вход по аккаунту


Basal ganglia pathophysiology in Parkinson's disease.

код для вставкиСкачать
Basal Ganglia Pathophysiology in Parkinson’s
Erwin B. Montgomery Jr., MD
Obeso and colleagues’1 review of parkinsonian pathophysiology perpetuates a mistaken notion that overactivity of the
globus pallidus pars interna (GPi) and subthalamic nucleus
(STN) are causal (the GPi rate theory) where motor dysfunction results from excessive GPi inhibition of the ventrolateral
thalamus (VL)-motor cortical circuits. Unfortunately, the authors considered only studies of 1-methyl-4-phenyl-1, 2, 3,
6-tetrahydroxypyridine (MPTP)– or 6-hydroxydopamine (6OHDA)–induced parkinsonism in laboratory animals. Not
considered was the most direct evidence against, at least,
STN overactivity. Microelectrode recordings in the STN of
patients with Parkinson’s disease after an overnight fast of
anti-Parkinson’s medications and patients with epilepsy demonstrate no differences in baseline neuronal activity.2 Further, the neuronal spike trains in the two conditions are virtually identical Poisson random possesses.
Closer analyses belie the GPi rate theory based on MPTP
studies. Demonstrated increased GPi and STN activity in
MPTP-treated nonhuman primates likely are artifact due to
overdosing of MPTP. The authors cite Filion and Trembly3 in
support of the GPi rate theory. However, not mentioned is
that the initial increase in GPi activity became more normal
with time despite continued parkinsonism. Other studies find
no change in baseline globus pallidus pars externa and VL
neuronal activities in nonhuman primates carefully dosed with
MPTP to produce moderate parkinsonism evidenced by concomitant typical changes in 2-deoxyglucose (2-DG) utilization.4 Furthermore, studies demonstrate no changes in motor
cortex neuronal discharge rates (reviewed elsewhere5). Obeso
and colleagues1 posit decreased rates in globus pallidus pars
externa, VL, and motor cortex.
The theories that Obeso and colleagues’1 advanced also fundamentally depend on the notion that GPi inhibits VL neurons.
This is not entirely true. Recordings of VL neurons in a human
with GPi deep brain stimulation demonstrates a period of inhibition as expected.6 However, most VL neurons demonstrate a
pronounced rebound excitation that for some is a net increase
analogous to delayed excitation and contrary to mechanisms
central to the theories that Obeso and colleagues’1 advanced.
No one can doubt the historical heuristic value of the GPi
rate theory; but its continued use in explaining observations,
framing hypotheses, and judging alternatives is likely to be
an obstacle to a greater understanding of basal ganglia physiology and pathophysiology.
Department of Neurology, National Primate Research Center,
University of Wisconsin-Madison, Madison, WI
Potential conflict of interest: Nothing to report.
1. Obeso J, Marin C, Rodriguez-Oroz C, et al. The basal ganglia in
Parkinson’s disease: current concepts and unexplained observations. Ann Neurol 2008;64:S30 –S46.
2. Montgomery EB, Jr. Subthalamic nucleus neuronal activity in
Parkinson’s disease and epilepsy patients. Parkinsonism Relat
Disord 2008;14:120 –125.
© 2009 American Neurological Association
3. Filion M, Tremblay L. Abnormal spontaneous activity of globus
pallidus neurons in monkeys with MPTP-induced parkinsonism.
Brain Res 1991;547:142–151.
4. Montgomery EB, Jr., Buchholz SR, Delitto A, Collins RC. Alterations in basal ganglia physiology following MPTP in monkeys. New York: Academic Press, 1986:679 – 682.
5. Montgomery EB Jr. Basal ganglia physiology and pathophysiology: a reappraisal. Parkinsonism Relat Disord 2007;13:
455– 465.
6. Montgomery EB Jr. Effects of GPi stimulation on human thalamic neuronal activity. Clin Neurophysiol 2006;117:2691–2702.
DOI: 10.1002/ana.21649
Reply to Montgomery
Jose A. Obeso, MD,1 and C. Warren Olanow, MD2
Montgomery1 questions the relevance and the accuracy of the
finding of increased neuronal firing frequency in the subthalamic nucleus (STN) and globus pallidus (GPi) in Parkinson’s
disease (PD) based on his own personal study comparing STN
firing frequency in nine patients with PD with two patients
with epilepsy and no healthy control subjects.1 Montgomery
presents no data about the GPi. Although we do not question
his findings, it should be noted that his is the only report we
are aware of indicating that STN firing rate is as low as 7.5Hz
in PD, and contrasts with multiple reports of greater firing
rates (approximately 30Hz) in the STN of patients with
PD.2,3 Indeed, we wonder if the low STN firing frequencies
that Montgomery reported were derived from nonmovementrelated neurons in the ventral STN, which typically have a
lower firing frequency than those in the dorsolateral motor
region.3 Support for increased activity in the STN and GPi in
the dopamine-depleted state is provided by findings in parkinsonian animals using multiple different methods (cytochrome
oxidase and glutamic acid decarboxylase immunostaining and
“in situ” hybridization, 2-deoxyglucose uptake, and neuronal
recordings) in multiple different models (1-methyl-4-phenyl1,2,3,6-tetrahydropyridine [MPTP] mice, unilateral and bilateral 6-hydrodopamine–treated rats, and MPTP monkeys).4
Moreover, studies in PD patients using positron emission tomography with 2-fluoro-deoxyglucose found increased metabolic activity in the STN and GPi, which became more pronounced with disease progression.5 Furthermore, 18-C-H2O
positron emission tomography showed hypoactivity of motor
cortical areas during a joystick movement task in PD patients,
which was reversed by pallidotomy.6 We emphasize in our article that firing frequency is just one component of the neuronal firing pattern, which also includes synchrony, pauses,
bursts, among others, which all likely combine to transmit information from the basal ganglia.
Montgomery1 cites studies showing that initial increases in
GPi firing after MPTP treatment in monkeys were followed by
a subsequent normalization of firing rate. We believe this likely
represents a compensatory effect that accounts for the spontaneous motor improvement that is frequently observed in these animals. The potential of the basal ganglia to act as a network, and
compensate for dopamine depletion and maintain relatively normal behavioral function is one of the key points we tried to
make in our article and could account for the occasional discrepancies in neuronal firing frequencies found in the literature.
How the motor thalamus handles increased afferent activ-
Без категории
Размер файла
39 Кб
disease, ganglia, parkinson, pathophysiology, basal
Пожаловаться на содержимое документа