Hengyi Cao1, Alessandro Bertolino2, Henrik Walter3, Michael Schneider1, Axel Schäfer1, Paolo Taurisano4, Giuseppe Blasi4, Leila Haddad1, Oliver Grimm1, Kristina Otto1, Luanna Dixson1, Susanne Erk3, Sebastian Mohnke3, Andreas Heinz3, Nina Romanczuk-Seiferth3, Thomas W Mühleisen5, Manuel Mattheisen6, Stephanie H Witt7, Sven Cichon8, Markus Noethen5, Marcella Rietschel7, Heike Tost1, Andreas Meyer-Lindenberg1. 1. Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. 2. 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. 3. Department of Psychiatry and Psychotherapy, Universitätsmedizin Charité, Berlin, Germany. 4. Department of Basic Medical Sciences, Neuroscience and Sense Organs, Università degli Studi di Bari "Aldo Moro," Bari, Italy. 5. 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. 6. Department of Genomic Mathematics, University of Bonn, Bonn, Germany9Department of Biomedicine, University of Aarhus, Aarhus, Denmark. 7. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. 8. 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.
Abstract
IMPORTANCE: 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. OBJECTIVES: 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. DESIGN, SETTING, AND PARTICIPATIONS: 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. MAIN OUTCOMES AND MEASURES: Conventional amygdala activity and seeded connectivity measures, graph-based global and local network connectivity measures, Spearman rank correlation, intraclass correlation, and gray matter volumes. RESULTS: 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). CONCLUSIONS AND RELEVANCE: 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.
IMPORTANCE: 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. OBJECTIVES: 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. DESIGN, SETTING, AND PARTICIPATIONS: 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. MAIN OUTCOMES AND MEASURES: Conventional amygdala activity and seeded connectivity measures, graph-based global and local network connectivity measures, Spearman rank correlation, intraclass correlation, and gray matter volumes. RESULTS: 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). CONCLUSIONS AND RELEVANCE: 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: Hengyi Cao; Sarah C McEwen; Yoonho Chung; Oliver Y Chén; Carrie E Bearden; Jean Addington; Bradley Goodyear; Kristin S Cadenhead; Heline Mirzakhanian; Barbara A Cornblatt; Ricardo E Carrión; Daniel H Mathalon; Thomas H McGlashan; Diana O Perkins; Aysenil Belger; Larry J Seidman; Heidi Thermenos; Ming T Tsuang; Theo G M van Erp; Elaine F Walker; Stephan Hamann; Alan Anticevic; Scott W Woods; Tyrone D Cannon Journal: Schizophr Bull Date: 2019-06-18 Impact factor: 9.306
Authors: Hengyi Cao; Anais Harneit; Henrik Walter; Susanne Erk; Urs Braun; Carolin Moessnang; Lena S Geiger; Zhenxiang Zang; Sebastian Mohnke; Andreas Heinz; Nina Romanczuk-Seiferth; Thomas Mühleisen; Manuel Mattheisen; Stephanie H Witt; Sven Cichon; Markus M Nöthen; Marcella Rietschel; Andreas Meyer-Lindenberg; Heike Tost Journal: Neuropsychopharmacology Date: 2017-06-07 Impact factor: 7.853
Authors: Hengyi Cao; Sarah C McEwen; Jennifer K Forsyth; Dylan G Gee; Carrie E Bearden; Jean Addington; Bradley Goodyear; Kristin S Cadenhead; Heline Mirzakhanian; Barbara A Cornblatt; Ricardo E Carrión; Daniel H Mathalon; Thomas H McGlashan; Diana O Perkins; Aysenil Belger; Larry J Seidman; Heidi Thermenos; Ming T Tsuang; Theo G M van Erp; Elaine F Walker; Stephan Hamann; Alan Anticevic; Scott W Woods; Tyrone D Cannon Journal: Cereb Cortex Date: 2019-03-01 Impact factor: 5.357
Authors: Urs Braun; Axel Schaefer; Richard F Betzel; Heike Tost; Andreas Meyer-Lindenberg; Danielle S Bassett Journal: Neuron Date: 2018-01-03 Impact factor: 17.173