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Microsoft word - parkinsons neurology journal submission 1.doc
Computer-Based Motor Training Activities Improve
Function in Parkinson’s Disease: a Pilot Study
The Parkinson’s Institute, 1170 Morse Avenue, Sunnyvale, CA 94089
This study was supported by a grant from Interactive Metronome
This pilot study examined the effect of computer-based motor training
activities upon the severity of signs and symptoms in patients with mild or moderate Parkinson’s
Thirty-six subjects were randomly assigned to train using the Interactive
Metronome (IM) device, which provides training for rhythmicity and timing, or to a control
regimen consisting of motor activities directed by a rhythm or a computer (e.g., clapping or
exercising to music or to a metronome tone or playing computer games). The severity of
parkinsonism was compared before and after 20 hour-long training sessions as measured by the
Unified Parkinson’s Disease Rating Scale (UPDRS) part 3 and, as secondary measures, the
UPDRS part 2, the Hoehn and Yahr stage, a timed finger tapping test, and the timed “Up & Go”
Twelve subjects completed training with the IM device and nine completed the
control regimen. Both groups improved in the scores on the UPDRS part 3 and the two timed
tests. Those patients trained on the IM device showed slightly more improvement, but the
difference between the two groups was not statistically significant. The IM-trained group
improved in the UPDRS part 2 score, but the control group did not. Neither group changed in the
Hoehn and Yahr stage. Conclusions:
These results suggest that computer-based motor training
regimens might be useful for improving or retaining motor function in Parkinson’s disease.
Parkinson’s disease is a neurodegenerative disorder that impairs motor function. There are a
number of pharmacologic therapies that are effective in alleviating the symptoms, but these
drugs all have side effects that can limit their use. Non-pharmacologic treatments can thus play
an important and useful role in this disease. In fact, approaches of this type are frequently sought
out by many patients who are looking for therapies that do not involve taking medications.
Exercise (as part of a regimen of physical therapy and otherwise) has often been
recommended as a component of the overall treatment program for Parkinson’s disease, and
there are a number of studies suggesting that it can be beneficial (1-11). This improvement in
parkinsonism does not appear to be related to a direct and immediate effect, insofar as single
episodes of exercise do not appear to affect motor function (i.e., “limbering up”) or influence
levodopa pharmacokinetics (12-14). In those studies demonstrating improvement, the change
was seen after multiple sessions. Various types of exercise regimens have been beneficial:
resistance training can increase muscle strength (15, 16); both physical therapy (5-10) and music
therapy (11) has been shown to provide beneficial effects; and exercise alone has been shown to
improve motor function (1-3). More recently, animal studies have suggested that exercise might
improve the neurochemical deficits in parkinsonism as well as the behavioral deficits (17-20), an
intriguing possibility that suggests that motor training might induce plasticity changes in the
brain that could partially correct the lesion in Parkinson’s disease.
The Interactive Metronome (IM) device is a timing and rhythmicity training apparatus that is
thought to improve the execution of motor programs (21). It employs a metronome beat to set a
rhythm that the subject uses to time motor tasks. A computerized system provides auditory
feedback to the subject to illustrate the accuracy of synchronization between his motor
performance and the cueing beat. This device has been used by children with attention deficit
hyperactivity disorder (ADHD), with improvement in both motor and cognitive activities after
To test its utility for treating Parkinson’s disease, this study examined the effect of training
with the IM device by comparing motor performance before and after training, as measured with
Part 3 of the Unified Parkinson’s Disease Rating Scale (UPDRS) and with other clinical and
timed tests. Comparison was made with a control group that underwent a similar amount of
computer-guided physical activity, but without the feedback provided by the IM device.
Participants were recruited from the patient population seen at The
Parkinson’s Institute and from support groups in the surrounding geographic area (south San
Francisco Bay area). Close proximity to The Parkinson’s Institute was necessary because of the
number and frequency of the training sessions.
Patients were eligible for enrollment in the study if they had a diagnosis of idiopathic
Parkinson’s disease, were between 30 and 80 years old, and were Hoehn and Yahr stage 3 or
less. They could not be receiving any other experimental therapy during the time of their
Patients were excluded from the study if they had cognitive dysfunction that impaired their
ability to give informed consent, if they had a medical condition that would preclude their ability
to properly participate in training (e.g., unable to hear, unable to tolerate physical activity) as
judged by the enrolling neurologist, or if their clinical condition for parkinsonism was unstable
such that it would likely require medication changes during the period that training would be
This study was conducted in accordance with Good Clinical Practice guidelines and the
protocol and consent form were approved by an independent institutional review board (Western
Institutional Review Board, Olympia, Washington). All patients signed written consent prior to
Objectives and Outcome Variables.
The primary objective of this study was to determine the
effect of movement training using a computer-based device (the IM device) on the severity of the
signs and symptoms of Parkinson’s disease. The effect was measured by comparing the total
scores before and after training for the motor subsection of the Unified Parkinson’s Disease
Rating Scale (UPDRS part 3). Additional outcome variables that were examined included the
following: the total score for the activities of daily living subsection of the UPDRS (part 2), a
timed finger tapping test, the timed “Up & Go” test, and the Hoehn and Yahr stage. All clinical
neurologic examinations were performed by a Movement Disorder Specialist. The examiner was
blinded regarding the group assignment of the subject being evaluated, except for seven subjects
enrolled as a separate open-label group.
The IM device (Interactive Metronome, Weston, Florida) consists of a
computer, a controller box, headphones, and a set of pressure-activated sensors (Fig. 1). The
subject wears headphones that are connected to the controller box. A rhythmic tone sounds at a
rate of 54 beats per minute. The subject performs motor tasks attempting to keep in synchrony
with the tone. These tasks were performed according to a predetermined protocol and included
clapping, toe tapping, thigh slapping, and other similar types of movements, which, at various
times, involve each of the four limbs. In making each movement, a sensor is activated. For
example, a button is affixed to the palm by a strap wrapped around the hand. With each clapping
movement, the button is pressed. For leg movements, a footpad containing a built-in sensor was
used. The controller box detects each activation of the sensor and records the accuracy of the
synchronization with the provided rhythmic tone. The time differences are stored on the
computer. The controller box also provides an audio tone as feedback to the subject when the
sensor is activated to indicate how accurately the movement coincides with the rhythmic tone. If
the sensor is activated in close temporal proximity to the provided rhythmic tone, the feedback
sound is a pleasant bell-like noise. As the accuracy of the movement decreases, and the time
between the sensor activation and the rhythmic tone increases, the feedback sound morphs into a
more unpleasant buzzing-like noise. This feedback allows the subject to become progressively
more accurate in these motor tasks. Throughout each session, a trainer guides and assists the
subject in a one-on-one interaction, providing suggestions and recommendations to increase
The training protocol for the IM device used in this study was provided by the manufacturer
based upon preliminary trials they did with several parkinsonian patients. In the course of that
pilot project, they initially used their standard protocol for children affected with ADHD, which
was then was modified (i
) to take into account the decreased ability of these patients to tolerate
the physical activity required and (ii
) to allow additional time for the patients to achieve the level
of expertise sufficient to be considered proficient in using the device. Generally, patients with
Parkinson’s disease fatigue more easily, so that the amount of activity possible during a single 1-
hour training session had to be reduced. Accordingly, the total number of training sessions was
increased from the 15 normally used in other subjects to 20 for these patients. That training
protocol was supplied to The Parkinson’s Institute and used to design this study.
The control group underwent a similar amount of training (20 sessions each lasting 1 hour).
Their activities consisted mostly of motor activity, but without the auditory feedback. This was
accomplished by having them make movements (i
) to music played through the computer (20
) to the tone from the IM device without the sensors and thus without the feedback
cues (15 minutes), and (iii
) by playing computer arcade games (25 minutes). Each subject was
guided through the control session by a trainer providing one-on-one assistance. The trainers for
the control sessions also were trainers for the IM sessions.
This was a single-blind, controlled, parallel-group study conducted at The
Parkinson’s Institute. Patients were randomly assigned to either the group receiving training with
the IM device or to the control group (by coin flip). The participants in the control group were
kept unaware that theirs was not the study group, as all subjects were told that this was a study of
computer-based movement training. An open-label group of seven patients all received training
with the IM device and were included in a separate analysis.
At baseline, each subject underwent neurologic examination to determine the UPDRS part 3
motor exam score and the Hoehn and Yahr stage. They also underwent evaluation for timed
finger tapping (23) and the timed “Up & Go” test (24). Finger tapping was performed by having
the subject alternately press a lever on one of two counters mounted 12 inches apart. The total
number of taps completed in 60 seconds is recorded for the dominant hand and averaged over 3
trials. For the timed “Up & Go” test, the seated subject is timed for how long it takes for him to
arise, walk ten feet, and return. The score from the activities of daily living section of the
UPDRS (part 2) was determined from the answers recorded by the subject on a self-administered
questionnaire (25). These evaluations were repeated following completion of the 20 training
After enrollment into the study and initial evaluation, each patient
underwent a series of training sessions. Each session lasted approximately 1 hour, but it was not
unusual for the sessions to last up to an additional 15 minutes to allow the subject extra rest time
between tasks (due to fatigability). The schedule for the sessions differed among subjects
because of individual circumstances, but the general guideline was training two or three times
weekly without large gaps between sessions. Because the patients differed greatly in their
stamina, and because of the difficulties scheduling the large number of sessions, there was a
relatively wide range of times the subjects needed to complete training: the control group took
from 39 to 119 days, except for a single outlier at 190 days, with an mean of 87 days; and the IM
group took from 42 to 134 days with a mean of 93 days.
All subjects, both in the IM group and in the control group, were trained by persons who
were Interactive Metronome certified providers.
Sample Size and Statistical Analysis.
This study was designed as a pilot study, as there was
no previous information for performing a power calculation to determine sample size. Our initial
goal was to enroll 20 subjects in each group (40 total).
Baseline comparisons of the variables between the treatment groups were performed by t
tests or by chi-square analyses. The effect of each intervention was determined by t
-tests on each
of the variables. Statistical analyses were performed using StatView for Windows version 5.0.1
(SAS Institute Inc., Cary, North Carolina). For all analyses, P
< .05 was considered statistically
significant. All results are reported as mean (SEM) unless specified otherwise.
Results. Study Population and Treatment Groups.
The subject flow is diagrammed in Fig. 2.
Seventy-seven patients were screened for entry into this study. Two subjects were excluded and
39 declined to participate. The major problem causing subjects to decline participation was the
logistical difficulty of having to attend 20 training sessions over approximately 2 months. The 36
subjects that entered the study were randomly assigned to one of the two groups. Nine patients in
the IM group and six patients in the control group discontinued from the study. One patient in the
control group withdrew after suffering a heart attack, which was deemed unrelated to his
participation in this study. The remaining subjects completed their course of training. Subjects
that did not complete the training were excluded from analysis. One of the control subjects that
completed training was excluded from analysis of the UPDRS part 2 scores because of missing
data and another was excluded from the timed “Up & Go” test analysis for the same reason. Two
subjects from the IM group also had missing data, but both patients dropped out of the study and
were thus excluded from any analyses. An additional seven subjects, all of whom completed
their training, were assigned to the IM group in an open-label extension of the study and were
The demographic and baseline disease characteristics for the study population are presented
in Table 2. The first patient was enrolled in June 2003 and the last was enrolled in March 2004.
The last evaluation was performed in July 2004.
A single subject in the IM group suffered a serious adverse event—a heart attack.
This occurred at night while the subject was at home, and did not appear to be related to any
activity associated with the study. He was treated with angioplasty and recovered without further
incident. He was withdrawn from the study, although he expressed a strong desire to resume
training. An additional subject in the IM group withdrew because of fatigue, i.e., being unable to
tolerate the physical demands. Two subjects in the IM group and one subject in the control group
withdrew because of needing adjustment of their antiparkinsonian medications.
-tests indicated that there was an improvement in the UPDRS part 3 scores
for both of the groups (Fig. 3A). The IM group improved by 4.4 (1.9) points (P
= .0415), and the
control group improved by 3.7 (1.2) points (P
= .0166). Although the IM group scores improved
slightly more, a direct comparison of the two groups indicated that there was no statistical
difference between them (P
The timed tests also improved for both groups (Fig. 3B,C). The number of finger taps
increased by 24.6 (5.9) taps per minute for the IM group and by 13.2 (4.7) for the control group.
The time required to perform the “Up & Go” test improved by 1.5 (0.4) seconds in the IM group
and by 1.3 (0.3) in the control group. Again, although the IM group improved slightly more for
both measures, there were no statistical differences between the groups (finger tapping, P
.1675; timed “Up & Go” test, P
= .7100). The UPDRS part 2 scores improved in the IM group
by 1.3 (0.6) points (P
= .0412); the control group showed a slightly larger improvement of 2.2
(1.3) points, but this change did not achieve statistical significance (P
= .1252). There were no
statistical differences between the groups (P
= .4528). The Hoehn and Yahr stages (Fig. 3E) did
not change for the IM group (P
= .7545) and the control group (P
These analyses were repeated with the inclusion of the seven subjects that were assigned to
the IM group in the open-label extension. Both sets of analyses had very similar outcomes, with
only one difference: the change in the UPDRS part 2 scores for the IM group with the additional
seven subjects did not show a statistically significant improvement when compared to baseline
In this controlled pilot study, computer-directed movement training, both with the
IM device and with the control training activities, was found to improve the motor signs of
parkinsonism, both on clinical examination (UPDRS part 3) and in objective timed tests (finger
tapping and the timed “Up & Go” test). This is the first direct demonstration that these types of
exercises can improve parkinsonism, lending support for the phrase “use it or lose it” that is
often quoted to patients. Non-pharmacologic interventions such as these are highly attractive to
patients, and they help to foster a sense of higher personal control over the disease. The use of
such interventions is generally embraced by patients with Parkinson’s disease (sometimes with a
Seven additional subjects were enrolled in an open-label extension of the IM treatment
group. A second set of analyses was carried out that included these seven subjects. The results of
this second analysis were essentially the same as the first. The only difference was that the
improvement in the UPDRS part 2 scores are found to lose statistical significance for the IM
group, perhaps suggesting that less weight can be given to this being a true effect.
The motor subscore on the UPDRS (part 3) was prospectively chosen as the primary outcome
measure in this study, as it is the standard measure of the severity of parkinsonism. It involves,
however, subjective evaluation, so that the observation of improvement with this instrument was
buttressed by the observation of improvement using the objective measures of the finger tapping
test and the timed “Up & Go” test. That these additional tests confirm improvement provides a
greater degree of comfort that the finding is valid. That there is a lack of change for both the
ADL subscore of the UPDRS and the Hoehn and Yahr stage for the subjects does not detract
from this result. This is especially true for the Hoehn and Yahr stages, as they are relatively
broad categories, and were not expected to improve with this type of intervention. The use of a
self-administered questionnaire for the UPDRS part 2 subscore, as opposed to an interviewer, is
not expected to be a detracting factor, as (i
) this instrument correlates well with live interviews,
) it was used both before and after training, so that there should not have been any bias
These observed improvements in motor function were only in patients with mild and
moderate Parkinson’s disease, as more severely affected patients were excluded. The subjects
had to have sufficient motor control and dexterity to perform the exercises needed in both
treatment arms. Because of the nature of the tasks, patients with great difficulty with balance or
with marked motor complications were self-selected out of the study. Furthermore, performance
of these tasks required cognition to be relatively intact, and participation would be impossible
with dementia. As such, these findings cannot be generalized to more severely affected patients,
who, in any case, would not be candidates for this type of intervention. Given that the subjects in
both treatment arms derived benefit, future studies would be important that examine the effects
of motor training using simpler tasks that can be performed by patients with more severe
This study also was not designed to examine how long the benefits provided by training
might last. The post-training evaluations generally occurred within a few days of the last training
session. One previous study investigating the effect of an exercise regimen on parkinsonism
found that the beneficial effects were still present 6 weeks later (1). Another study found that 6
months after finishing a course of physical therapy the beneficial effects had been lost, although
this might have occurred because the patients had stopped their home exercises despite being
instructed to continue with them (7). Another study found a loss of benefit from a course of
physical therapy after 6 weeks, but that a second group following the same training regimen
supplemented with sensory cues (visual, tactile, and auditory with a metronome) retained their
gains (5). This suggests that sensory cues, and possibly feedback, might play an important role in
retention of benefit. Determining whether there are long-term effects from these computer-based
training regimens would certainly be an area for further investigation in any study undertaken as
The IM device is of great interest as a treatment because part of its effect is improvement in
utilization of motor programs (21), which is an area thought to be deficient in patients with
Parkinson’s disease (26). Previously, this device has been shown to improve both motor and
cognitive function in children with ADHD (22) and to improve performance accuracy in golf
(27). As such, it seemed ideally suited as a treatment for parkinsonism. This study, however, did
not find a difference between the two treatment arms. Parkinsonism did improve slightly more in
the IM group, but the difference was not statistically significant. Both groups went through a
substantial training regimen, although that for the IM group was more structured than for the
control group. Of note, in neither group was the training aimed specifically at improving the
movements tested with the UPRDS or at improving gait and balance. This suggests that
participation in any physical activity regimen providing a concentrated degree of motor training
might benefit parkinsonism. Alternatively (or additionally), the interaction between the subject
and the trainer might play a role, although the theoretical basis for how this might improve motor
The rhythmic nature of the exercises might contribute to or be a necessary part of their ability
to improve motor function. There have been studies demonstrating that repetitive and rhythmic
movements as rehabilitative therapies following a stroke can improve arm paresis (28), and
might induce reorganization of motor networks within the central nervous system (29). The
investigators used a technique called bilateral arm training with rhythmic auditory cueing
(BATRAC). They suggest that important components of BATRAC include bilaterality,
rhythmicity, and sensory feedback. If rhythmicity is a necessary component of this therapeutic
approach, it could explain the trend toward greater improvement with the IM regimen as a dose
effect, since the subjects in this treatment arm received longer training with rhythmic activities.
Another advantage that was provided by the IM regimen over that of the control group was
greater retention of subjects. A lower percentage of withdrawals occurred among the IM trainees
(9/28 = 32%) than the control group (6/15 = 40%). This, surprisingly, might be related to the
more regimented structure of the training. Anecdotally, the IM group experienced a higher sense
of accomplishment, leading to a higher degree of motivation, as was evidenced by the subject
who strongly desired to resume training even after suffering a heart attack. Interestingly, subjects
in some prior studies of the effect of exercise and activity on parkinsonism reported
improvement in a sense of mood and well-being, when such measures were collected (2, 3, 11),
although this improvement was not universal (7).
A recent report indicated that whether negative or positive feedback is more effective for
motor training in a patient with Parkinson’s disease depends upon his or her treatment state (30).
Patients learn better with positive feedback when their dopaminergic medications are working,
but learn better with negative feedback when their medications have worn off. Because the IM
device uses both positive and negative feedback, it might have an advantage as a training tool
since it would be effective regardless of the medication state of the subject.
The logistics of attending frequent training sessions proved difficult, so that many potential
subjects declined participation, and a portion of the enrolled subjects withdrew because of
scheduling conflicts. In many cases, participation in this study required a considerable
commitment of time over 2 or 3 months. Training exercises that could be performed at home
would make it much easier for patients to complete the full number of sessions. Along these
lines, Interactive Metronome has recently developed and released a version of their device that
can be used for self-training at home. Comparing the effect on motor function between two
groups undergoing similar training regimens, one with a trainer and one self-directed, might also
provide a way to separate the contribution of the physical activity and the contribution of the
In summary, this investigation demonstrated improvement in motor function in patients with
mild and moderate parkinsonism with the use of computer-directed motor training. This training
utilized music therapy, computer games, and the IM device. These types of therapeutic
interventions are welcomed by patients and could provide a useful supplement to pharmacologic
This trial was supported by Interactive Metronome (Weston, Florida). I would like to thank
Sandy Gabrielli for designing the control group protocol and for training subjects. I would also
like to thank Edward Jonathans, Janet Rios, William Whitney, and Sarah Forsblad for training
subjects, and Rondalyn Varney Whitney and the Lighthouse Project for their assistance. Lee E.
Jacokes, Richard T. Margo, and Randy Dayle provided much helpful advice. I would like to
thank Caroline Tanner for her helpful comments on the manuscript. And, finally I would like to
thank Stephanie Yang for her invaluable help in keeping things on track.
TABLE 1. Study protocol and training session activities
Baseline evaluation (UPDRS 2 and 3, H&Y stage, timed tapping, timed Up & Go test)
Baseline evaluation (UPDRS 2 and 3, H&Y stage, timed tapping, timed Up & Go test)
Each subject underwent training for 20 1-hour sessions.
TABLE 2. Subject demographics
Data are mean (SD) unless otherwise indicated. UPDRS, Unified Parkinson’s Disease Rating
Scale; ADL, activities of daily living. There were no statistically-significant differences between the control and IM-randomized groups. *Differs from control group, P
= .0384. †Differs from IM-randomized group, P
The Interactive Metronome device.
Excluded (n=41) Not meeting inclusion criteria (n=2)
Wished to enroll in another study (n=1)
Suffered (unrelated) heart attack (n=1)
Flow diagram of subject progression from screening to study completion.
UPDRS Part 3
Change in Score
Finger Tapping Test
Taps / 60 sec
UPDRS Part 2
Change in Score
Hoehn and Yahr Stage
Changes from baseline in measures of parkinsonism in subjects trained with the IM
device (n = 12) or the non-feedback control regimen (n = 9, except †n = 8). Data expressed as
mean ± SEM. *p < .05.
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CRYSTALLOGRAPHIC IMAGING OF A MOLECULAR CRYSTAL : Aspirin C8H5O4-CH2D R.J. Papoular1, W. Paulus 1, P. Schiebel2, W. Prandl2, H. Zimmerman3, A. Detken3, U. Haeberlen3 1Laboratoire Léon Brillouin (CEA-CNRS)2Institut für Kristallographie, Universität Tübingen, Charlottenstr. 33, D-72070 Tübingen3Max-Plank Institut für medizinische Forschung, D-69120 HeidelbergThe nuclear density dis