Neural markers of errors as endophenotypes in neuropsychiatric disorders

Dara S Manoach, Yigal Agam, Dara S Manoach, Yigal Agam

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.

Keywords: anterior cingulate; error processing; error-related negativity; imaging genetics; response monitoring.

Figures

Figure 1
Figure 1
Trial-by-trial adjustments of reaction time (RT). (A) A schematic depiction of the SATO function. The circle denotes the optimum: the point at which the highest accuracy is achieved at the fastest possible speed. Beyond this point, speedier responses entail a cost (trade-off) in reduced accuracy. (B) Mean saccadic RT during an antisaccade task as a function of trial position relative to an error trial. Post-error slowing (PES) is defined as the difference in RT between the trial following the error (1Post) and the trial preceding the error (1Pre). Error bars represent the standard error of the mean.
Figure 2
Figure 2
The error-related negativity (ERN). (A) Grand average waveforms for correct (black) and error (red) antisaccade trials, time-locked to the onset of the saccade. (B) Difference waveform, obtained by subtracting the correct waveform from the error waveform. (C) Scalp distribution of the ERN, displayed on a template head model. Adapted from Agam et al. (2011).
Figure 3
Figure 3
Error-related activation in the anterior cingulate cortex (ACC). Statistical maps, displayed on medial cortical surface templates, show activation on correct trials vs. a fixation baseline (top), error vs. fixation (middle) and error vs. correct (bottom). Gray masks cover subcortical regions in which activation is displaced in a surface rendering. The dACC and rACC are outlined in blue and red, respectively. Adapted from Polli et al. (2005).
Figure 4
Figure 4
Model of a causal pathway for error processing. Specific genetic polymorphisms affect dopamine neurotransmission, which may interact with a neuropsychiatric disorder to affect neuroimaging-based endophenotypes. These endophenotypes, in turn, contribute to the expression of phenotypes, which may influence whether a psychiatric diagnosis is given.
Figure 5
Figure 5
A schematic illustration of the endophenotype concept. Shaded areas indicate the presence of the endophenotype in affected patients, individuals with spectrum disorders, syndromally-unaffected family members and the general population. Criteria taken from Gould and Gottesman (2006).

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