Download Basal ganglia discharge abnormalities in Parkinson`s disease

J Neural Transm (2006) [Suppl] 70: 21–25
# Springer-Verlag 2006
Basal ganglia discharge abnormalities in Parkinson’s disease
T. Wichmann1;2 and M. R. DeLong1
1
2
Department of Neurology, and
Yerkes National Primate Center, Emory University, Atlanta, GA, USA
Summary. In the traditional model of the
pathophysiology of parkinsonism, parkinsonian motor signs are viewed as the result of
changes in discharge rates in the basal ganglia. However, not all experimental findings
can be explained by rate changes alone, and
changes in discharge patterns in these nuclei
are increasingly emphasized as pathophysiologically important, including changes in
burst discharges, in synchrony, and in oscillatory activity. This brief review highlights
the pathophysiologic relevance of these rate
and pattern changes in the pathophysiology
of parkinsonism.
Introduction
In early Parkinson’s disease selective degeneration of a small number of dopaminergic
cells in the lateral portion of the substantia
nigra pars compacta (SNc) leads to the signs
of parkinsonism. Both the behavioral specificity and the seemingly disproportionate magnitude of the effect of such a small lesion in
the midbrain are artifacts of the anatomy of
the basal ganglia. The functional specificity
arises from the fact that the basal ganglia are
topographically organized, and that the early
degenerative process in Parkinson’s disease
affects predominately those SNc neurons that
project to the motor portion of the striatum
(the putamen) with relative sparing of other
striatal areas. The magnitude of the behavior-
al effect of SNc lesions is explained by the
fact that the basal ganglia are major components of circuits involving specific regions of
the cerebral cortex and thalamus (Alexander
et al., 1986) so that loss of dopamine in the
motor portion of the striatum (the putamen)
exerts strong effects on all other elements of
the ‘motor’ circuit, including motor areas of
the extrastriatal basal ganglia, and movementrelated areas in thalamus and precentral
motor fields. Thus, although pathologically
a localized problem (at least initially),
Parkinson’s disease is pathophysiologically
a disorder engaging the entire motor circuit.
We here review the changes in neuronal activity that occur in this circuit in Parkinson’s
disease.
Changes in discharge rate
Inputs from cortical sensory-motor areas
reach the basal ganglia through the putamen
and the subthalamic nucleus (STN), while
motor portions of the internal pallidal segment (GPi) and the substantia nigra pars reticulata (SNr) serve as output stations of the
basal ganglia, projecting to the ventral anterior and ventrolateral nuclei of the thalamus.
Information is conveyed between putamen and
GPi=SNr through a monosynaptic GABAergic
projection (‘direct’ pathway), and a polysynaptic (‘indirect’) pathway which involves
the external pallidal segment (GPe) and STN.
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T. Wichmann and M. R. DeLong
Tonic GABAergic output from neurons in
GPi=SNr is thought to inhibit their projection targets in thalamus, thereby reducing
cortical activation. Dopamine, released from
terminals of the nigrostriatal projection, is
thought to facilitate transmission along the
direct pathway, and to reduce transmission
along the indirect pathway. These dual dopamine actions lead to a net reduction of
inhibitory basal ganglia output, which may
facilitate cortical activity, and eventually
movement (Wichmann and DeLong, 2003).
Traditional models of the pathophysiology of parkinsonism are strongly influenced
by this anatomic arrangement (reviewed in
Wichmann and DeLong, 2003; Albin et al.,
1989), which suggests that the overall amount
of movement is in some way inversely related to the magnitude of basal ganglia output. According to the scheme mentioned
above, loss of striatal dopamine within the
motor circuit would result in increased STN
activity, and increased basal ganglia output,
reduced thalamocortical activity and the
development of parkinsonian motor signs,
such as akinesia or bradykinesia. Conversely,
dopamine-induced dyskinesias have been
postulated to result from decreased basal
ganglia output.
The prediction that the discharge rates of
neurons in the basal ganglia output nuclei
and in the STN are increased in Parkinson’s
disease has been generally confirmed in animal models of Parkinson’s disease, and is
also supported by recording studies in humans
undergoing functional neurosurgery as treatment for Parkinson’s disease. Moreover, decreases in discharge in GPi have been found
in animals with dyskinesias induced by
administration of dopaminergic drugs.
It is noteworthy, however, that the predicted rate changes have not been found in
all studies of parkinsonian subjects. More
importantly, in a recent monkey study
designed to test the rate-based model, we
showed that increased STN and GPi rates
(in this case produced by ibotenic acid
lesions of GPe) are not per se responsible
for parkinsonian signs (Soares et al., 2004).
Despite rate changes similar to those in
parkinsonian animals, the GPe-lesioned animals showed only minor motor impairments.
Lesion studies have also demonstrated problems with rate-based models of parkinsonian
pathophysiology. For example, based on the
model, pallidal lesions would be expected to
result in involuntary movements, but, in fact,
have little effect on normal motor behavior.
Similarly, thalamic inactivation, although
predicted to induce parkinsonism, does not.
Pattern changes
Given that changes in discharge rate of basal
ganglia neurons cannot fully explain the
generation of parkinsonism or the production
of drug-induced dyskinesias, changes in the
activity patterns of basal ganglia neurons
have been intensely studied. Although we
will discuss here different types of pattern
changes separately, all of them tend to occur
in parallel, and may result from the same
underlying mechanism(s).
Burst discharges
One of the firing properties that has been studied in detail is the incidence of burst discharges. Such burst discharges are a normal
feature of basal ganglia discharge, and the
timing and ‘strength’ of bursting may represent aspects of external events or behavior,
probably representing the increased synchronization of cortical inputs to the subthalamic
nucleus or striatum (Magill et al., 2000).
In parkinsonism, the incidence of bursts is
increased (e.g., Soares et al., 2004), most
often in the context of synchronized oscillatory activity (see below). In part, this may
occur because of an enhanced interaction
between cortical areas and basal ganglia
areas, particularly the STN, but other pathologic phenomena may also play a role.
For instance, in dopamine-free co-cultures of
STN and GPe cells, synchronized bursting
Basal ganglia discharge abnormalities in Parkinson’s disease
develops because of network properties
(Plenz and Kitai, 1999). Prominent bursts in
STN discharge have been shown to occur as
rebound phenomena in response to prolonged
or synchronized inhibitory GPe inputs to the
STN (e.g., Bevan et al., 2002). Although less
well studied, rebound bursts are also known
to occur in other basal ganglia areas.
Changes in inhibitory inputs to these areas
may increase rebound bursting.
Synchrony
A second important phenomenon affecting
the firing properties of basal ganglia cells in
parkinsonism are changes in the synchrony
of firing between neighboring neurons. Under
physiologic conditions, the firing of neighboring basal ganglia neurons is largely
uncorrelated (Bergman et al., 1994; Wilson
et al., 2004). In the dopamine-depleted state,
however, increased synchrony is observed in
the STN (Bergman et al., 1994; Levy et al.,
2002), in the pallidum (e.g., Heimer et al.,
2002), in the striatum (between tonically
active neurons, most likely corresponding to
cholinergic interneurons) (Raz et al., 2001),
and in frontal cortical areas (Goldberg et al.,
2002). The link between synchrony and
dopamine depletion is most clearly revealed
by the fact that treatment with dopaminergic
agents rapidly reduces the interneuronal synchronization observed in parkinsonism in
the monkey pallidum (Heimer et al., 2002)
and in the human STN (Levy et al., 2002).
However, the mechanisms by which dopamine exerts these effects remain unclear.
It has been proposed that dopamine loss in
the striatum may trigger enhanced electrotonic coupling between neighboring striatal
cells (see, e.g., Onn and Grace, 2000), or
activity changes in interneurons or axon collaterals (Guzman et al., 2003). In the STN,
synchrony is more likely to be the result of
synchronous (or divergent) inputs from external sources rather than locally generated
(Wilson et al., 2004). The potential synchro-
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nizing effects of local dopamine loss in
GPe, GPi, or SNr, has not been explored in
detail.
Oscillations
A third major change in the discharge patterns
of basal ganglia neurons in parkinsonism is
that dopamine loss enhances the tendency of
neurons in the basal ganglia-thalamocortical
circuitry to discharge in an oscillatory pattern
(Soares et al., 2004; Bergman et al., 1994).
These oscillatory changes are rapidly reversed
by systemic treatment with dopaminergic
agents (Levy et al., 2002), and are therefore
likely to represent a direct effect of dopamine
deficiency. Such oscillations are mostly confined to the extrastriatal basal ganglia, and
characteristically occur in the alpha- and beta
frequency bands. For instance, in parkinsonian monkeys and patients, oscillatory bursting typically emerges in both the 3–8 Hz
band, and a power spectral band around
10 Hz (Bergman et al., 1994; Levy et al.,
2000). Local field potential (LFP) recordings
through implanted deep brain stimulation
(DBS) electrodes in GPi and STN of untreated parkinsonian patients have shown
similar oscillatory activity in the 10–30 Hz
range, likely reflecting synchronized oscillatory neuronal spiking (Levy et al., 2002;
Brown, 2003). Given the relation between
the basal ganglia, thalamus and cortex, it is
not surprising that pathologic oscillatory activity in the ‘antikinetic’ 10–30 Hz band has
also been observed in areas of cortex that are
related to the basal ganglia in parkinsonian
patients and animals (Goldberg et al., 2002).
MEG studies have also identified an oscillatory network with pathologic coupling at
10 Hz in patients with parkinsonian tremor,
which included multiple cortical motor areas,
as well as diencephalic and cerebellar areas
(Timmermann et al., 2003).
Global engagement of the basal gangliathalamocortical circuits in synchronized oscillatory bursts may severely disrupt processing
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T. Wichmann and M. R. DeLong
at all levels of the circuitry. This may affect
cortical activities such as event-related modulation of beta-band oscillations, or functions
such as motor planning or sequence learning.
In support of this concept, 10-Hz stimulation
of the STN area has been shown to exacerbate akinesia (Timmermann et al., 2004). It
has been speculated that DBS may act to
desynchronize neurons in the basal ganglia
(Brown et al., 2004). A recent study in
MPTP-treated primates demonstrated that
high-frequency cortical stimulation may also
have antiparkinsonian effects, perhaps by the
same mechanism (Drouot et al., 2004).
Although it is tempting to speculate that
parkinsonian tremor may directly result from
synchronized oscillatory bursting in the basal
ganglia, studies of the correlation or coherence between tremor and basal ganglia oscillations have not been conclusive, perhaps
resulting from the fact that different limbs
of parkinsonian patients may engage in tremor of different frequencies (Bergman et al.,
1998), making it difficult to identify a
‘causative’ basal ganglia oscillation for a
given tremor movement. Although often associated with tremor (Levy et al., 2002), synchronized oscillations do not always result in
tremor (Soares et al., 2004; Heimer et al.,
2002). Additional anatomic or physiologic
factors (poorly defined at this moment) may
be necessary for tremor to occur.
It remains unclear at this point whether
clinical symptoms such as tremor, akinesia
or bradykinesia result from the impairment
of specific cortical regions or motor loop
sub-circuits (e.g., those centered on the supplementary motor area, motor cortex or other
pre-central motor fields) or from incomplete
functional compensation through less affected areas of frontal cortex.
Conclusion
Earlier models of the pathophysiology of
Parkinson’s disease that emphasized the importance of changes in discharge rates in the
basal ganglia of parkinsonian subjects, have
been supplanted by a more complex scheme
in which pattern changes take center stage.
Rate and pattern changes are not, however,
mutually exclusive. In fact, some of the rate
changes are probably explained by the emerging pattern abnormalities, such as bursts in
discharge. It appears that these rate and pattern changes in the basal ganglia-thalamocortical pathways actively disrupt cortical
processing. The strongest argument in favor
of this view is the fact that neurosurgical
interventions which eliminate the disordered
activity in the basal ganglia either through
chronic electrical stimulation or lesions result
in immediate improvements of parkinsonian
motor signs, and in a relative ‘normalization’
of activity in cortical motor areas (as judged
by functional imaging).
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Author’s address: M. R. DeLong, MD, Department
of Neurology, Emory University, Suite 6000, Woodruff
Memorial Research Building, 1639 Pierce Drive,
Atlanta, GA 30322, USA, e-mail: [email protected]