The pathophysiology of motor symptoms in Parkinson's disease
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Acta neurol. belg., 2003, 103, 129-134
The pathophysiology of motor symptoms in Parkinson’s disease
P. SANTENS, P. BOON, D. VAN ROOST and J. CAEMAERT
Departments of Neurology and Neurosurgery, Ghent University Hospital, De Pintelaan 185, B-9000 Gent
————
Abstract a direct and an indirect pathway, connecting the
This review focuses on some of the known and hypo- input nuclei of the basal ganglia, i.e. the striatum
thetical pathophysiological mechanisms underlying the (caudate nucleus and putamen) with the output
motor symptoms in Parkinson’s disease (PD). Current nuclei, the internal pallidum (GPi) and substantia
views on these mechanisms have largely been influenced nigra pars reticulata (SNr). These two pathways
by models of basal ganglia functioning and dysfunction- have opposite effects on the output of the basal
ing. These models have allowed to explain some clinical ganglia : the direct pathway has a net positive effect
findings and to predict a number of results of basal gan- on the basal ganglia output, while the indirect path-
glia surgery in movement disorders. However, neuro- way has a negative effect. Dopamine released from
physiological studies as well as neurochemical data striatal terminals of substantia nigra pars compacta
have broadened our vision on basal ganglia functioning (SNc) neurons has opposite effects on both path-
and dysfunctioning in PD. Moreover, these more funda-
mental insights in basal ganglia functioning allow new
ways, resulting in a net release of thalamic output
concepts on the development of treatment strategies, and to cortical motor areas. In this way a release of
on the prevention of motor fluctuations in PD. motor programs and inhibition of unwanted move-
ments can be balanced to result in finely tuned
motor behaviour.
Introduction : the basal ganglia Both direct and indirect pathways originate in
the matrix compartment of the striatum. Recently it
In contemporary neuro-anatomy the striatum was suggested that a third pathway, originating in
(putamen and caudate nucleus), the pallidum the striosomal compartment of the striatum also
(internal and external), the subthalamic nucleus exerts control over movement by means of its con-
and the substantia nigra (pars compacta and reticu- nections to the substantia nigra. This pathway
lata) are considered the nuclei of the basal ganglia. might therefore control dopamine release accord-
Over the last few years it has been demonstrated ing to variables such as experience and evaluation
that these nuclei play a key role in mediating motor (Graybiel A. M. et al., 2000). It is a well-known
and non-motor behaviour, cognition and emotion. that dopamine release is dependent on the predic-
The functions of the basal ganglia have been tion of reward of an action (Walters J. R. et al.,
explained in terms of anatomy and connectivity, 2000).
biochemistry and electrophysiology. Apart from dopamine, several other neurotrans-
Several models of the functional anatomy of the mitters have been implicated in basal ganglia func-
basal ganglia have been proposed. The most tion (Fig. 1), the most important being glutamate
familiar model was introduced in the 1980’s and GABA. Finally, the electrophysiological
(Alexander G. E. et al., 1990 ; DeLong M., 1990). properties of basal ganglia nuclei are complicated
This model is based on the existence of separate and differ substantially from one nucleus to another
parallel loops, mediating motor, cognitive and one. Tonic discharges can be interrupted by phasic
emotional functions, and running through the basal alterations which are related to initiation or perfor-
ganglia in a more or less uniform fashion (Fig. 1). mance of movements.
In this review we will focus on motor function, Two important characteristics of basal ganglia
unless otherwise specified. function included in this classical model are con-
In spite of the many criticisms raised and the vergence and segregation. Convergence refers to
obvious oversimplification of basal ganglia con- the fact that along the circuits the number of neu-
nectivity, this model has provided a framework that rons decreases by each step, thus converging infor-
allowed to predict outcomes of lesions and of sur- mation following each relay. Segregation not only
gical procedures in extrapyramidal disorders implies separation of the individual circuits along
(Obeso J. A. et al., 2000b). Central in the descrip- their path through the basal ganglia, but also the
tion of the model is the existence of two pathways, separation of information flow for motor functions130 P. SANTENS ET AL.
FIG. 1. — The model of basal ganglia functional anatomy as proposed by Alexander and DeLong. White arrows indicate an excita-
tory connection, dark arrows indicate an inhibitory connection. Neurotransmitters involved in these connections are indicated in ital-
ics. The existence of two pathways, a direct and indirect one, is indicated.
of individual parts of the body. The “focussing” chemical and electrophysiologic changes can be
hypothesis of basal ganglia function in movement predicted from the model. Many of these predic-
is based on this segregation. According to this tions have been confirmed by in vitro and in vivo
hypothesis the release of motor programs is findings in animal models and humans. A charac-
focussed to a specific body part, while movements teristic increase in firing rate of the GPi and STN
of surrounding body parts are inhibited by means has been found in MPTP-treated animals
of the indirect pathway. (Obeso J. A. et al., 2000b). The consequence of this
An important consideration is the fact that basal increased firing rate is an excessive activation of
ganglia output ultimately results in changes of cor- basal ganglia output nuclei, leading to inhibition of
tical output. Electrophysiological studies have the thalamo-cortical and brainstem motor systems.
demonstrated that basal ganglia modulate spatio- This increase is reversed by administration of
temporal organisation of cortical activity implicat- dopaminergic agents. Moreover pallidotomy and
ed in the selection and propagation of adequate deep brain stimulation of the STN or GPi can
movement (Brown P. et al., 1998). It appears that induce clinical improvement in patients with PD
basal ganglia are implicated in coherence of mus- (Obeso J. A. et al., 2000b).
cle and cortical activity at higher frequency ranges Electrophysiological studies in animal models
(Salenius S. et al., 2002). This leads to fusion of have suggested that oscillatory activity may appear
motor unit activities sufficient to sustain adequate within the basal ganglia nuclei following dopami-
force and speed of movement onset (Pfann K. D. et nergic depletion in the striatum. Studies of the elec-
al., 2001) (“scaling” – see below). trical activity of neighbouring neurons have shown
that coherence increases, which suggests a loss of
The consequences of dopaminergic deficit segregation within the basal ganglia (Bergman H.
in Parkinson’s disease et al., 2002 ; Brown P., 2003).
From a biochemical point of view dopaminergic
Following degeneration of the SNc dopaminer- denervation of the striatum increases expression of
gic neurons projecting to the striatum, several bio- preproenkephalin and D2 receptor mRNA inTHE PATHOPHYSIOLOGY OF MOTOR SYMPTOMS IN PARKINSON’S DISEASE 131
the occurrence of an isometric tremor in PD
patients, characteristically evoked by squeezing the
fingers of the examiner. Indeed, if fusion of motor
units does not occur appropriately when stronger
forces are to be generated, this might lead to inter-
ruptions of motor activity, and hence isometric
tremor. The frequency of this tremor is not corre-
lated to the frequency of the resting tremor which
may be present in the same patient (De Letter M. et
al., 2003 ; Salenius S. et al., 2002).
Finally, alterations in sensory processing have
FIG. 2. — Schematic representation of EMG bursts in ago- been suggested to contribute to bradykinesia and
nist and antagonist muscles during a reaching movement in hypokinesia. This suggestion is supported by the
normal controls and in PD. In normal controls the goal is reduced amplitude of the frontal component of the
reached by single agonist-antagonist mechanisms. In PD, ago- somatosensory evoked potentials in PD
nist bursts are hypometric, requiring multiple bursts to reach
the target (scaling).
(Abbruzzese G. et al., 2003).
Tremor
neurons of the indirect pathway. Conversely in neu-
rons of the direct pathway the expression of mRNA Although text books teach us that the classical
for the D1 receptor, substance P and dynorphin is tremor of PD is a resting tremor, a variety of
decreased (Obeso J. A. et al., 2000b). tremors can be found in PD (Deuschl G. et al.,
1998). Most frequently, a rest tremor and postural
Bradykinesia and hypokinesia or kinetic tremor with equal frequency ranging
from 4-7 Hz is found (classical parkinsonian
These cardinal features of parkinsonism point to tremor) although in the early stages and in severe
a number of different alterations of movement. akinetic-rigid symptoms higher frequencies may
They refer to slowness of movement, reduced occur (Deuschl G. et al., 2000).
movement amplitude, disturbances of movement Only two human conditions with resting tremor
initiation, and decrease of spontaneous or associat- are known : PD and Holmes’ tremor. Both condi-
ed movements (Berardelli A. et al., 2001). tions share the common factor of dopaminergic
Bradykinesia and hypokinesia are commonly deficiency in the striatum (Brooks D. et al., 1992).
explained by the changes occurring in the basal This would suggest that lesions of the SNc are
ganglia as explained above. It is frequently quoted indispensible for the occurrence of resting tremor.
in this sense that PD patients are “driving while Many observations support this hypothesis, but the
stepping on the brakes”. Of course this is an over- question is if dopamine deficiency is enough.
simplification, which becomes more clear when Indeed, in primate models resting tremor can only
these features of parkinsonism are analyzed in be evoked by combined lesions in the SNc, the red
greater detail. It has been demonstrated manifold nucleus and the cerebello-thalamic fibers
that PD patients have longer latency times before (Deuschl G. et al., 2000). PET studies have sug-
movement occurs, that they take longer before gested the influence of serotonergic denervation in
reaching appropriate forces to perform voluntary the origin of rest tremor (Doder M. et al., 2003).
movements, and that movements are more fre- Other PET studies of cerebral metabolism have
quently broken down in small steps, requiring mul- pointed to cerebellar hypermetabolism in tremor,
tiple EMG bursts to reach a target (Berardelli A. et which was reverted by thalamic stimulation leading
al., 2001) (Fig. 2). to tremor arrest (Deiber M. P. et al., 1993). This
These changes can be explained in part by the suggests a mechanism originating in the cerebel-
results of studies of alterations in cortical activity lum or its connecting systems, such as the oliva
in PD patients performing isometric contractions. It inferior.
has been shown that coherence between cortical In a clinical context, it is well known that dopa-
activity and muscular activity is decreasing in the minergic suppletion is not always able to control
higher frequency ranges (Salenius S. et al., 2002). parkinsonian tremor (Elble R. J., 2002). Moreover
This leads to a defective fusion of motor units it has been argued that patients displaying tremor
resulting in a slower recruitment of force, and an have a better prognosis as far as motor progression
inappropriate generation of muscular force to reach and development of mental deterioration is con-
a target. This might be implicated in the under- cerned (Deuschl G. et al., 2000). Recent findings
scaling of movement (hypometria), which is to be however have shed doubt on these dogmatically
corrected by multiple bursts of muscular activity accepted statements (Vingerhoets G. et al., 2003).
(Pfann K. D. et al., 2001) (Fig. 2). Furthermore this The pathophysiology of parkinsonian tremor
might explain a well-known phenomenon, which is remains a matter of debate. Peripheral influences, if132 P. SANTENS ET AL.
ever present, are minor and all available evidence long-loop reflexes originating in muscle spindles
points towards a central mechanism involved in the and running through cortical relays are at the basis
generation of the tremor in PD. of increased muscle tone. This view is based on an
So-called tremor cells, displaying rhythmic increase of M2-responses after arrest of a voluntary
activity linked to the tremor frequency have been movement. However, this finding has not been
found in several basal ganglia nuclei. Tremor cells accepted universally and several aspects of rigidity
are more frequently found in ventrolateral thalamic in PD do not fit the hypothesis of long-loop reflex-
nuclei than in the internal pallidum and subthala- es (Delwaide P. et al., 1990). Most compelling is
mic nucleus. Rare tremor cells have been described the equal distribution of rigidity in distal and proxi-
in the external pallidum and none were detected in mal as well as axial musculature. Another clinical
the striatum (Deuschl G. et al., 2000). This sug- finding which is hard to reconcile with this theory
gests that convergence may be implicated in the is the increase of rigidity by contralateral move-
generation and enhancement of tremor activity ment (Froment’s sign). Therefore other mecha-
along the basal ganglia-thalamic pathways. nisms must be involved.
Another observation linking clinical and electro- A very interesting and attractive hypothesis is
physiological data is that although frequency of the involvement of reticulospinal tracts. In fact,
parkinsonian tremor may be very similar in differ- electrophysiological studies have demonstrated
ent body parts, tremor activity is almost never that the activity of inhibitory interneurons at spinal
coherent between limbs, which suggests that the levels are differentially altered in PD. The activity
basic rhythm might be an inherent characteristic of of IA spinal inhibitory interneurons is increased,
a patient’s disturbed basal ganglia system, but the while the activity of IB interneurons seems to be
generators of the tremor might be different from decreased. This may lead to tonic facilitation of
one body part to another one (Deuschl G. et al., alpha motor neurons. These processes can be
2000). reversed by administration of L-DOPA. The only
It has been suggested manifold that the thalamic descending tract able to differentially influence
motor nuclei are at the origin of parkinsonian tremor. these interneurons is the reticulospinal tract
A putative mechanism involves specific voltage- (Delwaide P. et al., 1993). Reticular nuclei in the
dependent calcium channels that are able to gener- brainstem, such as the nucleus reticularis giganto-
ate a spontoneous rhytmicity of neurons in condi- cellularis and the nucleus pontis caudalis receive
tions of hyperpolarization. Indeed, in PD, thalamic afferents from the pedunculopontine nucleus,
nuclei are inhibited and hence hyperpolarized by en- which is connected to the basal ganglia as shown in
hanced GABA-ergic neurotransmission (Jahnsen H. the original model (Pahapill P. A. et al., 2000). The
et al., 1984 ; Magnin M. et al., 2000). However the activity of these reticular nuclei can be tested elec-
electrophysiological characteristics of the spikes trophysiologically by means of the startle reflex
generated by these calcium currents do not fit the and the audiospinal augmentation of the H-reflex
tremor-linked activity of thalamic neurons. (Delwaide P. et al., 1993).
Another very interesting putative mechanism is
the STN-GPe pacemaker. When neurons from The pathophysiology of motor fluctuations
these two nuclei are isolated in vitro, they develop
rhytmic activity (Plenz D. et al., 1999). The fre- Motor fluctuations are a serious burden in
quencies of these rhythms are lower than tremor advancing PD. It has been suggested that 50% of
frequencies in PD. However it cannot be excluded patients treated with L-DOPA for 5 years suffer
that filtering through downstream nuclei somehow from motor fluctuations (Marsden C. D. et al.,
modifies tremor frequencies, perhaps under the 1977). Several types of fluctuations have been
influence of dopaminergic deficiency. described, the most notable ones being end-of-dose
Finally loss of segregation, as mentioned above, and on-off fluctuations and dyskinesia. Advanced
might be at the origin of the coherence of neigh- disease, therapy duration and half-life of the
bouring neurons, leading to the development of dopaminergic agent used to initiate therapy have
functional units propagating tremor activity along consistently been correlated with the development
the cortico-subcortico-cortical pathways. These of motor fluctuations (Fahn S., 2000). Progressive
functional units may display coherence between degeneration of nigral neurons leads to loss of
their neurons, but not with neurons belonging to buffer capacity for L-DOPA and hence a deteriora-
other neighbouring functional units. In this way tion of the long-duration response. The remaining
different tremor generators may develop for differ- short-duration response may not be sufficient to
ent parts of the body (Deuschl G. et al., 2000). sustain motor function continuously and subse-
quently off-episodes develop before a new dose of
Rigidity L-DOPA is taken.
Current knowledge considers the development
The pathophysiology of rigidity in PD remains a of on-off fluctuations and dyskinesias a conse-
matter of debate. The traditional view holds that quence of plasticity in the basal ganglia induced byTHE PATHOPHYSIOLOGY OF MOTOR SYMPTOMS IN PARKINSON’S DISEASE 133
chronic intermittent stimulation with short-acting loss of segregation, causing increased coherence of
dopaminergic agents (Obeso J. A. et al., 2000a). neurons that are normally acting independently.
Indeed, compared to long-acting dopaminergic Further pathophysiological studies on coherence
agents, an increase in Immediate Early genes (IEG) within basal ganglia and coherence with cortical
in the Fos family and in mRNA for prepro- and muscular activity might enhance our knowl-
enkephalin is found in MPTP animals treated with edge of bradykinesia and tremor.
short-acting dopaminergic treatments. This means Finally, brainstem reticular nuclei seem to be
that the mechanisms involved in the development involved in the generation of rigidity and axial
of motor fluctuations and dyskinesias are essential- symptomatology. These nuclei are awaiting further
ly controlled by altered transcription of genes exploration to define their exact pathophysiological
(Bedard P. J. et al., 1999). However, it is unknown role in PD.
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