{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:10:23Z","timestamp":1753891823709,"version":"3.41.2"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,9]],"date-time":"2023-01-09T00:00:00Z","timestamp":1673222400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To evaluate cortical excitability during instructed threat processing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Single and paired transcranial magnetic stimulation (TMS) pulses were applied to the right dorsomedial prefrontal cortex (dmPFC) during high-density electroencephalography (EEG) recording in young healthy participants (<jats:italic>n<\/jats:italic> = 17) performing an instructed threat paradigm in which one of two conditioned stimuli (CS+ but not CS-) was paired with an electric shock (unconditioned stimulus [US]). We assessed TMS-induced EEG responses with spectral power (both at electrode and source level) and information flow (effective connectivity) using Time-resolved Partial Directed Coherence (TPDC). Support vector regression (SVR) was used to predict behavioral fear ratings for CS+ based on TMS impact on excitability.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>During intracortical facilitation (ICF), frontal lobe theta power was enhanced for CS+ compared to single pulse TMS for the time window 0\u20130.5 s after TMS pulse onset (<jats:italic>t<\/jats:italic>(16) = 3.9, <jats:italic>p<\/jats:italic> &amp;lt; 0.05). At source level, ICF led to an increase and short intracortical inhibition (SICI) to a decrease of theta power in the bilateral dmPFC, relative to single pulse TMS during 0\u20130.5 s. Compared to single pulse TMS, ICF increased information flows, whereas SICI reduced the information flows in theta band between dmPFC, amygdala, and hippocampus (all at <jats:italic>p<\/jats:italic> &amp;lt; 0.05). The magnitude of information flows between dmPFC to amygdala and dmPFC to hippocampus during ICF (0\u20130.5 s), predicted individual behavioral fear ratings (CS+; coefficient above 0.75).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Distinct excitatory and inhibitory mechanisms take place in the dmPFC. These findings may facilitate future research attempting to investigate inhibitory\/facilitatory mechanisms alterations in psychiatric disorders and their behavioral correlates.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnins.2022.1065469","type":"journal-article","created":{"date-parts":[[2023,1,10]],"date-time":"2023-01-10T12:28:48Z","timestamp":1673353728000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Inhibitory and excitatory responses in the dorso-medial prefrontal cortex during threat processing"],"prefix":"10.3389","volume":"16","author":[{"given":"Venkata C.","family":"Chirumamilla","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriel","family":"Gonzalez-Escamilla","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdul Rauf","family":"Anwar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Ding","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Radetz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tamara","family":"Bonertz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergiu","family":"Groppa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muthuraman","family":"Muthuraman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,1,9]]},"reference":[{"key":"B1","first-page":"2628","article-title":"Comparison of causality analysis on simultaneously measured fMRI and NIRS signals during motor tasks.","volume":"2013","author":"Anwar","year":"2013","journal-title":"Annu. Int. Conf. IEEE Eng. Med. Biol. Soc."},{"key":"B2","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1109\/10.668741","article-title":"Adaptive AR modeling of nonstationary time series by means of Kalman filtering.","volume":"45","author":"Arnold","year":"1998","journal-title":"IEEE Trans. Biomed. Eng."},{"key":"B3","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-021-87533-z","article-title":"TMS-EEG signatures of glutamatergic neurotransmission in human cortex.","volume":"11","author":"Belardinelli","year":"2021","journal-title":"Sci. Rep."},{"key":"B4","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.neuroscience.2016.12.047","article-title":"Oscillatory EEG activity induced by conditioning stimuli during fear conditioning reflects Salience and Valence of these stimuli more than expectancy.","volume":"346","author":"Chien","year":"2017","journal-title":"Neuroscience"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2019.00568","article-title":"Cortical excitability dynamics during fear processing.","volume":"13","author":"Chirumamilla","year":"2019","journal-title":"Front. Neurosci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1016\/s1388-2457(00)00533-2","article-title":"Scalp electrode impedance, infection risk, and EEG data quality.","volume":"112","author":"Ferree","year":"2001","journal-title":"Clin. Neurophysiol."},{"key":"B7","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.neuroimage.2010.07.056","article-title":"Human brain connectivity during single and paired pulse transcranial magnetic stimulation.","volume":"54","author":"Ferreri","year":"2011","journal-title":"Neuroimage"},{"key":"B8","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1007\/s00221-008-1620-5","article-title":"The effect of test TMS intensity on short-interval intracortical inhibition in different excitability states.","volume":"193","author":"Garry","year":"2009","journal-title":"Exp. Brain Res."},{"key":"B9","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1007\/s10548-018-0621-3","article-title":"Time-varying connectivity analysis from distributed EEG sources: A simulation study.","volume":"31","author":"Ghumare","year":"2018","journal-title":"Brain Topogr."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-32781-9","article-title":"Excitability regulation in the dorsomedial prefrontal cortex during sustained instructed fear responses: A TMS-EEG study.","volume":"8","author":"Gonzalez-Escamilla","year":"2018","journal-title":"Sci. Rep."},{"key":"B11","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1016\/j.clinph.2012.01.010","article-title":"A practical guide to diagnostic transcranial magnetic stimulation: Report of an IFCN committee.","volume":"123","author":"Groppa","year":"2012","journal-title":"Clin. Neurophysiol."},{"key":"B12","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1073\/pnas.98.2.694","article-title":"Dynamic imaging of coherent sources: Studying neural interactions in the human brain.","volume":"98","author":"Gross","year":"2001","journal-title":"Proc. Natl. Acad. Sci. U.S. A."},{"key":"B13","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1007\/s00221-005-0262-0","article-title":"Physiology of modulation of motor cortex excitability by low-frequency suprathreshold repetitive transcranial magnetic stimulation.","volume":"171","author":"Heide","year":"2006","journal-title":"Exp. Brain Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"14435","DOI":"10.1523\/JNEUROSCI.1833-15.2015","article-title":"Attention modulates TMS-locked alpha oscillations in the visual cortex.","volume":"35","author":"Herring","year":"2015","journal-title":"J. Neurosci."},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jstrokecerebrovasdis.2019.104452","article-title":"Transcranial magnetic stimulation-EEG biomarkers of poststroke upper-limb motor function.","volume":"28","author":"Hordacre","year":"2019","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"B16","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1109\/72.761722","article-title":"Fast and robust fixed-point algorithms for independent component analysis.","volume":"10","author":"Hyv\u00e4rinen","year":"1999","journal-title":"IEEE Trans. Neural Netw."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fnhum.2016.00504","article-title":"Pre-stimulus alpha oscillations and inter-subject variability of motor evoked potentials in single- and paired-pulse TMS paradigms","volume":"10","author":"Iscan","year":"2016","journal-title":"Front. Hum. Neurosci"},{"key":"B18","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1038\/nn.4251","article-title":"4-Hz oscillations synchronize prefrontal-amygdala circuits during fear behavior.","volume":"19","author":"Karalis","year":"2016","journal-title":"Nat. Neurosci."},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0021714","article-title":"Patterns of coupled theta activity in amygdala-hippocampal-prefrontal cortical circuits during fear extinction.","volume":"6","author":"Lesting","year":"2011","journal-title":"PLoS One"},{"key":"B20","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1017\/S0140525X11000446","article-title":"The brain basis of emotion: A meta-analytic review.","volume":"35","author":"Lindquist","year":"2012","journal-title":"Behav. Brain Sci."},{"key":"B21","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1016\/s1388-2457(02)00008-1","article-title":"Inter- and intra-individual variability of paired-pulse curves with transcranial magnetic stimulation (TMS).","volume":"113","author":"Maeda","year":"2002","journal-title":"Clin. Neurophysiol."},{"key":"B22","article-title":"Neurophysiological markers of network dysfunction in neurodegenerative diseases.","volume":"22","author":"McMackin","year":"","journal-title":"Neuroimage Clin."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1136\/jnnp-2018-319581","article-title":"Measuring network disruption in neurodegenerative diseases: New approaches using signal analysis.","volume":"90","author":"McMackin","year":"","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1760","DOI":"10.1016\/j.neuroimage.2009.09.040","article-title":"A meta-analysis of instructed fear studies: Implications for conscious appraisal of threat.","volume":"49","author":"Mechias","year":"2010","journal-title":"Neuroimage"},{"key":"B25","doi-asserted-by":"crossref","first-page":"7365","DOI":"10.1523\/JNEUROSCI.4793-14.2015","article-title":"Neural mechanisms of placebo anxiolysis.","volume":"35","author":"Meyer","year":"2015","journal-title":"J. Neurosci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"3201","DOI":"10.1093\/cercor\/bhy188","article-title":"The functional role of large-scale brain network coordination in placebo-induced anxiolysis.","volume":"29","author":"Meyer","year":"2019","journal-title":"Cereb Cortex"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-56398-8","article-title":"Multimodal alterations of directed connectivity profiles in patients with attention-deficit\/hyperactivity disorders.","volume":"9","author":"Muthuraman","year":"2019","journal-title":"Sci. Rep."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1770","DOI":"10.1093\/brain\/awy098","article-title":"Cerebello-cortical network fingerprints differ between essential. Parkinson\u2019s and mimicked tremors.","volume":"141","author":"Muthuraman","year":"2018","journal-title":"Brain"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1155\/2011\/156869","article-title":"FieldTrip: Open source software for advanced analysis of MEG, EEG, and invasive electrophysiological data.","volume":"2011","author":"Oostenveld","year":"2011","journal-title":"Comput. Intell. Neurosci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.pneurobio.2010.10.003","article-title":"Modulation of cortical excitability induced by repetitive transcranial magnetic stimulation: Influence of timing and geometrical parameters and underlying mechanisms.","volume":"93","author":"Pell","year":"2011","journal-title":"Prog. Neurobiol."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0129293","article-title":"Advanced insights into functional brain connectivity by combining tensor decomposition and partial directed coherence.","volume":"10","author":"Pester","year":"2015","journal-title":"PLoS One"},{"key":"B32","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1038\/86110","article-title":"Activation of the left amygdala to a cognitive representation of fear.","volume":"4","author":"Phelps","year":"2001","journal-title":"Nat. Neurosci."},{"key":"B33","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1006\/nimg.2001.0978","article-title":"Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain.","volume":"15","author":"Tzourio-Mazoyer","year":"2002","journal-title":"Neuroimage"}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2022.1065469\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,10]],"date-time":"2023-01-10T12:29:01Z","timestamp":1673353741000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2022.1065469\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,9]]},"references-count":33,"alternative-id":["10.3389\/fnins.2022.1065469"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2022.1065469","relation":{},"ISSN":["1662-453X"],"issn-type":[{"type":"electronic","value":"1662-453X"}],"subject":[],"published":{"date-parts":[[2023,1,9]]},"article-number":"1065469"}}