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Untangling cortico-striatal connectivity and cross-frequency coupling in L-DOPA-induced dyskinesia
KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST). KTH, Centres, Science for Life Laboratory, SciLifeLab. Bernstein Center Freiburg, University of Freiburg, Freiburg, Germany.
Lund University.
Lund University.
Lund University.
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2016 (English)In: Frontiers in Systems Neuroscience, ISSN 1662-5137, E-ISSN 1662-5137, Vol. 10, no 26, p. 1-12Article in journal (Refereed) Published
Abstract [en]

We simultaneously recorded local field potentials in the primary motor cortex and sensorimotor striatum in awake, freely behaving, 6-OHDA lesioned hemi-parkinsonian rats in order to study the features directly related to pathological states such as parkinsonian state and levodopa-induced dyskinesia. We analysed the spectral characteristics of the obtained signals and observed that during dyskinesia the most prominent feature was a relative power increase in the high gamma frequency range at around 80 Hz, while for the parkinsonian state it was in the beta frequency range. Here we show that during both pathological states effective connectivity in terms of Granger causality is bidirectional with an accent on the striatal influence on the cortex. In the case of dyskinesia, we also found a high increase in effective connectivity at 80 Hz. In order to further understand the 80- Hz phenomenon, we performed cross-frequency analysis and observed characteristic patterns in the case of dyskinesia but not in the case of the parkinsonian state or the healthy state. We noted a large decrease in the modulation of the amplitude at 80 Hz by the phase of low frequency oscillations (up to ~10 Hz) across both structures in the case of dyskinesia. This may suggest a lack of coupling between the low frequency activity of the recorded network and the group of neurons active at ~80 Hz.

Place, publisher, year, edition, pages
Frontiers , 2016. Vol. 10, no 26, p. 1-12
Keyword [en]
Cortico-striatal circuits, Levodopa-induced dyskinesia, Parkinson’s disease, effective connectivity, Cross-frequency coupling
National Category
Medical and Health Sciences Natural Sciences
Identifiers
URN: urn:nbn:se:kth:diva-184005DOI: 10.3389/fnsys.2016.00026ISI: 000372965400001Scopus ID: 2-s2.0-84964898882OAI: oai:DiVA.org:kth-184005DiVA, id: diva2:913826
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceSwedish Research Council
Note

QC 20160419

Available from: 2016-03-22 Created: 2016-03-22 Last updated: 2018-02-09Bibliographically approved
In thesis
1. Untangling Cortico-Striatal Circuitry and its Role in Health and Disease - A computational investigation
Open this publication in new window or tab >>Untangling Cortico-Striatal Circuitry and its Role in Health and Disease - A computational investigation
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The basal ganglia (BG) play a critical role in a variety of regular motor and cognitive functions. Many brain diseases, such as Parkinson’s diseases, Huntington’s disease and dyskinesia, are directly related to malfunctions of the BG nuclei. One of those nuclei, the input nucleus called the striatum, is heavily connected to the cortex and receives afferents from nearly all cortical areas. The striatum is a recurrent inhibitory network that contains several distinct cell types. About 95% of neurons in the striatum are medium spiny neurons (MSNs) that form the only output from the striatum. Two of the most examined sources of GABAergic inhibition into MSNs are the feedback inhibition (FB) from the axon collaterals of the MSNs themselves, and the feedforward inhibition (FF) via the small population (1-2% of striatal neurons) of fast spiking interneurons (FSIs). The cortex sends direct projections to the striatum, while the striatum can affect the cortex only indirectly through other BG nuclei and the thalamus. Understanding how different components of the striatal network interact with each other and influence the striatal response to cortical inputs has crucial importance for clarifying the overall functions and dysfunctions of the BG.

    In this thesis I have employed advanced experimental data analysis techniques as well as computational modelling, to study the complex nature of cortico-striatal interactions. I found that for pathological states, such as Parkinson’s disease and L-DOPA-induced dyskinesia, effective connectivity is bidirectional with an accent on the striatal influence on the cortex. Interestingly, in the case of L-DOPA-induced dyskinesia, there was a high increase in effective connectivity at ~80 Hz and the results also showed a large relative decrease in the modulation of the local field potential amplitude (recorded in the primary motor cortex and sensorimotor striatum in awake, freely behaving, 6-OHDA lesioned hemi-parkinsonian rats) at ~80 Hz by the phase of low frequency oscillations. These results suggest a lack of coupling between the low frequency activity of a presumably larger neuronal population and the synchronized activity of a presumably smaller group of neurons active at 80 Hz.

    Next, I used a spiking neuron network model of the striatum to isolate the mechanisms underlying the transmission of cortical oscillations to the MSN population. I showed that FSIs play a crucial role in efficient propagation of cortical oscillations to the MSNs that did not receive direct cortical oscillations. Further, I have identified multiple factors such as the number of activated neurons, ongoing activity, connectivity, and synchronicity of inputs that influenced the transfer of oscillations by modifying the levels of FB and FF inhibitions. Overall, these findings reveal a new role of FSIs in modulating the transfer of information from the cortex to striatum. By modulating the activity and properties of the FSIs, striatal oscillations can be controlled very efficiently. Finally, I explored the interactions in the striatal network with different oscillation frequencies and showed that the features of those oscillations, such as amplitude and frequency fluctuations, can be influenced by a change in the input intensities into MSNs and FSIs and that these fluctuations are also highly dependent on the selected frequencies in addition to the phase offset between different cortical inputs.

    Lastly, I investigated how the striatum responds to cortical neuronal avalanches. Recordings in the striatum revealed that striatal activity was also characterized by spatiotemporal clusters that followed a power law distribution albeit, with significantly steeper slope. In this study, an abstract computational model was developed to elucidate the influence of intrastriatal inhibition and cortico-striatal interplay as important factors to understand the experimental findings. I showed that one particularly high activation threshold of striatal nodes can reproduce a power law-like distribution with a coefficient similar to the one found experimentally. By changing the ratio of excitation and inhibition in the cortical model, I saw that increased activity in the cortex strongly influenced striatal dynamics, which was reflected in a less negative slope of cluster size distributions in the striatum.  Finally, when inhibition was added to the model, cluster size distributions had a prominently earlier deviation from the power law distribution compared to the case when inhibition was not present. 

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2018. p. 88
Series
TRITA-EECS-AVL ; 2018:9
Keyword
cortico-striatal circuits, levodopa-induced dyskinesia, Parkinson’s disease, effective connectivity, cross-frequency coupling, corticostriatal network, network oscillations, GABAergic transmission. basal ganglia, striatum, cortex, fast spiking interneurons, medium spiny neurons, neuronal avalanches
National Category
Neurosciences
Identifiers
urn:nbn:se:kth:diva-222467 (URN)978-91-7729-676-8 (ISBN)
Public defence
2018-03-05, F3, Lindstedtsvägen 26, KTH Campus, Stockholm, 13:15 (English)
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Supervisors
Note

QC 20180209

Available from: 2018-02-09 Created: 2018-02-09 Last updated: 2018-02-09Bibliographically approved

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Hellgren Kotaleski, Jeanette

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