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Phase-amplitude coupling (PAC) indicating the dynamic integration between the gamma amplitude and the phase of low-frequency (4\u201312\u2005Hz) oscillations is a useful alternative to capture local gamma activity. In addition, PAC is also an index of neuronal excitability as the phase of low-frequency oscillations that modulate gamma amplitude, effectively regulates the excitability of local neuronal firing. In this study, we sought to examine the local neuronal activity and excitability using gamma PAC, within brain regions vulnerable to early AD pathophysiology\u2014entorhinal cortex and parahippocampus, in a clinical population of patients with AD and age-matched controls. Our clinical cohorts consisted of a well-characterized cohort of AD patients (n = 50; age, 60 \u00b1 8 years) with positive AD biomarkers, and age-matched, cognitively unimpaired controls (n = 35; age, 63 \u00b1 5.8 years). We identified the presence or the absence of epileptiform activity in AD patients (AD patients with epileptiform activity, AD-EPI+, n = 20; AD patients without epileptiform activity, AD-EPI\u2212, n = 30) using long-term electroencephalography (LTM-EEG) and 1-hour long magnetoencephalography (MEG) with simultaneous EEG. Using the source reconstructed MEG data, we computed gamma PAC as the coupling between amplitude of the gamma frequency (30\u201340\u2005Hz) with phase of the theta (4\u20138\u2005Hz) and alpha (8\u201312\u2005Hz) frequency oscillations, within entorhinal and parahippocampal cortices. We found that patients with AD have reduced gamma PAC in the left parahippocampal cortex, compared to age-matched controls. Furthermore, AD-EPI+ patients showed greater reductions in gamma PAC than AD-EPI\u2212 in bilateral parahippocampal cortices. In contrast, entorhinal cortices did not show gamma PAC abnormalities in patients with AD. Our findings demonstrate the spatial patterns of altered gamma oscillations indicating possible region-specific manifestations of network hyperexcitability within medial temporal lobe regions vulnerable to AD pathophysiology. Greater deficits in AD-EPI+ suggests that reduced gamma PAC is a sensitive index of network hyperexcitability in AD patients. Collectively, the current results emphasize the importance of investigating the role of neural circuit hyperexcitability in early AD pathophysiology and explore its potential as a modifiable contributor to AD pathobiology.<\/jats:p>","DOI":"10.1093\/braincomms\/fcae121","type":"journal-article","created":{"date-parts":[[2024,4,7]],"date-time":"2024-04-07T18:43:38Z","timestamp":1712515418000},"source":"Crossref","is-referenced-by-count":25,"title":["Abnormal gamma phase-amplitude coupling in the parahippocampal cortex is associated with network hyperexcitability in Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"6","author":[{"given":"Pooja","family":"Prabhu","sequence":"first","affiliation":[{"name":"Department of Radiology and Biomedical Imaging, University of California San Francisco , San Francisco, CA 94158 , USA"},{"name":"Department of Data science and Computer Applications, Manipal Institute of Technology , Manipal 576104 , India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirofumi","family":"Morise","sequence":"additional","affiliation":[{"name":"Department of Radiology and Biomedical Imaging, University of California San Francisco , San Francisco, CA 94158 , USA"},{"name":"Medical Imaging Business Center, Ricoh Company Ltd. , Kanazawa 920-0177 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5732-7229","authenticated-orcid":false,"given":"Kiwamu","family":"Kudo","sequence":"additional","affiliation":[{"name":"Department of Radiology and Biomedical Imaging, University of California San Francisco , San Francisco, CA 94158 , USA"},{"name":"Medical Imaging Business Center, Ricoh Company Ltd. , Kanazawa 920-0177 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Beagle","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Department of Neurology, University of California San Francisco , San Francisco, CA 94158 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Mizuiri","sequence":"additional","affiliation":[{"name":"Department of Radiology and Biomedical Imaging, University of California San Francisco , San Francisco, CA 94158 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faatimah","family":"Syed","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Department of Neurology, University of California San Francisco , San Francisco, CA 94158 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karunakar A","family":"Kotegar","sequence":"additional","affiliation":[{"name":"Department of Data science and Computer Applications, Manipal Institute of Technology , Manipal 576104 , India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Findlay","sequence":"additional","affiliation":[{"name":"Department of Radiology and Biomedical Imaging, University of California San Francisco , San Francisco, CA 94158 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce L","family":"Miller","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Department of Neurology, University of California San Francisco , San Francisco, CA 94158 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel H","family":"Kramer","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Department of Neurology, University of California San Francisco , San Francisco, CA 94158 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine P","family":"Rankin","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Department of Neurology, University of California San Francisco , San Francisco, CA 94158 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A","family":"Garcia","sequence":"additional","affiliation":[{"name":"Epilepsy Center, Department of Neurology, University of California San Francisco , San Francisco, CA 94158 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi E","family":"Kirsch","sequence":"additional","affiliation":[{"name":"Department of Radiology and Biomedical Imaging, University of California San Francisco , San Francisco, CA 94158 , USA"},{"name":"Epilepsy Center, Department of Neurology, University of California San Francisco , San Francisco, CA 94158 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Vossel","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, Department of Neurology, University of California San Francisco , San Francisco, CA 94158 , USA"},{"name":"Mary S. 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