Characterization of Counterfactual Reasoning Deficits in Schizophrenia Patients and Non-Psychotic First-Degree Relatives in Comparison with Healthy Control Subjects

Abstract

Schizophrenia is one of the most serious and complex psychiatric illnesses supposing a great negative impact on the life of the individuals who suffer from it. Cognitive impairment is a core feature of the illness and is characterized by the presence of deficits in almost all neurocognitive and social cognition domains. As a strong correlate of these patients’ real-world functioning, such deficiencies are observable in individuals who share unexpressed genetic components of vulnerability to schizophrenia, including the unaffected first-degree relatives of these patients. Therefore, it is a high priority to identify the biological underpinnings of cognitive deficits in schizophrenia to develop effective treatments promoting the functional recovery of these patients. One way to do so is through the identification and further characterization of novel cognitive deficits specific for the disorder. Pervasive in everyday life, CFT involves mental representations of alternatives to past situations that were once factual possibilities but which never occurred. Counterfactual thoughts are mainly activated by negative outcomes in the form of “if only” conditional prepositions. Furthermore, counterfactual reasoning refers to the remarkable ability to make inferences through the generation of counterfactual thoughts. Overall, prefrontal cortex (PFC) regions seem to be the primary regions activated in people engaged in CFT tasks. Therefore, given that schizophrenia seems to be related, at least in part, to PFC dysfunction and that patients suffering from it show impoverished decision-making and problem-solving skills, studies centered on the evaluation of counterfactual reasoning in schizophrenia should be expected; especially for the impact that these deficits might have on these patients’ personal and social functioning. Unfortunately, despite preliminary findings seeming to suggest CFT disruption in this disorder, research on this matter is still scarce. Further research is needed to properly characterize counterfactual reasoning impairment in schizophrenia since it might lead to the identification of a new primary cognitive deficit of the illness susceptible to becoming a target for treatment in the future. The overall aim of the present thesis is to provide new insights into neurocognitive impairment in schizophrenia by further characterizing counterfactual reasoning impairment in this disorder. Using different neuropsychological methodologies, we sought to better describe these deficits and its relationship with cognitive functioning and clinical status by assessing adult schizophrenia patients and non-psychotic first-degree relatives in comparison with healthy control subjects. In a compendium of four studies, different counterfactual measures were explored: (1) activation of counterfactual thoughts, (2) generation of counterfactual-derived inferences, and (3) activation of behavioural intentions through counterfactual inference generation. In Study 1, 40 patients and 40 controls were examined. The analyses evidenced the abilities to activate counterfactual thoughts and counterfactual inferences to be globally altered in the group of patients. In Study 2, the same counterfactual measures were evaluated but in 78 patients meeting criteria for symptomatic remission (Andreasen et al., 2005) in comparison with 84 healthy controls. The results not only evidenced the same difficulties among the patients, but also significant negative associations between less number of counterfactual thoughts activated and: (i) symptom severity and (ii) more than ten years of illness duration. In Study 3, the same counterfactual measures were evaluated in 43 non-psychotic first-degree relatives, 54 patients and 44 controls. Results evidenced the relatives to present a subtle counterfactual deficit compared with the controls. Finally, in Study 4, the ability to generate behavioural intentions through the activation of CFT was explored in 37 patients and 37 controls. Results evidenced a similar facilitator effect of CFT between groups. Findings from the current thesis further characterize counterfactual reasoning impairment in schizophrenia by improving and extending existing preliminary studies on this field. Overall, whereas the abilities to activate counterfactual thoughts and to construct counterfactual inference seem to be altered in this disorder, the ability to activate behavioural intentions through counterfactual reasoning has been found to be preserved. Further, the present thesis provides basis for the study of counterfactual hypoactivation as a new putative cognitive endophenotype for schizophrenia.

Actualmente, existe un consenso general de que los déficits neurocognitivos son una característica nuclear de la esquizofrenia. Extensas líneas de investigación se han centrado en la identificación de déficits similares en familiares no afectados de pacientes con esquizofrenia que podrían ser considerados como posibles endofenotipos cognitivos de la enfermedad. El razonamiento contrafactual (RC) es un tipo específico de razonamiento condicional relacionado con la generación de simulaciones mentales de acontecimientos pasados que facilita la conducta adaptativa así como la toma de decisiones dirigida a un objetivo. Investigaciones preliminares evidencian un deterioro del RC en la esquizofrenia, lo cual podría suponer un importante impacto en el funcionamiento diario de estos pacientes. Por eso, es importante continuar estudiando el RC en la esquizofrenia ya que en el futuro podría suponer el desarrollo de una nueva herramienta de diagnóstico o incluso una nueva diana terapéutica. OBJETIVOS: Profundizar en la caracterización de los déficits de RC en pacientes con esquizofrenia y en familiares de primer grado no psicóticos en comparación con sujetos controles sanos. En un compendio de 4 estudios, diferentes medidas de RC se han evaluado incluyendo: (1) activación de pensamientos contrafactuales; (2) generación de inferencias contrafactuales; (3) el efecto de facilitador del RC en la activación de intenciones conductuales previas a la implementación de nuevas conductas. CONCLUSIONES: De forma integrada, los resultados de estos cuatro estudios sugieren la alteración en la capacidad de activar pensamientos contrafactuales como un déficit primario de la enfermedad, relativamente independiente de la gravedad de los síntomas que podría considerarse en el futuro como un potencial endofenotipo cognitivo de la esquizofrenia. Los resultados respecto a la habilidad de generar inferencias contrafactuales son más heterogéneos y necesitamos más investigación que ayude a clarificar estos hallazgos. Finalmente, des de un punto de vista más optimista, los resultados evidencian una capacidad de activar intenciones conductuales a través del RC preservada en la esquizofrenia. En general, estos hallazgos sugieren el RC como un candidato potencial para desarrollar programas de rehabilitación cognitiva diseñados para guiar estos pacientes en la comprensión de una experiencia negativa y en la activación de las correspondientes intenciones correctivas.