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Computers in Biology and Medicine 38 (2008) 1133 1139

www.intl.elsevierhealth.com/journals/cobm

Are rigidity and tremor two sides of the same coin in Parkinsons disease?
Maysam MashhadiMalek a , Farzad Towhidkhah a , Shahriar Gharibzadeh b, , Verya Daeichin b ,
Mohammad Ali Ahmadi-Pajouh a
a Biological Systems Modeling Laboratory, Faculty of Biomedical Engineering, Amirkabir University of Technology (Tehran Polytechnic),
Tehran 15875-4413, Iran
b Neuromuscular Systems Laboratory, Faculty of Biomedical Engineering, Amirkabir University of Technology (Tehran Polytechnic), Tehran 15875-4413, Iran

Received 29 November 2007; accepted 15 August 2008

Abstract
In this research, we evaluated the inter-relation of tremor and rigidity in Parkinsons disease. We included the agonist and antagonist skeletal
muscle models as well as the peripheral (spinal and long-loop reflexes) and central (basal ganglia and cortex) mechanisms and present a complete
model. All of our simulation is developed in SIMULINK, MATLAB 7. Our results showed that (1) increased supplementary motor area output
increases the rigidity and (2) rigidity and the tremor are correlated. Therefore, from our model it can be suggested that the simultaneous treatment
of these two abnormal motor behaviors could be more beneficial. Experimental studies are needed to validate this computational model.
2008 Elsevier Ltd. All rights reserved.

Keywords: Parkinsons disease; Tremor; Rigidity; Mathematical model; Long-loop reflex

1. Introduction
has included both central and peripheral loops. Terman et al.
[6] have developed a cell-level model of the external segment
Parkinsons disease (PD) is one of the most prevalent neu-
of globus pallidus and the subthalamic nucleus, and their inter-
ral diseases, in which substantia nigra (SN), a part of basal
actions. They proposed that conductance-based cellular models
ganglia, is destroyed seriously and dopamine level is reduced.
are required to capture the dynamic activity of these structures.
The essential symptoms of PD are rigidity, rest tremor with a
They also claimed that reciprocal connection between the ex-
frequency of 46 Hz, bradykinesia, and postural instability [1].
ternal globus pallidus and the subthalamic nucleus, along with
There are two hypotheses about the origin of tremor:
lateral inhibition within the external globus pallidus and input
(1) involvement of central mechanisms [2,3]. This hypothesis
from the striatum, could generate the oscillations seen in tremor
assumes a central origin, e.g. thalamic cells, basal ganglia, or
of PD. In a recent study, Haeri et al. [7] have modeled the
cerebellum, for the tremor and (2) peripheral feedback mecha-
physiological and pathological behavior of basal ganglia math-
nisms. This hypothesis claims that an unstable hyper-excitable
ematically, assuming the output of the model to be the velocity
long-loop reflex arc is responsible for PD tremor [4].
of hand tremor.
Since the tremor is a main sign of PD and can be easily
In contrast to the mechanism of tremor, which is still a mat-
measured, it is assumed to be the output in most mathematical
ter of debate, the mechanism of rigidity is widely accepted to
models of PD. As PD is related to loss of dopamine, Edwards
be due to the hyperactivity of a long-loop reflex. Those who
et al. [5] supposed a neural network model and lowered the con-
believe in the peripheral hypothesis of tremor suppose that
nection strength between the network units. Although this was
tremor and rigidity have common mechanisms [8]; however,
an abstract model obtained from physiological information, it
the relationship between rigidity and tremor has been studied
in few experimental studies. For example, few experimental
studies have evaluated the relation between rigidity and tremor
Corresponding author. Tel.: +98 21 6454 2369; fax: +98 21 6649 5655. using the duration of F-wave, which is an index for excitabil-
E-mail address: gharibzadeh@aut.ac.ir (S. Gharibzadeh). ity of long-loop reflex pathway. Naito et al. [9] reported that

0010-4825/$ - see front matter 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.compbiomed.2008.08.007
1134 M. MashhadiMalek et al. / Computers in Biology and Medicine 38 (2008) 1133 1139

excitability of the spinal motor neurons was increased in rigid


Parkinsonian patients. Although it seemed reasonable to as-
sume that the main underlying cause of rigidity is an excessive
supraspinal drive to the spinal motor neurons, they observed
no evidence for contribution of these mechanisms in tremor.
However, Milanov [10] reported that the F-wave duration was
prolonged both in Parkinsonian tremor and in Parkinsonian
rigidity.
The only mathematical model describing both rigidity and Fig. 1. Hill mechanical model of skeletal muscle. (a) Length-dependent
tremor is presented by Le Cavorzin et al. [11]. They ex- force generator and (b) damper, KPE and KSE : parallel and serial elasticity,
plored the involvement of spinal circuits in the generation of respectively.
Parkinsonian rigidity and related motor dysfunctions. The
combination of a low reflex gain and a decreased reflex thresh-
old simulated appropriately the experimental rigidity data.
These findings are consistent with studies reporting increased
spinal interneuron excitability and proprioception deficits in
PD. Moreover, as the threshold parameter was much lowered,
their model generated typical features of Parkinsonian rest-
ing tremor; this supported the hypothesis of participation of a
spinal oscillator in this disorder. Although the possible role of
spinal circuits in PD motor abnormalities was simulated care-
Fig. 2. The designed model and the related transform functions. k: muscle
fully in Le Cavorzins study, he could not support this idea by
stiffness, B: viscous damping, J: inertia of the forearm about the elbow joint,
perfect empirical evidences. In addition, they did not study the b: spinal control on the muscle, Td : delay of spindle, t: time constant, and
effect of rigidity on the tremor and vice versa. Moreover, the h: a constant value.
involvement of central mechanisms and periodic input from
basal ganglia were not included.
In this research, we evaluate the inter-relation of tremor and
rigidity in order to find whether they are the two sides of the
same coin in PD. We include the agonist and antagonist skeletal
muscle models as well as the peripheral (spinal and long-loop
reflexes) and central (basal ganglia and cortex) mechanisms and
try to present a complete model of PD.

2. Method

Our model contains two parts: (1) the agonist and an- Fig. 3. The feedback mechanism of alpha motor neurons for agonist and
tagonist muscles and their feedback to the spinal cord and antagonist muscles [1].
(2) the peripheral and central neural parts. The cortex and basal
ganglia, which send and receive signals to and from muscles, the muscle spindle to the spinal cord, which has a delay (lower
comprise the central neural part and the long-loop reflex, com- right box in Fig. 2).
prises the peripheral part. All of our simulations are developed According to physiological data, when the agonist muscle
in SIMULINK, MATLAB 7. is activated by the CNS, the antagonist muscle is in rest and
vice versa, because of a feedback mechanism (Ia in Fig. 3).
2.1. Muscle model Therefore, we need to join an antagonist muscle model with an
agonist one, as shown in Fig. 4.
For simulating the muscle dynamics, we used the mechanical We simulate this behavior with two gains in the spinal cord:
model of Hill [12], containing two springs representing the gaf and ganf . When the agonist muscle is excited, the gaf is 1
passive behavior of the tendon and the muscle connective tissue, and ganf is 0 and when the antagonist muscle is excited, the
a length-dependent force generator, and a damper that relates ganf is 1 and the gaf is 0.
the muscle force to the velocity (Fig. 1).
In order to implement the Hill model, we used Mains and 2.2. Peripheral and central neural models
Soechting [13] formulas, which were introduced for the muscles
of arm. Our designed model in SIMULINK is shown in Fig. 2. For modeling the peripheral neural part, a long loop was
Input of the model is from CNS and the output is hand considered, which begins from muscle spindle, goes to the dor-
angular movement, theta. The model contains the spinal cord, sal horn of the spinal cord, enters the central part of the model,
the effect of spinal cord on the muscle, and a feedback from and finally returns to alpha motor neurons and the muscle.
M. MashhadiMalek et al. / Computers in Biology and Medicine 38 (2008) 1133 1139 1135

Fig. 4. The schema of the model including agonist and antagonist muscles.
Theta: angular displacement.

Fig. 6. The schema of the peripheral and central neural parts involved in a
general motor task. BG: basal ganglia.

2.2.1. Cortex subsystem


Cortex has inputs from basal ganglia and SMA. We assume
two parameters: ga and gan , that present the amount of cortex
command to muscles. ga is the gain for agonist muscle and
equals 1 when it is activated and 0 when inactive. Moreover,
gan is related to antagonist muscle and equals 1 when acti-
vated and 0 when inactive. In order to indicate the alternating
commands of cortex, a time delay is used in the model (Fig. 7).
In normal subjects, the input of SMA to cortex inhibits the
cortex command on muscles, but in PD, it induces an increase in
the cortex command [14]. This behavior is modeled by putting
the input of SMA to cortex below 1 in normal subjects and
higher than 1 in PD, and multiplying this input by the motor
command.
The motor command represents the cortex command and
is supposed to be a constant value. The basal ganglia send a
sinusoidal signal. The amplitude and frequency of this signal
is different in normal and PD persons (see Fig. 7).

2.2.2. Basal ganglia subsystem


Tremor can be subdivided into physiological and pathologi-
cal tremors. Physiological tremor is a low-amplitude oscillation
that can be demonstrated in almost all normal subjects with
suitable recording techniques [7]. The frequency of this tremor
is in the range of 812 Hz, which is twice that of PD tremor.
We assume a sinusoidal nature for the basal ganglia:
Fig. 5. Peripheral and central neural parts involved in a general motor task.
SMA: supplementary motor area, Ia: muscle spindle feedback, and : alpha g = sin t
motor neuron [14].  = 2 f

The central part itself includes supplementary motor area With the Laplace transform:
(SMA), motor cortex, and basal ganglia (Fig. 5). Thalamus
was not included for the purpose of simplicity.  2 f
G(s) = = 2
The schema of the model is shown in Fig. 6. s2 + 2 s + (2 f )2
1136 M. MashhadiMalek et al. / Computers in Biology and Medicine 38 (2008) 1133 1139

Fig. 7. Model of the cortex.

Fig. 8. Basal ganglia subsystem. G(s): transform function of basal ganglia.


Fig. 9. SMA subsystem, which includes absolute function, saturation function,
gain, and a bias.
In which f (frequency) is related to the level of dopamine
neurotransmitter. When f is 5 Hz, basal ganglia are in PD state
and we have
the gain. The amount of saturation function is 0.51 in normal
f = 5 Hz  = 10 = 31.4
persons and between 1 and 2 in PD.
31.4 31.4
G(s) = = 2
s2 + (31.4) 2 s + 986 2.3. The complete model
and when f becomes twice (2f), the normal person is as
The complete model used in this study is depicted in Fig. 10.
f = 10 Hz  = 20 = 62.8 It is obtained by joining the compartments of Figs. 4 and 6.
62.8 62.8 The ba and ban are similar to the gain b of Fig. 2.
G(s) = = 2 Suppose that the person is sitting and the arm remains in
s 2 + (62.8)2 s + 3944
a fixed horizontal position, whereas the forearm is allowed to
The input of basal ganglia comes from the cortex and its move only in the vertical plane. Hand angular displacement is
output goes into the cortex. The source in the model represents supposed to be the output of the system.
the origin of tremor in the PD and is supposed to be a constant The nominal parameter values used for muscle modeling are
value, which is increased by progress of the PD (Fig. 8). The J = 0.1 kg m2 , k = 50 N m, B = 2 N m s, Td = 0.02 s,  = 1/300 s,
output of this source is zero in normal humans.  = 5, and  = 100.These values are consistent with the average
physiological quantities found in normal adults.
2.2.3. SMA subsystem The oscillatory changes of theta will be considered as tremor
SMA plays an inhibitory role in normal person. However, in our study.
for the PD person, this inhibitory effect decreases, and hence Choosing simultaneously the ga = 1 and gan = 1 is equiv-
excitability of long-loop reflex increases. alent to co-contraction, which can be interpreted as rigidity of
The SMA model is designed to change the amount of the mo- the muscle. The greater the motor command, the greater the
tor command by changing the long-loop reflex excitability. The amount of rigidity. Motor command itself is increased with in-
nonlinear function of SMA is shown in Fig. 9. The model con- crement of SMA output. Therefore, we can suggest that the
tains three components: absolute function, saturation function, amount of SMA output in co-contraction state is an indicator
and the gain. The SMA output can be augmented by changing of the degree of rigidity.
M. MashhadiMalek et al. / Computers in Biology and Medicine 38 (2008) 1133 1139 1137

Fig. 10. Complete SIMULINIK model, used in this study.

Fig. 13. Angular displacement in a normal person, when co-contraction is


Fig. 11. Excitation of agonist muscle in a normal person. present.

Fig. 14. Angular displacement in PD, when agonist muscle is excited.


Fig. 12. Excitation of antagonist muscle in a normal person.

3. Results Supposing that the agonist and antagonist muscles are receiv-
ing signal simultaneously (co-contraction), tremor increases
Fig. 11 shows the hand angular movement (theta), when (Fig. 13).
only the agonist muscle is excited in a normal person. Ex- Figs. 14 and 15 show theta change (tremor) in a person with
citing only the antagonist muscle has the result depicted in PD, when agonist and antagonist muscles are excited separately.
Fig. 12. Both the curves show the physiological tremor with In order to evaluate the effect of rigidity on tremor in PD,
10 Hz frequency. we allowed co-contraction in agonist and antagonist muscles
1138 M. MashhadiMalek et al. / Computers in Biology and Medicine 38 (2008) 1133 1139

we did not change the gain of SMA, but the output of SMA is
augmented by increasing the tremor.

4. Conclusion and discussion

As it was mentioned in the Introduction, the mechanism of


tremor in PD is still controversial. However, the mechanism of
rigidity is widely accepted to be due to hyperactivity of a long-
loop reflex. Some hypotheses express relations between tremor
and rigidity, but how these two phenomena are related to each
other is still unclear.
In this study, we tried to evaluate the inter-relation of tremor
Fig. 15. Angular displacement in PD, when antagonist muscle is excited. and rigidity in order to find whether they influence each other
and if so, what the result of these effects is.
Our model includes the long-loop reflex and spinal reflex,
peripheral mechanisms that are involved in tremor [4]. The cen-
tral mechanism, i.e. the involvement of basal ganglia in tremor,
is also included in the model. The agonist and antagonist mus-
cles were used in our model simultaneously to simulate the
tremor and its relation to the rigidity, because the motor cor-
tex gives alternating commands to the agonistic and antagonis-
tic muscles, resulting in the typical alternating pattern of the
Parkinsonian resting tremor [15].
The output of our model is theta. This is in coordination with
the velocity of tremor, which is presented in www.physionet.org
as the output.
Our abstract model of basal ganglia is able to simulate
the physiological tremor (see Figs. 11 and 12). Voluntary
co-contraction of muscles increases the tremor (see Fig. 13),
Fig. 16. Rest tremor in a patient with PD, when rigidity (co-contraction) is
present.
which is physiologically plausible.
The model is also able to produce the PD rest tremor (see
Figs. 16 and 17). Figs. 14 and 15 indicate that during activity,
tremor is also present in PD.
Because the long-loop reflex is supposed to be the main
mechanism of rigidity, we can evaluate truly the rigidity in this
model. It is claimed in experimental studies that SMA normally
inhibits the motor cortex. However, this loop would be less
inhibitory in PD [14]. Hayashi et al. [16] have indicated in an
experimental study that the rigidity increases by increasing the
feedback gain. In accordance with these studies, our results
showed that increased SMA output increases the rigidity.
In this study, we evaluated the effect of rigidity on tremor
by allowing co-contraction in agonist and antagonist muscles
and the effect of tremor on rigidity by increasing the amount of
source. As it is shown in Fig. 17 when rigidity increases by in-
creasing the gain of SMA, the amplitude of the tremor in a pa-
Fig. 17. Rest tremor in a patient with PD, when rigidity (co-contraction) is
increased. tient with PD will increase. On the other hand, we showed that
by increasing the source which is equivalent to high tremor, the
SMA output increases. Increased SMA output is in turn equiv-
(Fig. 16). The result was production of a tremor with higher alent to increased co-contraction and rigidity. Hence, greater
amplitude than when only one muscle was excited. rigidity will induce greater tremor and vice versa.
Increasing the gain of SMA, which is equivalent to more The tremor and rigidity are two signs of PD, which are related
severe PD, increases the amplitude of the tremor (Fig. 17). to each other. As our model proposes, increment of both these
Finally, in order to evaluate the effect of tremor on rigidity, signs occurs during aggravation of the disease, which is in
we increased the amount of source (the signal from basal gan- accordance with Iansek et al. [17] study. Our model predicts
glia in Fig. 8). This change increased the SMA output, which is that when one of these two signs is elevated, the other one is
equivalent to increased co-contraction and rigidity. In this case, also increased. Therefore, from our model it can be suggested
M. MashhadiMalek et al. / Computers in Biology and Medicine 38 (2008) 1133 1139 1139

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Conflict of interest statement [16] R. Hayashi, T. Hashimoto, T. Tada, S. Ikeda, Relation between changes
in long-latency stretch reflexes and muscle stiffness in Parkinsons
diseasecomparison before and after unilateral pallidotomy, Clin.
None declared. Neurophysiol. 112 (10) (2001) 18141821.
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