Review
INMED/TINS special issue
Pathological synchronization in Parkinson's disease: networks, models and treatments

https://doi.org/10.1016/j.tins.2007.05.004Get rights and content

Parkinson's disease is a common and disabling disorder of movement owing to dopaminergic denervation of the striatum. However, it is still unclear how this denervation perverts normal functioning to cause slowing of voluntary movements. Recent work using tissue slice preparations, animal models and in humans with Parkinson's disease has demonstrated abnormally synchronized oscillatory activity at multiple levels of the basal ganglia–cortical loop. This excessive synchronization correlates with motor deficit, and its suppression by dopaminergic therapies, ablative surgery or deep-brain stimulation might provide the basic mechanism whereby diverse therapeutic strategies ameliorate motor impairment in patients with Parkinson's disease. This review is part of the INMED/TINS special issue, Physiogenic and pathogenic oscillations: the beauty and the beast, based on presentations at the annual INMED/TINS symposium (http://inmednet.com/).

Section snippets

Parkinson's disease and its treatment

Parkinson's disease (PD) is a progressive age-related neurodegenerative disorder, second in frequency only to Alzheimer's disease. It affects tens of millions of people worldwide, and the frequency and associated socioeconomic burden of the condition are set to increase as the elderly population grows. The disease is characterized by poverty of voluntary movements (akinesia), slowness and impaired scaling of voluntary movement (bradykinesia), muscle rigidity and tremor of the limbs at rest. The

Cellular and network basis for oscillations in the basal ganglia

The operation of the basal ganglia network in health and disease is heavily determined by its dual composition: the striatum on the one hand and, on the other, all the other basal ganglia nuclei, comprising the globus pallidus pars externa (GPe) and interna (GPi), STN and the substantia nigra pars reticulata (SNr) (Figure 1). These two neuronal populations have different membrane properties and different organizational principles. Inside the second network, STN deserves a special mention, given

Excessive synchrony in animal models of PD

Monkeys treated with the toxin MPTP show an increase in the fraction of basal ganglia neurons that discharge in bursts. These bursts are either irregular or oscillatory (Figure 2) and have been found in STN, GPe and GPi [18]. In most cases, the bursts follow the frequency of tremor or its higher harmonics. Both STN inactivation [19] and dopamine replacement therapy [20] significantly ameliorate the MPTP tremor and other motor symptoms and reduce 8–20-Hz oscillations in GPi, supporting the

Excessive synchrony in patients with PD

LFPs are more readily recorded from the basal ganglia than the activity of single neurons in patients because the former recordings can also be made in the interval between surgical implantation of the STN or globus pallidus and connection of macroelectrodes to a subcutaneous stimulator a few days later (Figure 3a–c). LFP recordings in patients withdrawn from their antiparkinsonian medication have consistently revealed prominent oscillations between 8 Hz and 30 Hz 26, 27, 28, 29, 30, 31, 32, 33,

How might excessive synchrony impair motor processing?

Information theoretic studies reveal that the information encoded by the simultaneous activity of neurons can be independent, redundant or synergistic 39, 40. These activity modes are strongly, but not simply, related to the level of pairwise correlations between the neuronal elements of the network [41]. Usually, one can assume that a correlated network is redundant, offering stability against the possible results of the extinction of one or several neurons in the network. In that case, the

Do therapies for PD suppress excessive synchrony?

PD is treated today mainly by dopaminergic drugs, particularly levodopa, deep-brain stimulation or lesioning of the basal ganglia. The latter suppresses spontaneous beta synchrony at the operation target, but what of the other therapeutic approaches? As already stated, treatment with dopaminergic drugs suppresses beta synchrony, particularly that at lower frequencies within this band. This relationship is a graded one, with the amount of drug-induced suppression in the STN [27] and cerebral

Conclusion and future research

There are increasing amounts of data linking excessive synchrony at low beta frequencies in basal ganglia-cortical loops to impaired motor processing in PD. Nevertheless, this evidence remains correlative in nature and is notably challenged by a recent model of basal ganglia function that suggests that action selection is impaired before the appearance of oscillations [66], although interpretation of this model in the context of PD assumes that failure of action selection leads to bradykinesia.

Acknowledgements

P.B. was supported by the Medical Research Council, UK; H.B. was supported by the ‘Fighting against Parkinson’ Foundation of the Hebrew University Netherlands Association (HUNA); C.H. was supported by CNRS, Inserm and Fondation de France. C.H. thanks Liliana Garcia, Rachida Ammari and Bernard Bioulac.

References (72)

  • P. Brown et al.

    Basal ganglia local field potential activity: character and functional significance in the human

    Clin. Neurophysiol.

    (2005)
  • A. Priori

    Rhythm-specific pharmacological modulation of subthalamic activity in Parkinson's disease

    Exp. Neurol.

    (2004)
  • A.A. Kühn

    The relationship between local field potential and neuronal discharge in the subthalamic nucleus of patients with Parkinson's disease

    Exp. Neurol.

    (2005)
  • D. Devos

    Predominance of the contralateral movement-related activity in the subthalamo-cortical loop

    Clin. Neurophysiol.

    (2006)
  • P.J. Uhlhaas et al.

    Neural synchrony in brain disorders: relevance for cognitive dysfunctions and pathophysiology

    Neuron

    (2006)
  • H. Bergman

    Physiological aspects of information processing in the basal ganglia of normal and parkinsonian primates

    Trends Neurosci.

    (1998)
  • I. Bar-Gad

    Information processing, dimensionality reduction and reinforcement learning in the basal ganglia

    Prog. Neurobiol.

    (2003)
  • P. Brown

    Effects of stimulation of the subthalamic area on oscillatory pallidal activity in Parkinson's disease

    Exp. Neurol.

    (2004)
  • B. Wingeier

    Intra-operative STN DBS attenuates the prominent beta rhythm in the STN in Parkinson's disease

    Exp. Neurol.

    (2006)
  • G. Foffani

    Subthalamic oscillatory activities at beta or higher frequency do not change after high-frequency DBS in Parkinson's disease

    Br. Res. Bull.

    (2006)
  • M. Rivlin-Etzion

    Basal ganglia oscillations and pathophysiology of movement disorders

    Curr. Opin. Neurobiol.

    (2006)
  • L. Garcia

    High-frequency stimulation in Parkinson's disease: more or less?

    Trends Neurosci.

    (2005)
  • X. Drouot

    Functional recovery in a primate model of Parkinson's disease following motor cortex stimulation

    Neuron

    (2004)
  • N. Fogelson

    Frequency dependent effects of subthalamic nucleus stimulation in Parkinson's disease

    Neurosci. Lett.

    (2005)
  • C.C. Chen

    Excessive synchronisation of basal ganglia neurons at 20 Hz slows movement in Parkinson's disease

    Exp. Neurol.

    (2007)
  • H. Nakanishi

    Intracellular study of rat entopeduncular nucleus neurons in an in vitro slice preparation: response to subthalamic stimulation

    Brain Res.

    (1991)
  • J.P. Bolam

    Synaptic organisation of the basal ganglia

    J. Anat.

    (2000)
  • E.S. Nisenbaum et al.

    Potassium currents responsible for inward and outward rectification in rat neostriatal spiny projection neurons

    J. Neurosci.

    (1995)
  • N. Mallet

    Feedforward inhibition of projection neurons by fast-spiking GABA interneurons in the rat striatum in vivo

    J. Neurosci.

    (2005)
  • K.Y. Tseng

    Cortical slow oscillatory activity is reflected in the membrane potential and spike trains of striatal neurons in rats with chronic nigrostriatal lesions

    J. Neurosci.

    (2001)
  • P.J. Magill

    Relationship of activity in the subthalamic nucleus-globus pallidus network to cortical electroencephalogram

    J. Neurosci.

    (2000)
  • M.G. Murer

    Brain oscillations, medium spiny neurons, and dopamine

    Cell. Mol. Neurobiol.

    (2002)
  • J. Baufreton

    Enhancement of excitatory synaptic integration by GABAergic inhibition in the subthalamic nucleus

    J. Neurosci.

    (2005)
  • S.M. Nicola

    Dopaminergic modulation of neuronal excitability in the striatum and nucleus accumbens

    Annu. Rev. Neurosci.

    (2000)
  • T. Wichmann et al.

    Neuronal firing before and after burst discharges in the monkey basal ganglia is predictably patterned in the normal state and altered in parkinsonism

    J. Neurophysiol.

    (2006)
  • T. Wichmann

    The primate subthalamic nucleus. III. Changes in motor behavior and neuronal activity in the internal pallidum induced by subthalamic inactivation in the MPTP model of parkinsonism

    J. Neurophysiol.

    (1994)
  • Cited by (1306)

    View all citing articles on Scopus
    View full text