the muscle contractile mechanical properties after immobilization and 1 wk after cast removal. These findings provide insight on the basic alterations and time course of adaptations in corticospinal and contractile properties associated with disuse and function to illustrate the profound effect of immobilization on the human neuromuscular system as evidenced by the persistence of the adaptations remaining for at least 1 wk following recovery from the immobilization stimuli. Additionally, these findings should be considered when developing therapeutic theories to motor function and neurorehabilitative approaches targeting these responses and mechanisms.


   FOOTNOTES
 

Address for reprint requests and other correspondence: B. C. Clark, Dept. of Biomedical Sciences, 211 Irvine Hall, Ohio Univ. College of Osteopathic Medicine, Athens, OH 45701 (e-mail: clarkb2{at}ohio.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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