Explaining the cortical and spinal mechanisms of cross-education in humans.

Patients with a certain neurological (stroke) or orthopedic condition (wrist
fracture) could benefit from faster recovery of lost function in the involved
limb. There is emerging evidence to suggest that intensive motor practice with
muscles of one limb improves motor function of the homologous muscles in the
other limb, a phenomenon called cross-education (XED) (1, 4, 19). Meta analyses
suggest that the magnitude of transfer is about ~10% and the highest from the
right-dominant to non-dominant limb in both men and women (12). The most often
measured outcome is maximal voluntary force. Imaging and TMS studies suggest
that the mechanism of transfer is related to the reorganization and enlargement
of activation areas of the brain involved in the unilateral contraction and in
particular, modulation of interhemispheric inhibition via the corpus callosum
(3, 6, 8, 9). Recent studies also showed that XED can reduce the strength loss
produced by immobilization of healthy subjects* wrist (3), suggesting that the
XED-produced changes in voluntary muscle force are clinically meaningful.

A parallel neurological observation is the anatomical existence of the
mirror-neuron system and its functional role in motor rehabilitation. The
mirror-neuron system consists of neurons in the occipital, temporal, and
parietal visual areas and the two frontoparietal motor areas (10, 15). Mirror
neurons discharge action potentials when someone performs a specific motor
action and also when someone observes another individual performing a similar
motor action (5, 15). There is a growing suspicion that the mirror-neuron
system is involved in XED but this idea has not been tested.

A new form for inducing XED would include mirror therapy. The idea of mirror
therapy is that the mirror reflection of the training hand is superimposed over
the untrained hand (11, 13). In other words, when a volunteer performs a hand
grip and sees at the same time the mirror of image of this right hand in a
mirror as if it were the left hand, the notion evolves that the person sees the
left hand exercising. The fake view of the exercising left hand activates
elements of the mirror neuron system, and this activity, we hypothesize,
augments the transfer compared with practice that uses no mirror. Mirror
therapy has been used to help stroke patients with motor skill learning and
also in patients with phantom pain (17, 18) but none of these studies used the
idea to strengthen muscles and capitalize on the combination of mirror therapy
with XED.

In the present study participants will perform 18 session of isometric handgrip
contractions with the dominant right hand. Participant were randomly allocated
to three different groups. The mirror therapy group performed handgrip
contractions while viewing the exercising hand in the mirror, the XED group
performed handgrip contractions while viewing the non-exercising left hand, and
the third group is the non-exercising control group. Main outcome measure is
the maximal voluntary force of the left and right wrist flexors. The secondary
outcome measures are, in the left and right wrist flexors, the size of the
transcranial magnetic brain stimulation (TMS) produced motor evoked potentials
(MEPs), size of the short-interval intracortical inhibition (SICI), size of the
maximal compound size of the maximal spinal reflex (M-wave) and the size of the
spinal excitability, H-reflex. MEPs measure corticospinal excitability. SICI is
the inhibition of the test MEP when a sub-threshold conditioning TMS pulse
precedes by a few milliseconds a supra-threshold TMS test pulse. SICI is a
measure of motor cortical inhibition and can examine cortical influences. The
Hmax/Mmax ratio, on the contrary, is a measure of the spinal influences.

We will address the following questions:
1. Does unilateral exercise with the use of a mirror produce greater
adaptations in the untrained limb than exercise without a mirror?
2. Are the gains in muscle strength associated with changes in corticospinal
and cortical excitability measured in elements of the mirror-neuron system
using TMS?
3. Are the changes in force (behavior) and excitability (mechanism) specific to
the trained muscle group (spatial specificity)?
4. Do the changes outlast the duration of the training period for a month after
the end of the training program?

Our main expectation is that chronic unilateral gripping exercise with the use
of a mirror produces larger adaptations in the untrained target muscle than
exercise without a mirror in healthy young men and women.

Note: Reference numbers correspond with the reference number used in the
research protocol.

Primary objective: To determine if unilateral exercise with the use of a mirror
produces greater adaptations in the untrained limb than exercise without a
mirror.

Secondary objective: To determine corticospinal and cortical mechanisms of
adaptations to unilateral exercise with and without the use of a mirror.

This research project is a randomized clinical trial study with an open and
parallel design. This study contains three different groups and the subjects
are randomly assigned to one of three groups. Subjects will exercise the right
hand because the transfer is the biggest to the left hand when right-handed
individuals exercise the dominant right-hand (2).

Maximal one week before the start of the exercise program subjects will perform
the pre-test and maximal one week after the end of the exercise program they
will perform the post-test. Four weeks after the end of the exercise program
the follow-up measurement will be performed.

Note: Reference numbers correspond with the reference number used in the
research protocol.

Two groups (groups 1 and 2) will exercise three times per week, six week long.
Subject assigned to the third group will not exercise. Groups 1 and 2 will
perform isometric handgrip contractions of the right hand. The training program
will be completed using the handgrip dynamometer (JAMAR) in the same fashion as
for testing (seated position) and is supervised at all times. This was done to
ensure specificity between the strength training and the strength testing task.
The program was progressive in nature, beginning with three sets of eight
repetitions and increasing in volume by one additional set each training day,
up to a maximum training volume of six sets of eight repetitions. The training
program included a taper down to two sets of eight repetitions for the last
training session. The isometric repetitions were 3 seconds long and were
cadenced using a metronome. Participants were given feedback regarding the
force achieved during the repetitions and were given verbal encouragement.
During unilateral training, participants were reminded to completely relax the
non-exercising left arm. The program consisted of 18 training sessions in total.

Group 1, XED group: exercise the right wrist and looking at the left hand with
a view of the right hand blocked.

Group 2, Mirror group: exercise the right hand with a view of the right hand in
the mirror with view of the right hand blocked.

Group 3, Control group: Subjects attend the same number of sessions as groups 1
and 2, grasp the dynamometer but do not exercise. They look at the left hand
with a view of the right hand blocked.

Participant will visit the Center for Human Movement Sciences three times per
week for performing the exercise sessions, and also the control group will
visit the Center for Human Movement Sciences. Every training session will last
for 15 minutes. In total, the subjects will visit the Center for Human Movement
Sciences 18 times. There were no risks for participating in the strength
training program and the load for the joints and limbs is very low.
Furthermore, the training load for the exercising limb is build up gradually
and therefore overtraining will not occur.
Subject have to visit the Center for Human Movement Sciences three times extra
for performing the pre-test, post-test, and follow-up. The measurements will be
identical in all three tests. One testing session will last for maximal 1.5
hours, in which they will have to seat for most of the time. Resting periods of
2-3 minutes are given if needed. A longer resting period of 10 minutes is built
in between the TMS and H-reflex data collection.

Participation in this study comprises electrical stimulation of the medial
nerve and magnetic stimulation of the motor cortex during the performance of
submaximal isometric contractions of the wrist. The TMS may cause slight
discomfort lasting less than a second on the scalp near the coil. It may also
cause some twitching of the muscles, the face and jaw, which may be unpleasant
and surprising but not painful. Peripheral nerve stimulation causes the muscles
to twitch that can be more surprising than painful. It can cause some momentary
burning and tingling sensation. There are no known long-term risks of
peripheral nerve or magnetic brain stimulation. Electromyography (EMG) of the
flexor carpi ulnaris and extensor carpi ulnaris muscles will be recorded.
Therefore the skin underneath the three electrodes will be shaved and cleaned.
This may cause some light irritation of the skin.