Neural markers of errors as endophenotypes in neuropsychiatric disorders

Abstract

Learning from errors is fundamental to adaptive human behavior. It requires detecting errors, evaluating what went wrong, and adjusting behavior accordingly. These dynamic adjustments are at the heart of behavioral flexibility and accumulating evidence suggests that deficient error processing contributes to maladaptively rigid and repetitive behavior in a range of neuropsychiatric disorders. Neuroimaging and electrophysiological studies reveal highly reliable neural markers of error processing. In this review, we evaluate the evidence that abnormalities in these neural markers can serve as sensitive endophenotypes of neuropsychiatric disorders. We describe the behavioral and neural hallmarks of error processing, their mediation by common genetic polymorphisms, and impairments in schizophrenia, obsessive-compulsive disorder, and autism spectrum disorders. We conclude that neural markers of errors meet several important criteria as endophenotypes including heritability, established neuroanatomical and neurochemical substrates, association with neuropsychiatric disorders, presence in syndromally-unaffected family members, and evidence of genetic mediation. Understanding the mechanisms of error processing deficits in neuropsychiatric disorders may provide novel neural and behavioral targets for treatment and sensitive surrogate markers of treatment response. Treating error processing deficits may improve functional outcome since error signals provide crucial information for flexible adaptation to changing environments. Given the dearth of effective interventions for cognitive deficits in neuropsychiatric disorders, this represents a potentially promising approach.

Anxiety and error monitoring: the importance of motivation and emotion

“…We (Olvet and Hajcak, 2008) and others more recently (Manoach and Agam, 2013) have argued that there is considerable evidence that the ERN is a candidate psychiatric endophenotype. An endophenotype must be associated with an illness, heritable, evident in unaffected first-degree family members, and independent of current disease state (Gottesman and Gould, 2003; Miller and Rockstroh, 2013).…”

Endophenotype best practices

“…Amplitude of the event-related negativity (ERN) is associated with both internalizing and externalizing disorders (with different directions of effect). Several studies have demonstrated associations with candidate genes (summarized in Manoach & Agam, 2013). Nevertheless, as with P300 amplitude, another widely studied endophenotype, there have not been robust, validated findings.…”

“…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.…”

Attention bias modification reduces neural correlates of response monitoring

“…The ERN has excellent psychometric properties, including high test-retest reliability across two weeks (Olvet & Hajcak, 2009a) and two years (Weinberg & Hajcak, 2011), and high internal consistency in as few as six trials (Olvet & Hajcak, 2009b). The ERN is also moderately heritable (Anokhin, Golosheykin, & Heath, 2008) and related to particular genotypes (Manoach & Agam, 2013), suggesting genetic contributions.…”