{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T21:06:06Z","timestamp":1783371966046,"version":"3.54.6"},"reference-count":34,"publisher":"IOP Publishing","issue":"6","license":[{"start":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T00:00:00Z","timestamp":1764633600000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T00:00:00Z","timestamp":1764633600000},"content-version":"tdm","delay-in-days":1,"URL":"https:\/\/iopscience.iop.org\/info\/page\/text-and-data-mining"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["R01 NS097782"],"award-info":[{"award-number":["R01 NS097782"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["iopscience.iop.org"],"crossmark-restriction":false},"short-container-title":["J. Neural Eng."],"published-print":{"date-parts":[[2025,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Objective.<\/jats:italic>\n                    Brain networks communicate through long range phase coupling of low frequency oscillations (LFOs, less than 35 Hz) between brain regions. At the same time, phase-amplitude cross-frequency coupling (CFC), in which the phase of the same LFO have been shown to modulate the power of high frequency activity has also been reported across brain regions as a critical regulator of neural activity and excitability. While cross-regional CFC has been reported as a potential mechanism of long-distance modulation of neural excitability, the mechanism underlying this phenomenon has yet to be understood and methods to dissociate the effect of local vs remote LFO have not been developed. Cross-regional CFC can be a result of either LFOs in one region directly modulating high frequency oscillations in another region or due to a chain effect, in which apparent cross-regional CFC results from coupling of LFO across sites.\n                    <jats:italic>Approach.<\/jats:italic>\n                    A novel method of partial modulation index (PMI) is proposed as a derivation of modulation index (MI) and based on Pearl\u2019s do-calculus to remove the mathematical bias of simultaneous phase coupling and CFC measurements. Here, we first test the PMI on a simulated dataset, showing it can differentiate between biased and unbiased CFC. We then evaluate the method on intracranially collected local field potentials recorded simultaneously from thalamus and cortex in a patient undergoing deep brain stimulator implantation for essential tremor, demonstrating that the observed thalamocortical CFC was partially biased.\n                    <jats:italic>Main results.<\/jats:italic>\n                    For both simulated and human datasets, the PMI was compared to the conventional MI. In simulated data, the PMI was able to disentangle cross-regional phase coupling and focal CFC which is not possible using conventional MI. While there is no ground truth for comparison in human data, the results from the simulated data demonstrate the value of the proposed method in removing mathematical bias.\n                    <jats:italic>Significance.<\/jats:italic>\n                    This novel method facilitates a mathematically rigorous characterization of residual CFC, enabling investigations of differential contributions and roles of brain-wide LFO to CFC, which can lead to a more complete understanding of the pathophysiology of neurological processes and disorders.\n                  <\/jats:p>","DOI":"10.1088\/1741-2552\/ae2293","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T22:50:21Z","timestamp":1763765421000},"page":"066022","update-policy":"https:\/\/doi.org\/10.1088\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Untangling cross-regional cross-frequency coupling in dynamic neural oscillations"],"prefix":"10.1088","volume":"22","author":[{"given":"Soroush","family":"Niketeghad","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koorosh","family":"Mirpour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2395-7134","authenticated-orcid":true,"given":"Mahsa","family":"Malekmohammadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evangelia","family":"Tsolaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0426-3241","authenticated-orcid":true,"given":"Nader","family":"Pouratian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0890-8684","authenticated-orcid":true,"given":"William","family":"Speier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"266","published-online":{"date-parts":[[2025,12,2]]},"reference":[{"key":"jneae2293bib1","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.conb.2014.08.002","type":"journal-article","article-title":"Untangling cross-frequency coupling in neuroscience","volume":"31","author":"Aru","year":"2015","journal-title":"Curr. Opin. Neurobiol."},{"key":"jneae2293bib2","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1007\/s004220050556","type":"journal-article","article-title":"On the directionality of cortical interactions studied by structural analysis of electrophysiological recordings","volume":"81","author":"Bernasconi","year":"1999","journal-title":"Biol. Cybern."},{"key":"jneae2293bib3","doi-asserted-by":"publisher","first-page":"9849","DOI":"10.1073\/pnas.0308538101","type":"journal-article","article-title":"Beta oscillations in a large-scale sensorimotor cortical network: directional influences revealed by Granger causality","volume":"101","author":"Brovelli","year":"2004","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"jneae2293bib4","doi-asserted-by":"publisher","first-page":"17356","DOI":"10.1073\/pnas.1008306107","type":"journal-article","article-title":"Oscillatory phase coupling coordinates anatomically dispersed functional cell assemblies","volume":"107","author":"Canolty","year":"2010","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"jneae2293bib5","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1016\/j.tics.2010.09.001","type":"journal-article","article-title":"The functional role of cross-frequency coupling","volume":"14","author":"Canolty","year":"2010","journal-title":"Trends Cogn. Sci."},{"key":"jneae2293bib6","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1016\/j.jneumeth.2005.06.011","type":"journal-article","article-title":"Frequency decomposition of conditional Granger causality and application to multivariate neural field potential data","volume":"150","author":"Chen","year":"2006","journal-title":"J. Neurosci. Methods"},{"key":"jneae2293bib7","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.jneumeth.2003.10.009","type":"journal-article","article-title":"EEGLAB: an open source toolbox for analysis of single-trial EEG dynamics including independent component analysis","volume":"134","author":"Delorme","year":"2004","journal-title":"J. Neurosci. Methods"},{"key":"jneae2293bib8","doi-asserted-by":"publisher","first-page":"eadr3675","DOI":"10.1126\/science.adr3675","type":"journal-article","article-title":"Human high-order thalamic nuclei gate conscious perception through the thalamofrontal loop","volume":"388","author":"Fang","year":"2025","journal-title":"Science"},{"key":"jneae2293bib9","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1016\/j.tics.2005.08.011","type":"journal-article","article-title":"A mechanism for cognitive dynamics: neuronal communication through neuronal coherence","volume":"9","author":"Fries","year":"2005","journal-title":"Trends Cogn. Sci."},{"key":"jneae2293bib10","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1016\/j.conb.2012.11.010","type":"journal-article","article-title":"Analysing connectivity with Granger causality and dynamic causal modelling","volume":"23","author":"Friston","year":"2013","journal-title":"Curr. Opin. Neurobiol."},{"key":"jneae2293bib11","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1016\/j.jneumeth.2010.11.015","type":"journal-article","article-title":"EConnectome: a MATLAB toolbox for mapping and imaging of brain functional connectivity","volume":"195","author":"He","year":"2011","journal-title":"J. Neurosci. Methods"},{"key":"jneae2293bib12","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1186\/s10194-025-02135-8","type":"journal-article","article-title":"Neural oscillation mechanisms of repetitive subconcussive impacts: a network study of microstate-specific cross-frequency coupling","volume":"26","author":"He","year":"2025","journal-title":"J. Headache Pain"},{"key":"jneae2293bib13","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/S0165-0270(02)00366-7","type":"journal-article","article-title":"The use of time-variant EEG Granger causality for inspecting directed interdependencies of neural assemblies","volume":"124","author":"Hesse","year":"2003","journal-title":"J. Neurosci. Methods"},{"key":"jneae2293bib14","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.tics.2007.05.003","type":"journal-article","article-title":"Cross-frequency coupling between neuronal oscillations","volume":"11","author":"Jensen","year":"2007","journal-title":"Trends Cogn. Sci."},{"key":"jneae2293bib15","doi-asserted-by":"publisher","first-page":"186","DOI":"10.3389\/fnhum.2010.00186","type":"journal-article","article-title":"Shaping functional architecture by oscillatory alpha activity: gating by inhibition","volume":"4","author":"Jensen","year":"2010","journal-title":"Front. Hum. Neurosci."},{"key":"jneae2293bib16","doi-asserted-by":"publisher","first-page":"1904","DOI":"10.1152\/jn.00263.2005","type":"journal-article","article-title":"An oscillatory hierarchy controlling neuronal excitability and stimulus processing in the auditory cortex","volume":"94","author":"Lakatos","year":"2005","journal-title":"J. Neurophysiol."},{"key":"jneae2293bib17","doi-asserted-by":"publisher","first-page":"2875","DOI":"10.1097\/00001756-200009110-00009","type":"journal-article","article-title":"Causal influences in primate cerebral cortex during visual pattern discrimination","volume":"11","author":"Liang","year":"2000","journal-title":"NeuroReport"},{"key":"jneae2293bib18","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1016\/j.neuroimage.2013.08.056","type":"journal-article","article-title":"Phase transfer entropy: a novel phase-based measure for directed connectivity in networks coupled by oscillatory interactions","volume":"85","author":"Lobier","year":"2014","journal-title":"Neuroimage"},{"key":"jneae2293bib19","doi-asserted-by":"publisher","first-page":"1618","DOI":"10.1093\/cercor\/bht358","type":"journal-article","article-title":"Human thalamus regulates cortical activity via spatially specific and structurally constrained phase-amplitude coupling","volume":"25","author":"Malekmohammadi","year":"2015","journal-title":"Cerebral Cortex"},{"key":"jneae2293bib20","doi-asserted-by":"publisher","first-page":"2288","DOI":"10.1093\/brain\/awz169","type":"journal-article","article-title":"Propofol-induced loss of consciousness is associated with a decrease in thalamocortical connectivity in humans","volume":"142","author":"Malekmohammadi","year":"2019","journal-title":"Brain"},{"key":"jneae2293bib21","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.jneumeth.2007.03.024","type":"journal-article","article-title":"Nonparametric statistical testing of EEG- and MEG-data","volume":"164","author":"Maris","year":"2007","journal-title":"J. Neurosci. Methods"},{"key":"jneae2293bib22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1002655","type":"journal-article","article-title":"Human motor cortical activity is selectively phase-entrained on underlying rhythms","volume":"8","author":"Miller","year":"2012","journal-title":"PLOS Comput. Biol."},{"key":"jneae2293bib23","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2022.109578","type":"journal-article","article-title":"Measuring phase-amplitude coupling between neural oscillations of different frequencies via the Wasserstein distance","volume":"374","author":"Ohki","year":"2022","journal-title":"J. Neurosci. Methods"},{"key":"jneae2293bib24","doi-asserted-by":"publisher","first-page":"8124","DOI":"10.1523\/JNEUROSCI.1153-19.2019","type":"journal-article","article-title":"The functional role of thalamocortical coupling in the human motor network","volume":"39","author":"Opri","year":"2019","journal-title":"J. Neurosci."},{"key":"jneae2293bib25","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1017\/S0266466603004109","type":"book","article-title":"CAUSALITY: MODELS, REASONING, AND INFERENCE","volume":"vol 19","author":"Pearl","year":"2003"},{"key":"jneae2293bib26","doi-asserted-by":"publisher","first-page":"1545","DOI":"10.1111\/j.1469-8986.2012.01484.x","type":"journal-article","article-title":"Cross-frequency dynamics of neuromagnetic oscillatory activity: two mechanisms of emotion regulation","volume":"49","author":"Popov","year":"2012","journal-title":"Psychophysiology"},{"key":"jneae2293bib27","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1016\/j.neuroimage.2007.11.032","type":"journal-article","article-title":"Cross-frequency phase synchronization: a brain mechanism of memory matching and attention","volume":"40","author":"Sauseng","year":"2008","journal-title":"NeuroImage"},{"key":"jneae2293bib28","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1038\/nrn3137","type":"journal-article","article-title":"Spectral fingerprints of large-scale neuronal interactions","volume":"13","author":"Siegel","year":"2012","journal-title":"Nat. Rev. Neurosci."},{"key":"jneae2293bib29","doi-asserted-by":"publisher","first-page":"1418","DOI":"10.1093\/ndt\/gfu325","type":"journal-article","article-title":"Graphical presentation of confounding in directed acyclic graphs","volume":"30","author":"Suttorp","year":"2015","journal-title":"Nephrol. Dialysis Transplant."},{"key":"jneae2293bib30","doi-asserted-by":"publisher","first-page":"20942","DOI":"10.1073\/pnas.0911331106","type":"journal-article","article-title":"Theta-gamma coupling increases during the learning of item-context associations","volume":"106","author":"Tort","year":"2009","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"jneae2293bib31","doi-asserted-by":"publisher","first-page":"1195","DOI":"10.1152\/jn.00106.2010","type":"journal-article","article-title":"Measuring phase-amplitude coupling between neuronal oscillations of different frequencies","volume":"104","author":"Tort","year":"2010","journal-title":"J. Neurophysiol."},{"key":"jneae2293bib32","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1038\/35067550","type":"journal-article","article-title":"The brainweb: phase synchronization and large-scale integration","volume":"2","author":"Varela","year":"2001","journal-title":"Nat. Rev. Neurosci."},{"key":"jneae2293bib33","doi-asserted-by":"publisher","first-page":"15467","DOI":"10.1523\/JNEUROSCI.2929-12.2012","type":"journal-article","article-title":"Regulation of motor representation by phase-amplitude coupling in the sensorimotor cortex","volume":"32","author":"Yanagisawa","year":"2012","journal-title":"J. Neurosci."},{"key":"jneae2293bib34","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2025.150043","type":"journal-article","article-title":"Cross-frequency brain functional network analysis of auditory stimulation in acute disorders of consciousness","volume":"9","author":"Yin","year":"2025","journal-title":"Brain Res."}],"container-title":["Journal of Neural Engineering"],"original-title":[],"link":[{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1741-2552\/ae2293","content-type":"text\/html","content-version":"am","intended-application":"text-mining"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1741-2552\/ae2293\/pdf","content-type":"application\/pdf","content-version":"am","intended-application":"text-mining"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1741-2552\/ae2293","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1741-2552\/ae2293\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1741-2552\/ae2293\/pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1741-2552\/ae2293\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1741-2552\/ae2293\/pdf","content-type":"application\/pdf","content-version":"am","intended-application":"similarity-checking"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1741-2552\/ae2293\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T13:08:08Z","timestamp":1764680888000},"score":1,"resource":{"primary":{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1741-2552\/ae2293"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,1]]},"references-count":34,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,12,2]]},"published-print":{"date-parts":[[2025,12,1]]}},"URL":"https:\/\/doi.org\/10.1088\/1741-2552\/ae2293","relation":{},"ISSN":["1741-2560","1741-2552"],"issn-type":[{"value":"1741-2560","type":"print"},{"value":"1741-2552","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,1]]},"assertion":[{"value":"Untangling cross-regional cross-frequency coupling in dynamic neural oscillations","name":"article_title","label":"Article Title"},{"value":"Journal of Neural Engineering","name":"journal_title","label":"Journal Title"},{"value":"paper","name":"article_type","label":"Article Type"},{"value":"\u00a9 2025 The Author(s). Published by IOP Publishing Ltd","name":"copyright_information","label":"Copyright Information"},{"value":"2025-05-14","name":"date_received","label":"Date Received","group":{"name":"publication_dates","label":"Publication dates"}},{"value":"2025-11-21","name":"date_accepted","label":"Date Accepted","group":{"name":"publication_dates","label":"Publication dates"}},{"value":"2025-12-02","name":"date_epub","label":"Online publication date","group":{"name":"publication_dates","label":"Publication dates"}}]}}