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Original Investigation |

Altered Functional Subnetwork During Emotional Face Processing A Potential Intermediate Phenotype for Schizophrenia

Hengyi Cao, MB, MMedSc1; Alessandro Bertolino, MD, PhD2,3; Henrik Walter, MD, PhD4; Michael Schneider, MD1; Axel Schäfer, PhD1; Paolo Taurisano, PhD2; Giuseppe Blasi, MD, PhD2; Leila Haddad, PhD1; Oliver Grimm, MD1; Kristina Otto, MSc1; Luanna Dixson, BSc1; Susanne Erk, MD, PhD4; Sebastian Mohnke, MSc4; Andreas Heinz, MD, PhD4; Nina Romanczuk-Seiferth, PhD4; Thomas W. Mühleisen, PhD5,6,7; Manuel Mattheisen, MD8,9; Stephanie H. Witt, PhD10; Sven Cichon, PhD5,6,7,11; Markus Noethen, MD, PhD5,6,7; Marcella Rietschel, MD, PhD10; Heike Tost, MD, PhD1; Andreas Meyer-Lindenberg, MD, PhD1
[+] Author Affiliations
1Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
2Department of Basic Medical Sciences, Neuroscience and Sense Organs, Università degli Studi di Bari “Aldo Moro,” Bari, Italy
3Biomarkers and Clinical Imaging, Hoffmann-La Roche, Basel, Switzerland
4Department of Psychiatry and Psychotherapy, Universitätsmedizin Charité, Berlin, Germany
5Institute of Human Genetics, University of Bonn, Bonn, Germany
6Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany
7Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany
8Department of Genomic Mathematics, University of Bonn, Bonn, Germany
9Department of Biomedicine, University of Aarhus, Aarhus, Denmark
10Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
11Department of Biomedicine, University of Basel, Basel, Switzerland
JAMA Psychiatry. 2016;73(6):598-605. doi:10.1001/jamapsychiatry.2016.0161.
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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.

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Figure 1.
Altered Visual-Limbic Subnetwork in Relatives of Patients With Schizophrenia During Emotional Face Processing

All links in this subnetwork show decreased connectivity in relatives compared with controls. Cluster-level P corrected for familywise error = .006.

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Figure 2.
Follow-up Analyses for the Identified Subnetwork

The mean subnetwork connectivity is negatively correlated with trait anxiety scores derived from the State-Trait Anxiety Inventory (STAI) in the subsample of healthy controls. The mean subnetwork connectivity reveals a significant difference between relatives of patients with schizophrenia and healthy controls during the emotional face-matching task but not in the resting state. The group by task interaction is significant. Bars indicate mean values. Error bars indicate SEs.

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Figure 3.
Alteration of the Identified Subnetwork in Patients

Similar to first-degree relatives of patients with schizophrenia, patients with schizophrenia have significantly decreased connectivity estimates in the identified visual-limbic subnetwork compared with healthy controls. Bars indicate mean values. Error bars indicate SEs.

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