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Currently, for human disease there are few formal models to explain how cortical networks underlying cognition are affected by synaptic loss. We advocate that biophysical models of neurophysiology offer both a bridge from preclinical to clinical models of pathology and quantitative assays for experimental medicine. Such biophysical models can also disclose hidden neuronal dynamics generating neurophysiological observations such as EEG and magnetoencephalography. Here, we augment a biophysically informed mesoscale model of human cortical function by inclusion of synaptic density estimates as captured by 11C-UCB-J PET, and provide insights into how regional synapse loss affects neurophysiology. We use the primary tauopathy of progressive supranuclear palsy (Richardson\u2019s syndrome) as an exemplar condition, with high clinicopathological correlations. Progressive supranuclear palsy causes a marked change in cortical neurophysiology in the presence of mild cortical atrophy and is associated with a decline in cognitive functions associated with the frontal lobe. Using parametric empirical Bayesian inversion of a conductance-based canonical microcircuit model of magnetoencephalography data, we show that the inclusion of regional synaptic density\u2014as a subject-specific prior on laminar-specific neuronal populations\u2014markedly increases model evidence. Specifically, model comparison suggests that a reduction in synaptic density in inferior frontal cortex affects superficial and granular layer glutamatergic excitation. This predicted individual differences in behaviour, demonstrating the link between synaptic loss, neurophysiology and cognitive deficits. The method we demonstrate is not restricted to progressive supranuclear palsy or the effects of synaptic loss: such pathology-enriched dynamic causal models can be used to assess the mechanisms of other neurological disorders, with diverse non-invasive measures of pathology, and is suitable to test the effects of experimental pharmacology.<\/jats:p>","DOI":"10.1093\/brain\/awac471","type":"journal-article","created":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T17:52:01Z","timestamp":1670867521000},"page":"2584-2594","source":"Crossref","is-referenced-by-count":19,"title":["Neurophysiological consequences of synapse loss in progressive supranuclear palsy"],"prefix":"10.1093","volume":"146","author":[{"given":"Natalie E","family":"Adams","sequence":"first","affiliation":[{"name":"Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge , Cambridge CB2 0SZ , UK"},{"name":"MRC Cognition and Brain Sciences Unit, University of Cambridge , Cambridge CB2 7EF , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amirhossein","family":"Jafarian","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge , Cambridge CB2 0SZ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alistair","family":"Perry","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge , Cambridge CB2 0SZ , UK"},{"name":"MRC Cognition and Brain Sciences Unit, University of Cambridge , Cambridge CB2 7EF , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew A","family":"Rouse","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge , Cambridge CB2 0SZ , UK"},{"name":"MRC Cognition and Brain Sciences Unit, University of Cambridge , Cambridge CB2 7EF , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander D","family":"Shaw","sequence":"additional","affiliation":[{"name":"Washington Singer Laboratories, University of Exeter , Exeter EX4 4QG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander G","family":"Murley","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge , Cambridge CB2 0SZ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas E","family":"Cope","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge , Cambridge CB2 0SZ , UK"},{"name":"MRC Cognition and Brain Sciences Unit, University of Cambridge , Cambridge CB2 7EF , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W Richard","family":"Bevan-Jones","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge , Cambridge CB2 0SZ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7937-0615","authenticated-orcid":false,"given":"Luca","family":"Passamonti","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge , Cambridge CB2 0SZ , UK"},{"name":"MRC Cognition and Brain Sciences Unit, University of Cambridge , Cambridge CB2 7EF , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duncan","family":"Street","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge , Cambridge CB2 0SZ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Negin","family":"Holland","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge , Cambridge CB2 0SZ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Nesbitt","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge , Cambridge CB2 0SZ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura E","family":"Hughes","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge , Cambridge CB2 0SZ , UK"},{"name":"MRC Cognition and Brain Sciences Unit, University of Cambridge , Cambridge CB2 7EF , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7984-8909","authenticated-orcid":false,"given":"Karl J","family":"Friston","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Human Neuroimaging, University College London , London WC1N 3AR , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7216-8679","authenticated-orcid":false,"given":"James B","family":"Rowe","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge , Cambridge CB2 0SZ , UK"},{"name":"MRC Cognition and Brain Sciences Unit, University of Cambridge , Cambridge CB2 7EF , 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