Neurocognitive Endophenotypes : an update on the field

6 The endophenotype construct, initially formulated by Lewis and Gottesman in the 1960s, referred to an indicator of vulnerability, not necessarily expressed as a clinical marker of status. However, this subclinical marker was established in the phenotype as a component that co-segregated with the genetic disease background. The endophenotype not only determined both potential and differentiated types within the same phenotype of interest, but also related to changes in the prognosis and evolution of the syndrome or disorder. It increased or decreased the risk and outlined the pathogenesis of the syndrome itself at the molecular level while exhibiting a continuous variation in the general population. Every endophenotypes must fulfill various criteria to be validated as an intermediate phenotype involved in a syndrome. It must be closely related to disease, independent of its state and heritable and stable over the time. Therefore, endophenotypes may contribute to the discrimination of complex diseases such as mental illness or psychopathology as well as of molecular pathways underlying genetic effects (Cuartas, 2011). Different approaches to searching for endophenotypes have used neuroimaging, neurophysiology, allelic variants and neurochemistry. Neurocognitive findings and their potential as candidate endophenotypes are a novel approach to the clinical treatment of mental or psychopathological syndromes. Recently, changes in executive function have been studied as candidate endophenotypes. Executive functioning is an integral component for human development of adaptive cognitive and behavioral patterns to favor the success as a species. In fact, aspects such as problems solving, decisions making, flexible behavior and self-regulation before the reward according to their working memory and attentional performance, allows us to successfully evolve in response to the stressor. Showing all these efficient conducts as a species, determine the great evolution that we have had in the frontal lobes. These lobes are organized hierarchically and comprise 20% of the neocortex. The prefrontal cortex is the main structure that accounts for human behavior and that has enabled our species to colonize the current evolutionary time called by Steven Pinker as the "cognitive niche" (Pinker 1999). This term refers to the use of abstraction and social cohesion as an evolutionary and intelligent way that favors human’s problem solving and self-regulated behavior. Taken into account the phylogenetic heritage of cognitive function, to delineate the temporary architecture of behavior it is helpful to evaluate the different executive domains. This allows circumscription of the neuropsychological network operating in three regions of the prefrontal cortex: dorsolateral prefrontal cortex, medial or paralimbic prefrontal cortex and orbital prefrontal cortex. This cortical topology is formed of a large network of corticosubcorticales interconnections that supports the operating mode. Today, different studies have identified candidate executive domains that, together with genetic factors, explain greater than 40% of the phenotype variance (González-Giraldo, et al. 2015). Even though for mental disorders there is a high heritability, is not clear yet what genes are directly responsible. This is mainly due to both the large pre-existing genetic heterogeneity and lack of consistent replication of specific allelic variants in association studies. Neurocognitive Endophenotypes: an update on the field Endofenotipos Neurocognitivos: una actualización en el área