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Alterations in Brain Connectivity Underlying Beta Oscillations in Parkinsonism

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  • Rosalyn J Moran
  • Nicolas Mallet
  • Vladimir Litvak
  • Raymond J Dolan
  • Peter J Magill
  • Karl J Friston
  • Peter Brown

Abstract

Cortico-basal ganglia-thalamocortical circuits are severely disrupted by the dopamine depletion of Parkinson's disease (PD), leading to pathologically exaggerated beta oscillations. Abnormal rhythms, found in several circuit nodes are correlated with movement impairments but their neural basis remains unclear. Here, we used dynamic causal modelling (DCM) and the 6-hydroxydopamine-lesioned rat model of PD to examine the effective connectivity underlying these spectral abnormalities. We acquired auto-spectral and cross-spectral measures of beta oscillations (10–35 Hz) from local field potential recordings made simultaneously in the frontal cortex, striatum, external globus pallidus (GPe) and subthalamic nucleus (STN), and used these data to optimise neurobiologically plausible models. Chronic dopamine depletion reorganised the cortico-basal ganglia-thalamocortical circuit, with increased effective connectivity in the pathway from cortex to STN and decreased connectivity from STN to GPe. Moreover, a contribution analysis of the Parkinsonian circuit distinguished between pathogenic and compensatory processes and revealed how effective connectivity along the indirect pathway acquired a strategic importance that underpins beta oscillations. In modelling excessive beta synchrony in PD, these findings provide a novel perspective on how altered connectivity in basal ganglia-thalamocortical circuits reflects a balance between pathogenesis and compensation, and predicts potential new therapeutic targets to overcome dysfunctional oscillations. Author Summary: Parkinson's disease is a progressive age-related neurodegenerative disorder that severely disrupts movement. The major pathology in Parkinson's disease is the degeneration of a group of neurons that contain a chemical known as dopamine. Treatment of Parkinsonism includes pharmacological interventions that aim to replace dopamine and more recently, implanted devices that aim to restore movement through electrical stimulation of the brain's movement circuits. Understanding the electrical properties that emerge as a result of depleted dopamine may reveal new avenues for developing these technologies. By combining a novel model-based approach with multi-site electrophysiological recordings from an animal model of Parkinson's disease we provide empirical evidence for a link between abnormal electrical activity in the Parkinsonian brain and its physiological basis. We have examined the connections along the brain's motor circuits, and found an abnormality in inter-area connections in a particular neural pathway, a pathway critically dependent on dopamine. The scheme makes strong and testable predictions about which neural pathways are significantly altered in the pathological state and so represent empirically motivated therapeutic targets.

Suggested Citation

  • Rosalyn J Moran & Nicolas Mallet & Vladimir Litvak & Raymond J Dolan & Peter J Magill & Karl J Friston & Peter Brown, 2011. "Alterations in Brain Connectivity Underlying Beta Oscillations in Parkinsonism," PLOS Computational Biology, Public Library of Science, vol. 7(8), pages 1-15, August.
  • Handle: RePEc:plo:pcbi00:1002124
    DOI: 10.1371/journal.pcbi.1002124
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    References listed on IDEAS

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    1. Alexxai V. Kravitz & Benjamin S. Freeze & Philip R. L. Parker & Kenneth Kay & Myo T. Thwin & Karl Deisseroth & Anatol C. Kreitzer, 2010. "Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry," Nature, Nature, vol. 466(7306), pages 622-626, July.
    2. Dietmar Plenz & Stephen T. Kital, 1999. "A basal ganglia pacemaker formed by the subthalamic nucleus and external globus pallidus," Nature, Nature, vol. 400(6745), pages 677-682, August.
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