title: Altered Functional Subnetwork During Emotional Face Processing: A Potential Intermediate Phenotype for Schizophrenia.
abstract: Although deficits in emotional processing are prominent in schizophrenia, it has been difficult to identify neural mechanisms related to the genetic risk for this highly heritable illness. Prior studies have not found consistent regional activation or connectivity alterations in first-degree relatives compared with healthy controls, suggesting that a more comprehensive search for connectomic biomarkers is warranted.
  
  
  
  To identify a potential systems-level intermediate phenotype linked to emotion processing in schizophrenia and to examine the psychological association, task specificity, test-retest reliability, and clinical validity of the identified phenotype.
  
  
  
  The study was performed in university research hospitals from June 1, 2008, through December 31, 2013. We examined 58 unaffected first-degree relatives of patients with schizophrenia and 94 healthy controls with an emotional face-matching functional magnetic resonance imaging paradigm. Test-retest reliability was analyzed with an independent sample of 26 healthy participants. A clinical association study was performed in 31 patients with schizophrenia and 45 healthy controls. Data analysis was performed from January 1 to September 30, 2014.
  
  
  
  Conventional amygdala activity and seeded connectivity measures, graph-based global and local network connectivity measures, Spearman rank correlation, intraclass correlation, and gray matter volumes.
  
  
  
  Among the 152 volunteers included in the relative-control sample, 58 were unaffected first-degree relatives of patients with schizophrenia (mean [SD] age, 33.29 [12.56]; 38 were women), and 94 were healthy controls without a first-degree relative with mental illness (mean [SD] age, 32.69 [10.09] years; 55 were women). A graph-theoretical connectivity approach identified significantly decreased connectivity in a subnetwork that primarily included the limbic cortex, visual cortex, and subcortex during emotional face processing (cluster-level P corrected for familywise error = .006) in relatives compared with controls. The connectivity of the same subnetwork was significantly decreased in patients with schizophrenia (F = 6.29, P = .01). Furthermore, we found that this subnetwork connectivity measure was negatively correlated with trait anxiety scores (P = .04), test-retest reliable (intraclass correlation coefficient = 0.57), specific to emotional face processing (F = 17.97, P < .001), and independent of gray matter volumes of the identified brain areas (F = 1.84, P = .18). Replicating previous results, no significant group differences were found in face-related amygdala activation and amygdala-anterior cingulate cortex connectivity (P corrected for familywise error =.37 and .11, respectively).
  
  
  
  Our results indicate that altered connectivity in a visual-limbic subnetwork during emotional face processing may be a functional connectomic intermediate phenotype for schizophrenia. The phenotype is reliable, task specific, related to trait anxiety, and associated with manifest illness. These data encourage the further investigation of this phenotype in clinical and pharmacologic studies.
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Hengyi
authors.initials: H
authors.lastname: Cao
authors.affiliation: Department of Basic Medical Sciences, Neuroscience and Sense Organs, Università degli Studi di Bari "Aldo Moro," Bari, Italy3Biomarkers and Clinical Imaging, Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bertolino
authors.affiliation: Department of Psychiatry and Psychotherapy, Universitätsmedizin Charité, Berlin, Germany.
authors.forename: Henrik
authors.initials: H
authors.lastname: Walter
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schneider
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Schäfer
authors.affiliation: Department of Basic Medical Sciences, Neuroscience and Sense Organs, Università degli Studi di Bari "Aldo Moro," Bari, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Taurisano
authors.affiliation: Department of Basic Medical Sciences, Neuroscience and Sense Organs, Università degli Studi di Bari "Aldo Moro," Bari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Blasi
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Leila
authors.initials: L
authors.lastname: Haddad
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Grimm
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Otto
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Luanna
authors.initials: L
authors.lastname: Dixson
authors.affiliation: Department of Psychiatry and Psychotherapy, Universitätsmedizin Charité, Berlin, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Erk
authors.affiliation: Department of Psychiatry and Psychotherapy, Universitätsmedizin Charité, Berlin, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mohnke
authors.affiliation: Department of Psychiatry and Psychotherapy, Universitätsmedizin Charité, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Heinz
authors.affiliation: Department of Psychiatry and Psychotherapy, Universitätsmedizin Charité, Berlin, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Romanczuk-Seiferth
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany6Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany7Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Mühleisen
authors.affiliation: Department of Genomic Mathematics, University of Bonn, Bonn, Germany9Department of Biomedicine, University of Aarhus, Aarhus, Denmark.
authors.forename: Manuel
authors.initials: M
authors.lastname: Mattheisen
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Witt
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany6Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany7Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany11Department of Biomedic.
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany6Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany7Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Noethen
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Tost
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Meyer-Lindenberg
mesh_terms: D000328:Adult; D000679:Amygdala / Q000000981:diagnostic imaging / Q000503:physiopathology; D001921:Brain / Q000000981:diagnostic imaging / Q000503:physiopathology*; D016022:Case-Control Studies; D004192:Discrimination, Psychological / Q000502:physiology; D004644:Emotions / Q000502:physiology*; D000066499:Facial Recognition / Q000502:physiology*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008032:Limbic System / Q000000981:diagnostic imaging / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D008297:Male; D009415:Nerve Net / Q000000981:diagnostic imaging / Q000503:physiopathology*; D010641:Phenotype; D012016:Reference Values; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology*; D013223:Statistics as Topic; D014793:Visual Cortex / Q000000981:diagnostic imaging / Q000503:physiopathology; D055815:Young Adult