title: Separating depressive comorbidity from panic disorder: A combined functional magnetic resonance imaging and machine learning approach.
abstract: BACKGROUND
  Depression is frequent in panic disorder (PD); yet, little is known about its influence on the neural substrates of PD. Difficulties in fear inhibition during safety signal processing have been reported as a pathophysiological feature of PD that is attenuated by depression. We investigated the impact of comorbid depression in PD with agoraphobia (AG) on the neural correlates of fear conditioning and the potential of machine learning to predict comorbidity status on the individual patient level based on neural characteristics.
  
  
  METHODS
  Fifty-nine PD/AG patients including 26 (44%) with a comorbid depressive disorder (PD/AG+DEP) underwent functional magnetic resonance imaging (fMRI). Comorbidity status was predicted using a random undersampling tree ensemble in a leave-one-out cross-validation framework.
  
  
  RESULTS
  PD/AG-DEP patients showed altered neural activation during safety signal processing, while +DEP patients exhibited generally decreased dorsolateral prefrontal and insular activation. Comorbidity status was correctly predicted in 79% of patients (sensitivity: 73%; specificity: 85%) based on brain activation during fear conditioning (corrected for potential confounders: accuracy: 73%; sensitivity: 77%; specificity: 70%).
  
  
  CONCLUSIONS
  No primary depressed patients were available; only medication-free patients were included. Major depression and dysthymia were collapsed (power considerations).
  
  
  CONCLUSIONS
  Neurofunctional activation during safety signal processing differed between patients with or without comorbid depression, a finding which may explain heterogeneous results across previous studies. These findings demonstrate the relevance of comorbidity when investigating neurofunctional substrates of anxiety disorders. Predicting individual comorbidity status may translate neurofunctional data into clinically relevant information which might aid in planning individualized treatment. The study was registered with the
  ISRCTN80046034.
authors.affiliation: Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital Würzburg, Füchsleinstr. 15, D-97080 Würzburg, Germany; Institute of Clinical Psychology and Psychotherapy, Department of Psychology, Technische Universität Dresden, Dresden, Germany. Electronic address: Lueken_U@ukw.de.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Lueken
authors.affiliation: Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Straube
authors.affiliation: Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany.
authors.forename: Yunbo
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Cognitive Psychology II, Goethe-Universität Frankfurt, Frankfurt, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Hahn
authors.affiliation: Institute of Clinical Psychology and Psychotherapy, Department of Psychology, Technische Universität Dresden, Dresden, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Beesdo-Baum
authors.affiliation: Institute of Clinical Psychology and Psychotherapy, Department of Psychology, Technische Universität Dresden, Dresden, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Wittchen
authors.affiliation: Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Konrad
authors.affiliation: Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité-University Medicine Berlin, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ströhle
authors.affiliation: Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité-University Medicine Berlin, Berlin, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Wittmann
authors.affiliation: Department of Psychology, University of Cologne, Cologne, Germany.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Gerlach
authors.affiliation: Department of Clinical Radiology, University Hospital Münster, Münster, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Pfleiderer
authors.affiliation: Department of Psychiatry and Psychotherapy, University Hospital Münster, Münster, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Arolt
authors.affiliation: Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany.
authors.forename: Tilo
authors.initials: T
authors.lastname: Kircher
mesh_terms: D000328:Adult; D000379:Agoraphobia / Q000150:complications / Q000523:psychology; D015897:Comorbidity; D003213:Conditioning, Psychological; D003866:Depressive Disorder / Q000175:diagnosis* / Q000473:pathology / Q000523:psychology; D003865:Major Depressive Disorder / Q000150:complications / Q000175:diagnosis / Q000523:psychology; D003937:Diagnosis, Differential; D039721:Diagnostic and Statistical Manual of Mental Disorders; D005108:Extinction, Psychological; D005239:Fear / Q000523:psychology; D005260:Female; D006801:Humans; D000069550:Machine Learning; D008279:Magnetic Resonance Imaging; D008297:Male; D009483:Neuropsychological Tests; D016584:Panic Disorder / Q000150:complications / Q000175:diagnosis* / Q000473:pathology / Q000523:psychology; D011237:Predictive Value of Tests
keywords: Amygdala; Depression; Fear conditioning; Machine learning; Panic disorder; fMRI