Vagal control of the heart decreases during increasing imminence of interoceptive threat in patients with panic disorder and agoraphobia Author: Jan Richter1, Anne Pietzner2, Julian Koenig3,4, Julian F Thayer5, Christiane A Pané-Farré2,6, Alexander L Gerlach7, Andrew T Gloster8, Hans-Ulrich Wittchen9, Thomas Lang10,11, Georg W Alpers12, Sylvia Helbig-Lang13, Jürgen Deckert14, Thomas Fydrich15, Lydia Fehm15, Andreas Ströhle16, Tilo Kircher17, Volker Arolt18, Alfons O Hamm2 Affiliation: <sup>1</sup> Department of Biological and Clinical Psychology, University of Greifswald, Franz-Mehring-Str. 47, 17487, Greifswald, Germany. jan.richter@uni-greifswald.de. <sup>2</sup> Department of Biological and Clinical Psychology, University of Greifswald, Franz-Mehring-Str. 47, 17487, Greifswald, Germany. <sup>3</sup> Section for Experimental Child and Adolescent Psychiatry, Department of Child and Adolescent Psychiatry, Centre for Psychosocial Medicine, Heidelberg University, Heidelberg, Germany. <sup>4</sup> University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland. <sup>5</sup> Department of Psychological Science, University of California, Irvine, Irvine, USA. <sup>6</sup> Department of Clinical Psychology and Psychotherapy, University of Marburg, Marburg, Germany. <sup>7</sup> Clinical Psychology and Psychotherapy, University of Cologne, Cologne, Germany. <sup>8</sup> Department of Psychology, Division of Clinical Psychology and Intervention Science, University of Basel, Basel, Switzerland. <sup>9</sup> Department of Psychiatry &amp; Psychotherapy, Ludwig-Maximilians-Universität Munich, Munich, Germany. <sup>10</sup> Christoph-Dornier-Foundation for Clinical Psychology, Institute for Clinical Psychology Bremen, Bremen, Germany. <sup>11</sup> Department for Psychology &amp; Methods, Jacobs University Bremen, Bremen, Germany. <sup>12</sup> Department of Psychology, School of Social Sciences, University of Mannheim, Mannheim, Germany. <sup>13</sup> Department of Psychology and Psychotherapy, University of Hamburg, Hamburg, Germany. <sup>14</sup> Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University of Würzburg, Würzburg, Germany. <sup>15</sup> Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany. <sup>16</sup> Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany. <sup>17</sup> Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany. <sup>18</sup> Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany. Conference/Journal: Sci Rep Date published: 2021 Apr 12 Other: Volume ID: 11 , Issue ID: 1 , Pages: 7960 , Special Notes: doi: 10.1038/s41598-021-86867-y. , Word Count: 230 Theoretically, panic disorder and agoraphobia pathology can be conceptualized as a cascade of dynamically changing defensive responses to threat cues from inside the body. Guided by this trans-diagnostic model we tested the interaction between defensive activation and vagal control as a marker of prefrontal inhibition of subcortical defensive activation. We investigated ultra-short-term changes of vagally controlled high frequency heart rate variability (HRV) during a standardized threat challenge (entrapment) in n = 232 patients with panic disorder and agoraphobia, and its interaction with various indices of defensive activation. We found a strong inverse relationship between HRV and heart rate during threat, which was stronger at the beginning of exposure. Patients with a strong increase in heart rate showed a deactivation of prefrontal vagal control while patients showing less heart rate acceleration showed an increase in vagal control. Moreover, vagal control collapsed in case of imminent threat, i.e., when body symptoms increase and seem to get out of control. In these cases of defensive action patients either fled from the situation or experienced a panic attack. Active avoidance, panic attacks, and increased sympathetic arousal are associated with an inability to maintain vagal control over the heart suggesting that teaching such regulation strategies during exposure treatment might be helpful to keep prefrontal control, particularly during the transition zone from post-encounter to circa strike defense.Trial Registration Number: ISRCTN80046034. PMID: 33846417 DOI: 10.1038/s41598-021-86867-y