Homologous basal-ganglia networks in physiological and parkinsonian conditions

The classical model of basal ganglia (BG) has been regularly updated with discoveries of new sub-populations within a nucleus or new projections from existing nuclei in recent years. It is unclear how these new insights on the structure of the BG network foster our understanding of its function. The effective connectivities among these recently identified BG sub-populations are only partially known. In the framework of a simple firing-rate model subjected to a genetic algorithm, we identified effective BG connectivities which are consistent with experimentally established firing-rate and phase relationships in Subthalamic Nucleus (STN) and two GPe subpopulations (arkypallidal [GPe-TA] and prototypical [GPe -TI]) in both healthy and PD states [1].Firstly, we found that multiple parameter combinations can fit the data. We functionally re-classified these PD and healthy network models on the basis of two dynamical features: suppression of GPi activity and susceptibility of the BG network to oscillate in the presence of cortical input. These features were chosen because task execution requires GPi suppression while oscillations in the STN-GPe subnetwork are characteristic of PD. We found that most putative pathological networks showed insufficient suppression of GPi activity and high susceptibility to oscillations whereas most putative healthy networks showed sufficient suppression of GPi activity and low susceptibility to oscillations. This is consistent with experimental data that shows that lack of GPi suppression [2] or oscillations [3,4] is correlated with Parkinsonian symptoms such as stymied movement and tremor. A small fraction of networks, however, in both cases show deficiency in only one of the features. This could indicate the configurations of healthy networks that might be more pathology prone and in contrast configurations of pathological networks that might be easier to push into a healthy state. Further analysis of estimated BG connectivity revealed that transitions between the putative PD and healthy networks were possible by modifying the strength of the relevant projections. Most of the transitions involved changes in corticostriatal, striatopallidal and pallidopallidal projections. Finally, the variance observed in the functional classification of putative pathological and healthy networks might hint at the variance observed in manifestation of Parkinson's disease (PD).AcknowledgementsKlinische Forschergruppe (KFO219, TP12) of the Deutsche Forschungsgemeinschaft; Helmholtz Association, EuroSPIN and Erasmus Mundus Joint Doctorate Programme.References1.Abdi A, Mallet N, Mohamed FY, Sharott A, Dodson PD, Nakamura KC, Suri S, Avery SV, Larvin JT, Garas FN, Garas SN, Vinciati F, Morin S, Bezard E, Baufreton J, Magill PJ: Prototypic and Arkypallidal Neurons in the Dopamine-Intact External Globus Pallidus . J Neurosci 2015, 37(17): 6667-6688.2. Boraud T, Bezard E, Bioulac B, Gross CE: Ratio of inhibited-to-activated pallidal neurons decreases dramatically during passive limb movement in the MPTP-treated monkey. J. Physiol 2000, 83(3): 1760-1763. 3. Chen CC, Litvak V, Gilbertson T, Kühn A, Lu CS, Lee ST, Tsai CH, Tisch S, Limousin P, Hariz M, Brown P: Excessive synchronization of basal ganglia neurons at 20 Hz slows movement in Parkinson's disease. Exp Neurol. 2007, 205(1): 214-221.4. Moran A, Bergman H, Israel Z, Bar-Gad I: Subthalamic nucleus functional organization revealed by parkinsonian neuronal oscillations and synchrony. Brain 2008, 131(Pt-12): 3395-3409