Functional classification of homologous basal-ganglia networks

The basal ganglia (BG) are a set of nuclei that play an important role in motor and cognitive functions. Indeed many brain diseases such as Parkinson's disease (PD) can be attributed to dysfunction of one or more BG nuclei. The classical model of basal ganglia 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].This is in extension to an earlier model that identified effective connectivities for the STN-TA-TI- sub circuit [2]. As expected, we found that multiple parameter combinations can fit the data [1]. We re-classified these homologous networks that reproduced the healthy and PD state, 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 [3] or oscillations [4,5] 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.Mallet A, Pogosyan A, Márton LF, Bolam JP, Brown P, Magill PJ: Parkinsonian beta oscillations in the external globus pallidus and their relationship with subthalamic nucleus activity. J Neurosci 2008, 28(52): 14245-14258.2.Nevado-Holgado AJ, Mallet N, Magill PJ, Bogacz R: Effective connectivity of the subthalamic nucleus-globus pallidus network during Parkinsonian oscillations. J. Physiol 2014, 592(7): 1429-1455. 3. 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. 4. 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): 214-221.5. 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