{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T22:05:17Z","timestamp":1791410717165,"version":"4.3.3"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T00:00:00Z","timestamp":1657238400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U54 NS065736"],"award-info":[{"award-number":["U54 NS065736"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001594","name":"Familial Dysautonomia Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001594","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,11,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Despite its increasing recognition and extensive research, there is no unifying hypothesis on the pathophysiology of the postural tachycardia syndrome. In this cross-sectional study, we examined the role of fear conditioning and its association with tachycardia and cerebral hypoperfusion on standing in 28 patients with postural tachycardia syndrome (31 \u00b1 12 years old, 25 females) and 21 matched controls. We found that patients had higher somatic vigilance (P = 0.0167) and more anxiety (P &amp;lt; 0.0001). They also had a more pronounced anticipatory tachycardia right before assuming the upright position in a tilt-table test (P = 0.015), a physiological indicator of fear conditioning to orthostasis. While standing, patients had faster heart rate (P &amp;lt; 0.001), higher plasma catecholamine levels (P = 0.020), lower end-tidal CO2 (P = 0.005) and reduced middle cerebral artery blood flow velocity (P = 0.002). Multi-linear logistic regression modelling showed that both epinephrine secretion and excessive somatic vigilance predicted the magnitude of the tachycardia and the hyperventilation. These findings suggest that the postural tachycardia syndrome is a functional disorder in which standing may acquire a frightful quality, so that even when experienced alone it may elicit a fearful conditioned response. Heightened somatic anxiety is associated with and may predispose to a fear-conditioned hyperadrenergic state when standing. Our results have therapeutic implications.<\/jats:p>","DOI":"10.1093\/brain\/awac249","type":"journal-article","created":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T16:57:56Z","timestamp":1657299476000},"page":"3763-3769","source":"Crossref","is-referenced-by-count":22,"title":["Fear conditioning as a pathogenic mechanism in the postural tachycardia syndrome"],"prefix":"10.1093","volume":"145","author":[{"given":"Lucy","family":"Norcliffe-Kaufmann","sequence":"first","affiliation":[{"name":"Department of Neurology, New York University School of Medicine , New York, NY 10019 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1345-6774","authenticated-orcid":false,"given":"Jose-Alberto","family":"Palma","sequence":"additional","affiliation":[{"name":"Department of Neurology, New York University School of Medicine , New York, NY 10019 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose","family":"Martinez","sequence":"additional","affiliation":[{"name":"Department of Neurology, New York University School of Medicine , New York, NY 10019 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celeste","family":"Camargo","sequence":"additional","affiliation":[{"name":"Department of Neurology, New York University School of Medicine , New York, NY 10019 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Horacio","family":"Kaufmann","sequence":"additional","affiliation":[{"name":"Department of Neurology, New York University School of Medicine , New York, NY 10019 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,7,8]]},"reference":[{"key":"2023053018582009600_awac249-B1","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1016\/j.mayocp.2012.08.013","article-title":"Postural tachycardia syndrome: A heterogeneous and multifactorial disorder","volume":"87","author":"Benarroch","year":"2012","journal-title":"Mayo Clinic Proc"},{"key":"2023053018582009600_awac249-B2","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1007\/s10286-011-0119-5","article-title":"Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome","volume":"21","author":"Freeman","year":"2011","journal-title":"Clin Auton Res"},{"key":"2023053018582009600_awac249-B3","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1017\/S1047951117002888","article-title":"Demographics of a large paediatric postural orthostatic tachycardia syndrome program","volume":"28","author":"Boris","year":"2018","journal-title":"Cardiol Young"},{"key":"2023053018582009600_awac249-B4","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1056\/NEJMra1509723","article-title":"Baroreflex dysfunction","volume":"382","author":"Kaufmann","year":"2020","journal-title":"N Engl J Med"},{"key":"2023053018582009600_awac249-B5","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1056\/NEJM200002243420803","article-title":"Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency","volume":"342","author":"Shannon","year":"2000","journal-title":"N Engl J Med"},{"key":"2023053018582009600_awac249-B6","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1056\/NEJM200010053431404","article-title":"The neuropathic postural tachycardia syndrome","volume":"343","author":"Jacob","year":"2000","journal-title":"N Engl J Med"},{"key":"2023053018582009600_awac249-B7","doi-asserted-by":"crossref","first-page":"3086","DOI":"10.1161\/01.CIR.102.25.3086","article-title":"Abnormal baroreflex responses in patients with idiopathic orthostatic intolerance","volume":"102","author":"Farquhar","year":"2000","journal-title":"Circulation"},{"key":"2023053018582009600_awac249-B8","doi-asserted-by":"crossref","first-page":"H1319","DOI":"10.1152\/ajpheart.00086.2004","article-title":"Regional blood volume and peripheral blood flow in postural tachycardia syndrome","volume":"287","author":"Stewart","year":"2004","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2023053018582009600_awac249-B9","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1161\/01.CIR.0000160356.97313.5D","article-title":"Renin-aldosterone paradox and perturbed blood volume regulation underlying postural tachycardia syndrome","volume":"111","author":"Raj","year":"2005","journal-title":"Circulation"},{"key":"2023053018582009600_awac249-B10","doi-asserted-by":"crossref","first-page":"2858","DOI":"10.1016\/j.jacc.2010.02.043","article-title":"Cardiac origins of the postural orthostatic tachycardia syndrome","volume":"55","author":"Fu","year":"2010","journal-title":"J Am Coll Cardiol"},{"key":"2023053018582009600_awac249-B11","doi-asserted-by":"crossref","first-page":"2871","DOI":"10.1073\/pnas.1400335111","article-title":"Coming to terms with fear","volume":"111","author":"LeDoux","year":"2014","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2023053018582009600_awac249-B12","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1146\/annurev.neuro.24.1.897","article-title":"Neurobiology of Pavlovian fear conditioning","volume":"24","author":"Maren","year":"2001","journal-title":"Annu Rev Neurosci"},{"key":"2023053018582009600_awac249-B13","first-page":"1049","article-title":"Hemodynamics, renal function, plasma renin, and aldosterone in man after 5 to 14 days of bedrest","volume":"46","author":"Melada","year":"1975","journal-title":"Aviat Space Environ Med"},{"key":"2023053018582009600_awac249-B14","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S0022-3956(98)00051-X","article-title":"Epinephrine-induced panic attacks and hyperventilation","volume":"33","author":"van Zijderveld","year":"1999","journal-title":"J Psychiatr Res"},{"key":"2023053018582009600_awac249-B15","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1002\/ana.24877","article-title":"Natural history of pure autonomic failure: A United States prospective cohort","volume":"81","author":"Kaufmann","year":"2017","journal-title":"Ann Neurol"},{"key":"2023053018582009600_awac249-B16","volume-title":"Manual for the State-Trait Anxiety Inventory","author":"Spielberger","year":"1983"},{"key":"2023053018582009600_awac249-B17","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/S0033-3182(71)71479-0","article-title":"A rating instrument for anxiety disorders","volume":"12","author":"Zung","year":"1971","journal-title":"Psychosomatics"},{"key":"2023053018582009600_awac249-B18","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1037\/0022-006X.65.2.214","article-title":"Body vigilance in panic disorder: evaluating attention to bodily perturbations","volume":"65","author":"Schmidt","year":"1997","journal-title":"J Consult Clin Psychol"},{"key":"2023053018582009600_awac249-B19","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1161\/01.CIR.0000155613.20376.CA","article-title":"Neurocirculatory abnormalities in chronic orthostatic intolerance","volume":"111","author":"Goldstein","year":"2005","journal-title":"Circulation"},{"key":"2023053018582009600_awac249-B20","first-page":"1396","article-title":"Hemodynamic characteristics of postural hyperventilation: POTS with hyperventilation versus panic versus voluntary hyperventilation","volume":"125","author":"Stewart","year":"2018","journal-title":"J Appl Physiol 1985"},{"key":"2023053018582009600_awac249-B21","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1002\/ana.21205","article-title":"Enhanced vascular responses to hypocapnia in neurally mediated syncope","volume":"63","author":"Norcliffe-Kaufmann","year":"2008","journal-title":"Ann Neurol"},{"key":"2023053018582009600_awac249-B22","doi-asserted-by":"crossref","first-page":"H1040","DOI":"10.1152\/ajpheart.2001.281.3.H1040","article-title":"PET(CO(2)) inversely affects MSNA response to orthostatic stress","volume":"281","author":"Shoemaker","year":"2001","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2023053018582009600_awac249-B23","doi-asserted-by":"crossref","first-page":"H1226","DOI":"10.1152\/ajpheart.01243.2004","article-title":"Baroreflex control of muscle sympathetic nerve activity in postural orthostatic tachycardia syndrome","volume":"289","author":"Swift N","year":"2005","journal-title":"Am J Physiol Heart Circ Physiol"},{"issue":"6","key":"2023053018582009600_awac249-B24","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/S0361-9230(98)00125-7","article-title":"Connections of the rostral ventral respiratory neuronal cell group: An anterograde and retrograde tracing study in the rat","volume":"47","author":"Gaytan","year":"1998","journal-title":"Brain Res Bull"},{"key":"2023053018582009600_awac249-B25","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.autneu.2016.10.004","article-title":"The genesis and presentation of anxiety in disorders of autonomic overexcitation","volume":"203","author":"Owens","year":"2017","journal-title":"Auton Neurosci"},{"key":"2023053018582009600_awac249-B26","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1152\/japplphysiol.00927.2006","article-title":"Excessive heart rate response to orthostatic stress in postural tachycardia syndrome is not caused by anxiety","volume":"102","author":"Masuki","year":"2007","journal-title":"J Appl Physiol (1985)"},{"key":"2023053018582009600_awac249-B27","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.autneu.2018.03.004","article-title":"Cognitive and psychological issues in postural tachycardia syndrome","volume":"215","author":"Raj","year":"2018","journal-title":"Auton Neurosci"},{"key":"2023053018582009600_awac249-B28","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.brat.2011.04.001","article-title":"A cognitive-behavioral treatment for irritable bowel syndrome using interoceptive exposure to visceral sensations","volume":"49","author":"Craske","year":"2011","journal-title":"Behav Res Ther"},{"key":"2023053018582009600_awac249-B29","doi-asserted-by":"crossref","first-page":"13897","DOI":"10.1073\/pnas.1821032116","article-title":"An interoceptive illusion of effort induced by false heart-rate feedback","volume":"116","author":"Iodice","year":"2019","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2023053018582009600_awac249-B30","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.jns.2017.03.032","article-title":"Quantitative assessment of autonomic symptom burden in Postural tachycardia syndrome (POTS)","volume":"377","author":"Rea","year":"2017","journal-title":"J Neurol Sci"}],"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awac249\/45790807\/awac249.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/145\/11\/3763\/50491295\/awac249.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/145\/11\/3763\/50491295\/awac249.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,30]],"date-time":"2023-05-30T18:59:04Z","timestamp":1685473144000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/article\/145\/11\/3763\/6634171"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,8]]},"references-count":30,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,7,8]]},"published-print":{"date-parts":[[2022,11,21]]}},"URL":"https:\/\/doi.org\/10.1093\/brain\/awac249","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,11,1]]},"published":{"date-parts":[[2022,7,8]]}}}