Electrophysiological Endophenotypes for Schizophrenia

Abstract

Endophenotypes are quantitative, heritable traits that may help to elucidate the pathophysiologic mechanisms underlying complex disease syndromes, such as schizophrenia. They can be assessed at numerous levels of analysis; here, we review electrophysiological endophenotypes that have shown promise in helping us understand schizophrenia from a more mechanistic point of view. For each endophenotype, we describe typical experimental procedures, reliability, heritability, and reported gene and neurobiological associations. We discuss recent findings regarding the genetic architecture of specific electrophysiological endophenotypes, as well as converging evidence from EEG studies implicating disrupted balance of glutamatergic signaling and GABA-ergic inhibition in the pathophysiology of schizophrenia. We conclude that refining the measurement of electrophysiological endophenotypes, expanding genetic association studies, and integrating datasets are important next steps for understanding the mechanisms that connect identified genetic risk loci for schizophrenia to the disease phenotype.

Endophenotype best practices

“…Many thoughtful endophenotype articles populate the literature (for recent examples, see Anokhin, 2014; Beauchaine, 2009; Burton et al, 2015; Campanella, Pogarell, & Boutros, 2014; Euser et al, 2012; Faraone, Bonvicini, & Scassellati, 2014; Ferrarelli, 2013; Glahn et al, 2014; Goldstein & Klein, 2014; W. G. Iacono & Malone, 2011; Lenzenweger, 2013; Loo, Lenartowicz, & Makeig, 2015; Manoach & Agam, 2013; Miller & Rockstroh, 2013; Moses-Kolko, Horner, Phillips, Hipwell, & Swain, 2014; Owens, Bachman, Glahn, & Bearden, 2016; Pearlson, 2015; Rosen, Spellman, & Gordon, 2015; Rubenstein, Wiggins, & Lee, 2015; Salvatore, Gottesman, & Dick, 2015; Swerdlow, Gur, & Braff, 2015), and many of these share a conviction that endophenotypes are valuable for identifying genetic liability . However, despite their introduction to psychiatry by Gottesman and Shields (I.…”

Biologically relevant subgroups within the schizophrenia syndrome

“…As a conclusion, our data are consistent with an effect of NRG1 on functional connectivity 372 , perhaps through variation in expression of NRG1-ErbB4 pathway, which could contribute to GABAergic and glutamatergic imbalance. Since our results are significant in theta, alpha and beta-1 frequencies bands, which may support transitory, task-related coupling between distant areas of the brain 373 neurobiological mechanisms 374,375 . Electroencephalography (EEG) is an excellent tool for studying neurophysiological intermediate phenotypes in schizophrenia 376 .…”

Exploring electrophysiological correlates of social cognition in subclinical schizotypy

“…Recent research suggests positive schizotypy overlaps substantially with positive symptoms of schizophrenia, but links to negative, disorganization and cognitive symptoms of schizophrenia may be weaker . Given this complexity, researchers are seeking links between dimensions of the schizotypy continuum and more endophenotypic constructs related to psychosis …”

“…15 Given this complexity, researchers are seeking links between dimensions of the schizotypy continuum and more endophenotypic constructs related to psychosis. [16][17][18] Impairments in social cognition and behaviour are found in schizophrenia 19 and the schizophrenia prodrome, 20 stimulating the hypothesis that such impairments in schizotypy represent mechanisms of vulnerability. In schizophrenia, these impairments are associated with more basic neurocognitive performance, 21 as well as abnormalities in brain function as measured by eventrelated electrophysiological responses (ERPs) to social stimuli, e.g.…”

“…All three ERPs are blunted or attenuated in schizophrenia, with some evidence for correlation with specific symptoms and cognitive impairments. 16,23,[27][28][29][30][31][32][33] The ERP abnormalities are clearly linked to cognitive impairment in schizophrenia, but whether these links involve distinctively social cognition remains debatable.…”