Although many studies have demonstrated that bipolar disorder (BD) is heritable, the disorder's genetic basis remains elusive despite the substantial evidence. Hence, indicators of processes mediating between genotype and phenotype, known as endophenotypes, may be necessary to provide more information about this issue. Given that endophenotypes could provide information for elucidating the genetic underpinnings of BD, many studies have focused on one class of endophenotypic marker, the neuropsychological measures. In order for a cognitive measure to be considered an endophenotype, it has to 1. be highly heritable, 2. be associated with the illness, 3. be independent of the clinical state and, 4. the impairment must co-segregate with the illness within a family, with non-affected family members showing impairment relative to general population. In this sense, failures in attention, executive functions and verbal memory are the most consistently reported deficits with the characteristics for endophenotypes. With these factors in mind, the primary interest of this paper was to review the existing literature on neurocognitive functioning in BD as possible endophenotypes. Studies were identified by searching the major databases (MEDLINE and PSYCINFO) from 1990 to 2007 with the following key words: endophenotype, neurocognitive assessment, bipolar disorder, attention, memory, executive functions, neuropsychological assessment and neuroimaging. The titles and abstracts of the articles identified were examined and those that appeared to fullfil our inclusion criteria were retrieved. Articles were included if they met the following criteria: 1. included adult patients (aged: 16-65), 2. included a psychiatric or normal comparison group, 3. used well-established diagnostic criteria to ascertain diagnosis (DSM, 3rd. and 4th. eds.), 4. provided information about the clinical status of the patients being assessmed and 5. cognitive assessment was based on standardized or well established cognitive tasks. Declarative memory has been studied in BD patients through tests that imply learning of words and stories to evaluate immediate memory, delayed recall and recognition, also considering the kind of strategies that the patients use to evoke verbal material. It seems that BD patients in depressive phase present deficits in immediate memory and delayed recall, but recognition memory is preserved. This impairment is due to difficulties in the planning and evoking strategies used, associated to prefrontal dysfunction. In manic phase, the patients make a lot of irrelevant associations because the failure in the system to control impulses. In the absence of the depressive and maniac symptoms, patients continue with anomalies in memory. Euthymic patient can use a similar semantic clustering strategy so that they can recall and recognize fewer words than controls, suggesting impaired encoding of verbal information and there is lack of rapid forgetting, which suggests a relative absence of a storage deficit. Results of studies in declarative memory impairment in BD suggests that the impairments are consistent with deficits in learning, but do not appear to be related to different organizational strategies during learning, and do not appear to be secondary to clinical state. Rather, they are associated with the underlying pathophysiology of the illness. Regarding executive functions, patients with BD have deficiencies related to planning, organizational strategies, lack of control in the action, conceptual formation and cognitive flexibility. In depressive phase, patients have problems with concept formation, meanwhile the deficit in verbal fluency is due because they use phonemic rather than semantic clues. In maniac episodes, the executive functions are altered, and it is observed that concept formation and attentional shift are deficient and more evident in patients with a history of psychosis. These deficits explain why maniac persons engage in more risk behaviors, specifically in the inhibiting impulses system. Also in the absence of symptoms, euthymic bipolar disorder patients show no significant differences with respect to controls on attentional set-shifting, problem solving or planning. However, they show qualitative differences involving slower functioning on measures of speed and slower to initiate a response, and present more errors across measures of verbal fluency. With respect to attentional deficits in BD, several studies have pointed to deficits in sustained attention, also known as concentration, related to the capability to sustain the focus during a considerable amount of time. This attentional domain is deficient in manic patients because the lack of behavioral inhibition which is prevalent in this phase, the increased false responding (commission errors), perseveration and vigilance deficits. In contrast, when patients are depressive, they make more mistakes by omission of relevant stimuli. Also in euthymic patients, a deficit in the inattentive component of sustained attention is reported because of decreased target sensitivity (omission errors) and response time inconsistency. It is possible that the observed findings do not reflect dysfunction in one isolated brain area, rather a dysregulation of cortical modulation of subcortical networks is considered. In particular, a neuroanatomic model of mood regulation comprising the prefrontal cortex, amygdala-hippocampal complex, thalamus, basal ganglia, and their inter-connections has been proposed to be implicated in the pathophysiology of mood disorders. Functional neuroimaging studies also support evidence of these neurocognitive anomalies through the application of neuropsychological paradigms, in which metabolic increments in ventral striate and diminished function in prefrontal cortex during executives assignments is common. During maniac or hypomaniac episodes, an increment of activity in the ventral prefrontal cortex of the right hemisphere was observed; meanwhile, in depressive phase the patients show an increase in the same sector but in the left hemisphere compared to euthymic patients. During the depressive episodes of the BD type II, it is observed a reduction of the dorsolateral and medial prefrontal cortex metabolism, and an increase in thalamus and amygdala while resolving cognitive activities. Finally, there is a reduction of metabolism in ventral caudal and prefrontal cortex and an increase in amygdala in patients without depressive or maniac symptoms. This finding supports the hypothesis of permanent prefrontal dysfunction although the absence of clinical symptoms. Finally, as Glahn et al. (2004) have suggested, neurocognitive markers may indicate the presence of quantifiable deviation on a genetically influenced dimension that underlies BD. Such endophenotypes would not identify illness genes per se; rather they would indicate a realiably characterized heritable behavioral phenomenon. Nevertheless, at present it is not known which of the many candidate genes for BD may be associated with neurocognitive endophenotypes for the disorder. Some studies have reported promising preliminary findings indicating a relationship between executive performance and a brain-derived neurotrophic factor gene polymorphism. Given that this gene has been implicated in memory and learning as a function of its role in synaptic transmission, and other genetic association studies have linked this gene to risk for BD, allelic variation in this gene may be associated with cognitive dysfunction in BD.
En los últimos años se ha planteado la necesidad de identificar los procesos que median entre el genotipo y el fenotipo del Trastorno Bipolar (TB), dando importancia al estudio de los endofenotipos. Los endofenotipos tratan del fenotipo interno y que no se observa clínicamente, que se encuentra mas cercano a la etiología biológica de la enfermedad que sus signos y síntomas, y que se encuentra influenciado por uno o más genes susceptibles al trastorno. Para que un marcador pueda ser considerado como endofenotipo debe cubrir las siguientes características: 1) ser heredable, 2) estar asociado con la enfermedad, 3) ser independiente del estado clínico y 4) mostrar co-segregación familiar. Dentro de los métodos disponibles para identificar a los endofenotipos se encuentran las mediciones neuropsicológicas y cognitivas entre otras. Diversos autores han señalado la utilidad de identificar los endofenotipos neurocognitivos del TB para mejorar la capacidad de detección de los genes que predisponen a la aparición del trastorno y ayudar a una mejor definición de los criterios diagnósticos. En este sentido, se han señalado a las alteraciones en los dominios de atención selectiva, memoria verbal y funciones ejecutivas, como marcadores endofenotípicos más representativos del TB porque cumplen con los criterios antes mencionados. Por lo tanto, en el presente artículo se realizó una revisión de los estudios neuropsicológicos reportados en pacientes con TB en estos dominios cognitivos y la descripción de estas deficiencias, así como de los circuitos neuronales asociados con estas alteraciones. Se realizó una búsqueda de artículos en MEDLINE y psycINFO desde 1990 a 2007 con las siguientes palabras clave: endofenotipo, evaluación neuropsicológica, trastorno bipolar, atención, memoria, funciones ejecutivas, neurocognición y neuroimagen. Los títulos y resúmenes de los artículos identificados fueron examinados y se conservaron aquellos que cubrían nuestros criterios de inclusión. Los artículos se tomaron en cuenta si cubrían los siguientes criterios: 1) incluían pacientes adultos (edad: 16-65), 2) incluían un grupo de comparación psiquiátrico o normal, 3) utilizaban criterios diagnósticos bien establecidos para el diagnóstico (DSM 3ª. y 4ª. eds.), 4) describían información sobre el estado clínico del paciente al momento de la evaluación y 5) utilizaban evaluaciones cognitivas con tareas estandarizadas y bien establecidas. En relación a la memoria declarativa, los pacientes en un episodio depresivo muestran alteraciones en las pruebas de aprendizaje y de memoria de listas de palabras en las variables de recuerdo libre, tanto a corto como a largo plazo; estas subyacen a deficiencias en la planeación y en la memoria operativa o de trabajo, mismas que persisten después de la fase aguda de cualquier etapa de este padecimiento. Durante la manía se observa un pobre desempeño caracterizado por intrusiones y asociaciones verbales irrelevantes. Se ha señalado que durante la eutimia existen deficiencias asociadas con fallas en la codificación de la información y que no se deben al olvido o a deficiencias en su almacenamiento. Las evaluaciones que se han realizado de las funciones ejecutivas, coinciden al señalar incapacidad para planear, organizar y controlar la conducta en las fases depresivas y de manía/hipomanía, mientras que en la eutimia los pacientes únicamente muestran diferencias cualitativas en comparación con los sujetos sanos, caracterizadas por fallas ante tareas de fluidez verbal semántica y enlentecimiento en la velocidad de procesamiento. Con respecto a la atención selectiva, ha sido posible identificar que los pacientes con manía/hipomanía fallan porque presentan mayor cantidad de errores de comisión, asociado con impulsividad y deficiencias en la autorregulación; por otra parte, durante la fase depresiva se observa incapacidad para responder a estímulos importantes y mayor presencia de errores de omisión. Durante la eutimia, se encuentra alterado el componente de inatención debido a que obtienen menores puntajes en la detección del estímulo y requieren mayor tiempo de reacción. Los hallazgos neuropsicológicos antes descritos parecen reflejar la disregulación en la modulación cortical de las redes subcorticales, particularmente en el circuito que implica a la corteza prefrontal, al complejo amígdala-hipocampal, el tálamo, los ganglios basales y sus interconexiones; circuito que ha sido propuesto como un modelo neuroanatómico de la regulación afectiva. Además de la disregulación en este circuito, parecen estar involucradas disfunciones en los sectores laterales del lóbulo temporal durante las fases de manía/hipomanía.
