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
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.
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
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.
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
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.
that the simultaneous treatment of these two abnormal motor [13] R.E. Mains, J.F. Soechting, A model for the neuromuscular response to
behaviors could be more beneficial. It seems that curing one sudden disturbances, J. Dyn. Syst. Meas. Control December (1971) 1.
of these two symptoms without decreasing the other is not [14] P.J. Delwaide, Parkinsonian rigidity, Funct. Neurol. 16 (2) (2001)
147156.
realistic. Surely experimental studies are needed to validate this [15] A. Schnitzler, L. Timmermann, J. Gross, Physiological and pathological
computational model. oscillatory networks in the human motor system, J. Physiol. Paris 99
(1) (2006) 37 Epub 2005 July 27.
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.
[17] R. Iansek, J.V. Rosenfeld, F.E. Huxham, Deep brain stimulation of the
References subthalamic nucleus in Parkinsons disease, Med. J. Aust. 177 (3) (2002)
142146.
[1] A.C. Guyton, J. Hall, Text Book of Medical Physiology, 10th ed,
Saunders, Philadelphia, 2001.
[2] G. Deuschl, J. Raethjen, R. Baron, M. Lindemann, H. Wilms, P. Krack, Maysam MashhadiMalek received the M.Sc. degree from Faculty of
The pathophysiology of Parkinsonian tremor: a review, J. Neurol. 247 Biomedical Engineering, Amirkabir University of Technology in Tehran. His
(Suppl. 5) (2000) V33V48. area of interest is basal ganglia and modeling its diseases.
[3] G. Deuschl, J. Raethjen, M. Lindemann, P. Krack, The pathophysiology
of tremor, Muscle Nerve 24 (6) (2001) 716735.
[4] P.M. Rack, H.F. Ross, The role of reflexes in the resting tremor of Farzad Towhidkhah is with the Biological Systems Modeling Laboratory,
Faculty of Biomedical Engineering, Amirkabir University of Technology in
Parkinsons disease, Brain 109 (Part 1) (1986) 115141.
Tehran. His areas of interest are biological system control, motor control, and
[5] R. Edwards, A. Beuter, L. Glass, Parkinsonian tremor and simplification intelligent control. Educational background: Ph.D.: Biomedical Engineering,
in network dynamics, Bull. Math. Biol. 61 (1) (1999) 157177. University of Saskatchewan, Canada, 1996; M.Sc.: Electrical Engineering,
[6] D. Terman, J.E. Rubin, A.C. Yew, C.J. Wilson, Activity patterns in Amirkabir University of Technology, Iran, 1989; and B.Sc.: Electrical
a model for the subthalamopallidal network of the basal ganglia, Engineering, Amirkabir University of Technology, Iran, 1984.
J. Neurosci. 22 (7) (2002) 29632976.
[7] M. Haeri, Y. Sarbaz, S. Gharibzadeh, Modeling the Parkinsons tremor
and its treatments, J. Theor. Biol. 236 (3) (2005) 311322. Shahriar Gharibzadeh is with Neuromuscular Systems Laboratory, Faculty
of Biomedical Engineering, Amirkabir University of Technology in Tehran.
[8] P. Pakarian, S.M. Rayegani, S. Shahzadi, Effect of Vim thalamic DBS in
His area of interest is neural modeling. Educational Background: M.D. and
Parkinsons disease on F wave duration, Neurosci. Lett. 367 (3) (2004) Ph.D. of Physiology, Tehran University of Medical Sciences.
323326.
[9] Y. Naito, Y. Komatsu, I. Kanazawa, T. Nakanishi, F response abnormality
in Parkinsons disease, Jpn. J. Psychiatry Neurol. 42 (4) (1988) 811818. Verya Daeichin received the B.Sc. degree from Faculty of Biomedical
[10] I. Milanov, Motoneuron activity in patients with different types of tremor, Engineering, Amirkabir University of Technology in Tehran. He was selected
Electromyogr. Clin. Neurophysiol. 41 (8) (2001) 479484. by Young Scholar Club in physics. His area of interest is neural modeling.
[11] P. Le Cavorzin, G. Carrault, F. Chagneau, P. Rochcongar, H. Allain, A
computer model of rigidity and related motor dysfunction in Parkinsons Mohammad Ali Ahmadi-Pajouh received the M.Sc. from Faculty of
disease, Mov. Disord. 18 (11) (2003) 12571265. Biomedical Engineering, Amirkabir University of Technology in Tehran. He
[12] A.V. Hill, First and Last Experiments in Muscle Mechanics, Cambridge is now a student of Ph.D. in this university. His area of interest is motor
University Press, Cambridge, 1970. control.