{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T09:02:26Z","timestamp":1793437346572,"version":"4.5.0"},"reference-count":51,"publisher":"Wiley","issue":"22","license":[{"start":{"date-parts":[[2017,9,30]],"date-time":"2017-09-30T00:00:00Z","timestamp":1506729600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Cyberonics","award":["27237"],"award-info":[{"award-number":["27237"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2017,11,15]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>The evoked cardiac response to bipolar cervical vagus nerve stimulation (VNS) reflects a dynamic interaction between afferent mediated decreases in central parasympathetic drive and suppressive effects evoked by direct stimulation of parasympathetic efferent axons to the heart.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The neural fulcrum is defined as the operating point, based on frequency\u2013amplitude\u2013pulse width, where a null heart rate response is reproducibly evoked during the on\u2010phase of VNS.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Cardiac control, based on the principal of the neural fulcrum, can be elicited from either vagus.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Beta\u2010receptor blockade does not alter the tachycardia phase to low intensity VNS, but can increase the bradycardia to higher intensity VNS.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>While muscarinic cholinergic blockade prevented the VNS\u2010induced bradycardia, clinically relevant doses of ACE inhibitors, beta\u2010blockade and the funny channel blocker ivabradine did not alter the VNS chronotropic response.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>While there are qualitative differences in VNS heart control between awake and anaesthetized states, the physiological expression of the neural fulcrum is maintained.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Vagus nerve stimulation (VNS) is an emerging therapy for treatment of chronic heart failure and remains a standard of therapy in patients with treatment\u2010resistant epilepsy. The objective of this work was to characterize heart rate (HR) responses (HRRs) during the active phase of chronic VNS over a wide range of stimulation parameters in order to define optimal protocols for bidirectional bioelectronic control of the heart. In normal canines, bipolar electrodes were chronically implanted on the cervical vagosympathetic trunk bilaterally with anode cephalad to cathode (<jats:italic>n<\/jats:italic>\u00a0=\u00a08, \u2018cardiac\u2019 configuration) or with electrode positions reversed (<jats:italic>n<\/jats:italic>\u00a0=\u00a08, \u2018epilepsy\u2019 configuration). In awake state, HRRs were determined for each combination of pulse frequency (2\u201320\u00a0Hz), intensity (0\u20133.5\u00a0mA) and pulse widths (130\u2013750\u00a0\u03bcs) over 14\u00a0months. At low intensities and higher frequency VNS, HR increased during the VNS active phase owing to afferent modulation of parasympathetic central drive. When functional effects of afferent and efferent fibre activation were balanced, a null HRR was evoked (defined as \u2018neural fulcrum\u2019) during which HRR\u00a0\u2248\u00a00. As intensity increased further, HR was reduced during the active phase of VNS. While qualitatively similar, VNS delivered in the epilepsy configuration resulted in more pronounced HR acceleration and reduced HR deceleration during VNS. At termination, under anaesthesia, transection of the vagi rostral to the stimulation site eliminated the augmenting response to VNS and enhanced the parasympathetic efferent\u2010mediated suppressing effect on electrical and mechanical function of the heart. In conclusion, VNS activates central then peripheral aspects of the cardiac nervous system. VNS control over cardiac function is maintained during chronic therapy.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp274678","type":"journal-article","created":{"date-parts":[[2017,9,1]],"date-time":"2017-09-01T11:52:40Z","timestamp":1504266760000},"page":"6887-6903","source":"Crossref","is-referenced-by-count":152,"title":["Defining the neural fulcrum for chronic vagus nerve stimulation: implications for integrated cardiac control"],"prefix":"10.1113","volume":"595","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9241-0864","authenticated-orcid":false,"given":"Jeffrey L.","family":"Ardell","sequence":"first","affiliation":[{"name":"UCLA Neurocardiology Research Center of Excellence and UCLA Cardiac Arrhythmia Center, Los Angeles  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heath","family":"Nier","sequence":"additional","affiliation":[{"name":"Biomedical Sciences East Tennessee State University  Johnson City TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Hammer","sequence":"additional","affiliation":[{"name":"UCLA Neurocardiology Research Center of Excellence and UCLA Cardiac Arrhythmia Center, Los Angeles  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. Marie","family":"Southerland","sequence":"additional","affiliation":[{"name":"Biomedical Sciences East Tennessee State University  Johnson City TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher L.","family":"Ardell","sequence":"additional","affiliation":[{"name":"Biomedical Sciences East Tennessee State University  Johnson City TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2907-7768","authenticated-orcid":false,"given":"Eric","family":"Beaumont","sequence":"additional","affiliation":[{"name":"Biomedical Sciences East Tennessee State University  Johnson City TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce H.","family":"KenKnight","sequence":"additional","affiliation":[{"name":"New Ventures LivaNova plc  Houston TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Andrew","family":"Armour","sequence":"additional","affiliation":[{"name":"UCLA Neurocardiology Research Center of Excellence and UCLA Cardiac Arrhythmia Center, Los Angeles  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,9,30]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1088\/1741-2560\/8\/3\/034004"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP271869"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/cphy.c150046"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00557.2015"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2016.07.009"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1113\/expphysiol.2007.041178"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00939.2015"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2006.01.002"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/nmo.12076"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2016.08.089"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12265-014-9540-1"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.80"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.114.302589"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.304679"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2016.03.525"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP270818"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP271840"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.90306.2008"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ahj.2012.03.021"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1964.sp007520"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0114498"},{"key":"e_1_2_5_23_1","first-page":"581","volume-title":"Handbook of Physiology","author":"Levy MN","year":"1979"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1997.272.6.H2525"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.53.8.1731"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.98.15.1510"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02260935"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1973.53.1.159"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardfail.2014.08.009"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardfail.2015.11.002"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1985.249.1.H133"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplegacy.1974.227.2.444"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2009.04.015"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10741-010-9209-z"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00443.2016"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2014.04.032"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2013.08.009"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP271870"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autneu.2012.03.003"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00087.2006"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2014.12.026"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)61198-1"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.114.03699"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.05.011"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00252.2015"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00558.2015"},{"key":"e_1_2_5_47_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00279.2014"},{"key":"e_1_2_5_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2016.05.011"},{"key":"e_1_2_5_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2013.05.019"},{"key":"e_1_2_5_50_1","doi-asserted-by":"publisher","DOI":"10.1088\/1741-2560\/10\/2\/026003"},{"key":"e_1_2_5_51_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehu345"},{"key":"e_1_2_5_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hfc.2011.08.007"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1113%2FJP274678","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP274678","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,26]],"date-time":"2023-09-26T15:12:53Z","timestamp":1695741173000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP274678"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9,30]]},"references-count":51,"journal-issue":{"issue":"22","published-print":{"date-parts":[[2017,11,15]]}},"alternative-id":["10.1113\/JP274678"],"URL":"https:\/\/doi.org\/10.1113\/jp274678","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,9,30]]}}}