{"doi":"10.1111/ejn.12868","title":"Combined lesions of direct and indirect basal ganglia pathways but not changes in dopamine levels explain learning deficits in patients with Huntington's disease","abstract":"<jats:title>Abstract</jats:title><jats:p>Huntington's disease (<jats:styled-content style=\"fixed-case\">HD</jats:styled-content>) is a hereditary neurodegenerative disease of the basal ganglia that causes severe motor, cognitive and emotional dysfunctions. In the human basal ganglia, these dysfunctions are accompanied by a loss of striatal medium spiny neurons, dysfunctions of the subthalamic nucleus and globus pallidus, and changes in dopamine receptor binding. Here, we used a neuro‐computational model to investigate which of these basal ganglia dysfunctions can explain patients’ deficits in different stimulus–response learning paradigms. We show that these paradigms are particularly suitable for scrutinising the effects of potential changes in dopamine signaling and of potential basal ganglia lesions on overt behavior in <jats:styled-content style=\"fixed-case\">HD</jats:styled-content>. We find that combined lesions of direct and indirect basal ganglia pathways, but none of these lesions alone, reproduce patients’ learning impairments. Degeneration of medium spiny neurons of the direct pathway accounts for patients’ deficits in facilitating correct responses, whereas degeneration of indirect pathway medium spiny neurons explains their impairments in inhibiting dominant but incorrect responses. The empirical results cannot be explained by lesions of the subthalamic nucleus, which is part of the hyperdirect pathway, or by changes in dopamine levels. Overall, our simulations suggest combined lesions of direct and indirect pathways as a major source of <jats:styled-content style=\"fixed-case\">HD</jats:styled-content> patients’ learning impairments and, tentatively, also their motor and cognitive deficits in general, whereas changes in dopamine levels are suggested to not be causally related to patients’ impairments.</jats:p>","journal":"European Journal of Neuroscience","year":2015,"id":594610,"datarank":0.4335557636844247,"base_score":2.8903717578961645,"endowment":2.8903717578961645,"self_citation_contribution":0.4335557636844247,"citation_network_contribution":0.0,"self_endowment_contribution":0.4335557636844247,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":17,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":618357,"name":"Christian Beste","orcid":"0000-0002-2989-9561","position":1,"is_corresponding":false},{"id":1522244,"name":"Fred H. 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Here, we used a neuro‐computational model to investigate which of these basal ganglia dysfunctions can explain patients’ deficits in different stimulus–response learning paradigms. We show that these paradigms are particularly suitable for scrutinising the effects of potential changes in dopamine signaling and of potential basal ganglia lesions on overt behavior in <jats:styled-content style=\"fixed-case\">HD</jats:styled-content>. We find that combined lesions of direct and indirect basal ganglia pathways, but none of these lesions alone, reproduce patients’ learning impairments. Degeneration of medium spiny neurons of the direct pathway accounts for patients’ deficits in facilitating correct responses, whereas degeneration of indirect pathway medium spiny neurons explains their impairments in inhibiting dominant but incorrect responses. The empirical results cannot be explained by lesions of the subthalamic nucleus, which is part of the hyperdirect pathway, or by changes in dopamine levels. Overall, our simulations suggest combined lesions of direct and indirect pathways as a major source of <jats:styled-content style=\"fixed-case\">HD</jats:styled-content> patients’ learning impairments and, tentatively, also their motor and cognitive deficits in general, whereas changes in dopamine levels are suggested to not be causally related to patients’ impairments.</jats:p>","is_dataset_classified":null,"base_score":2.8903717578961645,"endowment":2.8903717578961645,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"25778633","pmcid":null,"openalex_id":"https://openalex.org/W2089643759","authors":[],"funders":[{"funder_name":"Deutsche Forschungsgemeinschaft","grant_id":"DFG HA2630/7-2","title":null},{"funder_name":"Deutsche Forschungsgemeinschaft","grant_id":"DFG HA2630/8-1","title":null},{"funder_name":"Deutsche Forschungsgemeinschaft","grant_id":"DFG BE4045/10-1","title":null},{"funder_name":"Deutsche Forschungsgemeinschaft","grant_id":"DFG BE4045/10-2","title":null},{"funder_name":"Deutsche Forschungsgemeinschaft","grant_id":"unidentified","title":"unidentified"}],"total_grants":5,"fwci":1.241,"citation_percentile":0.75910158,"influential_citations":0,"citation_trend":[{"year":2015,"count":2},{"year":2016,"count":1},{"year":2017,"count":3},{"year":2018,"count":3},{"year":2019,"count":1},{"year":2020,"count":1},{"year":2021,"count":3},{"year":2022,"count":1},{"year":2024,"count":2}],"oa_status":"closed","license":"Wiley Online Library User Agreement","oa_locations":[{"url":"https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1111%2Fejn.12868","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/pdf/10.1111/ejn.12868","host_type":"publisher"},{"url":"https://doi.org/10.1111/ejn.12868","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/25778633","host_type":"repository"},{"url":"https://dx.doi.org/10.1111/ejn.12868","host_type":""}],"fields_of_study":["Genetic Neurodegenerative Diseases","Neurological disorders and treatments","Neuroscience and Neuropharmacology Research","0301 basic medicine","03 medical and health sciences","0302 clinical medicine"],"mesh_terms":["Basal Ganglia","Dopamine","Humans","Huntington Disease","Learning","Models, Neurological"],"keywords":["Basal ganglia","Medium spiny neuron","Indirect pathway of movement","Dopamine","Subthalamic nucleus","Neuroscience","Globus pallidus","Direct pathway of movement","Psychology","Huntington's disease","Parkinson's disease","Basal ganglia disease","Disease","Medicine","Central nervous system","Pathology","Deep brain stimulation","Striatum","Neurodegeneration","Computational Modeling","Stimulus-response Learning","Huntington Disease","Models, Neurological","Humans","Learning"],"sdg_mappings":[{"sdg_number":2,"sdg_label":"2. 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