Combining fMRI and DISC1 gene haplotypes to understand working memory-related brain activity in schizophrenia

Altres ajuts: Ministerio de Ciencia e Innovación; Fondo Europeo de Desarrollo Regional (FEDER); European Social Fund ("Investing in your future"); Generalitat de Catalunya, Departament de Salut (SLT017/20/000233).The DISC1 gene is one of the most relevant susceptibility genes for psychosis. However, the complex genetic landscape of this locus, which includes protective and risk variants in interaction, may have hindered consistent conclusions on how DISC1 contributes to schizophrenia (SZ) liability. Analysis from haplotype approaches and brain-based phenotypes can contribute to understanding DISC1 role in the neurobiology of this disorder. We assessed the brain correlates of DISC1 haplotypes associated with SZ through a functional neuroimaging genetics approach. First, we tested the association of two DISC1 haplotypes, the HEP1 (rs6675281-1000731-rs999710) and the HEP3 (rs151229-rs3738401), with the risk for SZ in a sample of 138 healthy subjects (HS) and 238 patients. This approach allowed the identification of three haplotypes associated with SZ (HEP1-CTG, HEP3-GA and HEP3-AA). Second, we explored whether these haplotypes exerted differential effects on n-back associated brain activity in a subsample of 70 HS compared to 70 patients (diagnosis × haplotype interaction effect). These analyses evidenced that HEP3-GA and HEP3-AA modulated working memory functional response conditional to the health/disease status in the cuneus, precuneus, middle cingulate cortex and the ventrolateral and dorsolateral prefrontal cortices. Our results are the first to show a diagnosis-based effect of DISC1 haplotypes on working memory-related brain activity, emphasising its role in SZ

High incidence of PTSD diagnosis and trauma-related symptoms in a trauma exposed bipolar I and II sample

Post-traumatic stress disorder (PTSD) is an established comorbidity in Bipolar Disorder (BD), but little is known about the characteristics of psychological trauma beyond a PTSD diagnosis and differences in trauma symptoms between BD-I and BD-II. (1) To present characteristics of a trauma-exposed BD sample; (2) to investigate prevalence and trauma symptom profile across BD-I and BD-II; (3) to assess the impact of a lifetime PTSD diagnosis vs. a history of trauma on BD course; and (4) to research the impacts of sexual and physical abuse. This multi-center study comprised 79 adult participants with BD with a history of psychological trauma and reports baseline data from a trial registered in Clinical Trials (; ref: NCT02634372). Clinical variables were gathered through clinical interview, validated scales and a review of case notes. The majority (80.8%) of our sample had experienced a relevant stressful life event prior to onset of BD, over half of our sample 51.9% had a lifetime diagnosis of PTSD according to the Clinician Administered PTSD scale. The mean Impact of Event Scale-Revised scores indicated high levels of trauma-related distress across the sample, including clinical symptoms in the PTSD group and subsyndromal symptoms in the non-PTSD group. Levels of dissociation were not higher than normative values for BD. A PTSD diagnosis (vs. a history of trauma) was associated with psychotic symptoms [2(1) = 5.404, p = 0.02] but not with other indicators of BD clinical severity. There was no significant difference between BD-I and BD-II in terms of lifetime PTSD diagnosis or trauma symptom profile. Sexual abuse significantly predicted rapid cycling [2(1) = 4.15, p = 0.042], while physical abuse was not significantly associated with any clinical indicator of severity. Trauma load in BD is marked with a lack of difference in trauma profile between BD-I and BD-II. Although PTSD and sexual abuse may have a negative impact on BD course, in many indicators of BD severity there is no significant difference between PTSD and subsyndromal trauma symptoms. Our results support further research to clarify the role of subsyndromic PTSD symptoms, and highlight the importance of screening for trauma in BD patients

Brain structural changes in schizoaffective disorder compared to schizophrenia and bipolar disorder

Brain structural changes in schizoaffective disorder, and how far they resemble those seen in schizophrenia and bipolar disorder, have only been studied to a limited extent. Forty-five patients meeting - and criteria for schizoaffective disorder, groups of patients with 45 matched schizophrenia and bipolar disorder, and 45 matched healthy controls were examined using voxel-based morphometry (). Analyses comparing each patient group with the healthy control subjects found that the patients with schizoaffective disorder and the patients with schizophrenia showed widespread and overlapping areas of significant volume reduction, but the patients with bipolar disorder did not. A subsequent analysis compared the combined group of patients with the controls followed by extraction of clusters. In regions where the patients differed significantly from the controls, no significant differences in mean volume between patients with schizoaffective disorder and patients with schizophrenia in any of five regions of volume reduction were found, but mean volumes in the patients with bipolar disorder were significantly smaller in three of five. The findings provide evidence that, in terms of structural gray matter brain abnormality, schizoaffective disorder resembles schizophrenia more than bipolar disorder

Neuropsychological and brain functional changes across the different phases of schizoaffective disorder

El término esquizoafectivo fue introducido por J. Kasanin en 1933, para describir a un grupo de pacientes que no encajaban ni con el diagnóstico de esquizofrenia ni en el de las psicosis maníaco-depresivas. La nosología del trastorno esquizoafectivo siempre ha sido un tema controvertido y se han llevado a cabo pocos estudios que hayan sido útiles para clarificarla. El objetivo de la presente tesis es estudiar las bases neurobiológicas de esta enfermedad, evaluando las alteraciones que aparecen tanto en las fases de descompensación como los cambios a nivel longitudinal. Este trabajo está compuesto por dos estudios que usan la resonancia magnética funcional para examinan a un grupo de pacientes con trastorno esquizoafectivo, tipo bipolar, diagnosticados según los criterios RDC y DSM-IV. Los pacientes fueron comparados con un grupo de sujetos sanos, apareados por edad, sexo y CI pre-mórbido. A todos los sujetos se les realizó al menos un escáner, mientras realizaban una tarea de memoria de trabajo ‘N-back’. Paralelamente, se realizó un estudio neuropsicológico, evaluando la memoria y función ejecutiva. Se obtuvieron los mapas de activación y desactivación cerebral mediante un modelo lineal general y se realizó un análisis longitudinal de medidas repetidas. En el primer estudio transversal, se examinaron los patrones de activación cerebral durante un episodio de descompensación, esquizomaníaco o esquizodepresivo. Los pacientes mostraron una hipoactivación del DLPFC, así como un déficit en desactivar la corteza frontal medial, comparado con los sujetos sanos. Esta última región corresponde al nodo anterior de la red neuronal por defecto o DMN. En el segundo estudio, los mismos pacientes fueron revaluados tras alcanzar la remisión clínica, definida como un periodo de eutimia superior a dos meses. El subgrupo de pacientes esquizomaníacos mostró una hipoactivación frontal en la fase aguda que revirtió al alcanzar la eutimia. Por el contrario, en el subgrupo de pacientes esquizodepresivos no se observaron diferencias entre la fase aguda y la remisión clínica. Al comparar todos los pacientes esquizoafectivos en remisión clínica con los sujetos sanos, los pacientes mostraron un déficit en desactivar la corteza frontal medial, indicando una disfunción del DMN. En el segundo estudio también se evaluó la memoria y función ejecutiva. En ambas pruebas, todos los pacientes en remisión clínica mostraron un menor rendimiento en comparación al grupo de sujetos sanos. En el subgrupo de pacientes esquizomaníacos mejoró la memoria al alcanzar la remisión clínica, sin embargo, no hubo cambios en la función ejecutiva. Por el contrario, en el subgrupo de pacientes esquizodepresivos no se encontraron diferencias significativas entre la fase aguda de la enfermedad y la remisión clínica. Globalmente, los resultados de la presente tesis sugieren que las fases agudas del trastorno esquizoafectivo se caracterizan por una hipoactivación del DLPFC. Esta alteración equipara el trastorno esquizoafectivo con la esquizofrenia y el trastorno bipolar, en los cuales la hipoactivación del DLPFC ha sido también descrita. Por otro lado, el fracaso en desactivar la corteza frontal medial, apareció tanto en la fase aguda como la fase de remisión clínica, independientemente del estado psicopatológico, sugiriendo una disfunción del DMN, como factor de rasgo intrínseco a la enfermedad. La disfunción del DMN ha sido previamente descrita en otras patologías psiquiátricas, entre las que se encuentran la esquizofrenia y el trastorno bipolar. Otro hallazgo de la presente tesis, son las alteraciones cognitivas en los pacientes esquizoafectivos, presentes tanto en las fases agudas, como en los periodos de eutimia. Únicamente se objetivó una mejora parcial en la memoria en el subgrupo de pacientes esquizomaníacos al alcanzar la eutimia.The term schizoaffective psychosis was introduced by Kasanin in 1933 to describe the apparent occurrence of patients who did not fit into the category of either schizophrenia or manic-depressive psychosis. Ever since, its nosology has been a matter of controversy and studies have been scarce dedicated to shed light into the neurobiology of this disorder. The present thesis aimed to add insight to the literature of neurobiological underpinnings of schizoaffective disorder, taking into account also longitudinal aspects of the disease. Specifically, the thesis reports two fMRI studies which examined a sample of patients meeting both RDC and DSM-IV criteria for schizoaffective disorder, bipolar type. This patient sample was compared with age, sex and premorbid-IQ matched healthy controls. All subjects underwent at least one fMRI scan, during performance of the n-back working memory test. Additionally, memory and executive functioning were assessed. Linear models were used to obtain maps of activations and de-activations in the groups. The first study was a cross-sectional study evaluating patterns of brain activation and de-activation in acute schizomanic or schizodepressive schizoaffective patients. Compared to controls, the schizoaffective patients showed a reduced activation in the DLPFC and also a failure of de-activation in the medial frontal cortex. This latter area corresponds to the anterior node of the DMN. In the second study the same patients were reassessed after at least two months of clinical remission. The subgroup of schizomanic patients were found to show a reversible frontal hypoactivation during n-back performance when compared to clinical remission, while no changes in the brain response to the task were seen in schizodepressive patients in comparison to clinical remission. The whole group of schizoaffective patients in clinical remission showed a failure of de-activation in the medial frontal cortex compared to the healthy controls. The cognitive assessment in the second study showed that schizomanic patients improved in memory but not in executive functioning from active illness to remission, while schizodepressive patients did not show changes in either domain. All schizoaffective patients in clinical remission continued to show memory and executive impairment compared to the controls. Overall, the present thesis suggests that DLPFC hypoactivation is a state feature of schizoaffective disorder. This finding aligns it with schizophrenia but also with bipolar disorder, where reduced DLPFC activity has also been described. Failure of de-activation, and by extension DMN dysfunction, appeared across all different phases of the disorder, as a trait feature of the illness. DMN dysfunction has also been described in a range of psychiatric disorders, including schizophrenia and bipolar disorder. Cognitive impairment was a further finding of this thesis. There was some evidence of memory improvement in euthymic schizomanic patients, but this was partial and the patients still showed deficits in remission, in particular executive dysfunction

Neuropsychological and brain functional changes across the different phases of schizoaffective disorder

El término esquizoafectivo fue introducido por J. Kasanin en 1933, para describir a un grupo de pacientes que no encajaban ni con el diagnóstico de esquizofrenia ni en el de las psicosis maníaco-depresivas. La nosología del trastorno esquizoafectivo siempre ha sido un tema controvertido y se han llevado a cabo pocos estudios que hayan sido útiles para clarificarla. El objetivo de la presente tesis es estudiar las bases neurobiológicas de esta enfermedad, evaluando las alteraciones que aparecen tanto en las fases de descompensación como los cambios a nivel longitudinal. Este trabajo está compuesto por dos estudios que usan la resonancia magnética funcional para examinan a un grupo de pacientes con trastorno esquizoafectivo, tipo bipolar, diagnosticados según los criterios RDC y DSM-IV. Los pacientes fueron comparados con un grupo de sujetos sanos, apareados por edad, sexo y CI pre-mórbido. A todos los sujetos se les realizó al menos un escáner, mientras realizaban una tarea de memoria de trabajo 'N-back'. Paralelamente, se realizó un estudio neuropsicológico, evaluando la memoria y función ejecutiva. Se obtuvieron los mapas de activación y desactivación cerebral mediante un modelo lineal general y se realizó un análisis longitudinal de medidas repetidas. En el primer estudio transversal, se examinaron los patrones de activación cerebral durante un episodio de descompensación, esquizomaníaco o esquizodepresivo. Los pacientes mostraron una hipoactivación del DLPFC, así como un déficit en desactivar la corteza frontal medial, comparado con los sujetos sanos. Esta última región corresponde al nodo anterior de la red neuronal por defecto o DMN. En el segundo estudio, los mismos pacientes fueron revaluados tras alcanzar la remisión clínica, definida como un periodo de eutimia superior a dos meses. El subgrupo de pacientes esquizomaníacos mostró una hipoactivación frontal en la fase aguda que revirtió al alcanzar la eutimia. Por el contrario, en el subgrupo de pacientes esquizodepresivos no se observaron diferencias entre la fase aguda y la remisión clínica. Al comparar todos los pacientes esquizoafectivos en remisión clínica con los sujetos sanos, los pacientes mostraron un déficit en desactivar la corteza frontal medial, indicando una disfunción del DMN. En el segundo estudio también se evaluó la memoria y función ejecutiva. En ambas pruebas, todos los pacientes en remisión clínica mostraron un menor rendimiento en comparación al grupo de sujetos sanos. En el subgrupo de pacientes esquizomaníacos mejoró la memoria al alcanzar la remisión clínica, sin embargo, no hubo cambios en la función ejecutiva. Por el contrario, en el subgrupo de pacientes esquizodepresivos no se encontraron diferencias significativas entre la fase aguda de la enfermedad y la remisión clínica. Globalmente, los resultados de la presente tesis sugieren que las fases agudas del trastorno esquizoafectivo se caracterizan por una hipoactivación del DLPFC. Esta alteración equipara el trastorno esquizoafectivo con la esquizofrenia y el trastorno bipolar, en los cuales la hipoactivación del DLPFC ha sido también descrita. Por otro lado, el fracaso en desactivar la corteza frontal medial, apareció tanto en la fase aguda como la fase de remisión clínica, independientemente del estado psicopatológico, sugiriendo una disfunción del DMN, como factor de rasgo intrínseco a la enfermedad. La disfunción del DMN ha sido previamente descrita en otras patologías psiquiátricas, entre las que se encuentran la esquizofrenia y el trastorno bipolar. Otro hallazgo de la presente tesis, son las alteraciones cognitivas en los pacientes esquizoafectivos, presentes tanto en las fases agudas, como en los periodos de eutimia. Únicamente se objetivó una mejora parcial en la memoria en el subgrupo de pacientes esquizomaníacos al alcanzar la eutimia.The term schizoaffective psychosis was introduced by Kasanin in 1933 to describe the apparent occurrence of patients who did not fit into the category of either schizophrenia or manic-depressive psychosis. Ever since, its nosology has been a matter of controversy and studies have been scarce dedicated to shed light into the neurobiology of this disorder. The present thesis aimed to add insight to the literature of neurobiological underpinnings of schizoaffective disorder, taking into account also longitudinal aspects of the disease. Specifically, the thesis reports two fMRI studies which examined a sample of patients meeting both RDC and DSM-IV criteria for schizoaffective disorder, bipolar type. This patient sample was compared with age, sex and premorbid-IQ matched healthy controls. All subjects underwent at least one fMRI scan, during performance of the n-back working memory test. Additionally, memory and executive functioning were assessed. Linear models were used to obtain maps of activations and de-activations in the groups. The first study was a cross-sectional study evaluating patterns of brain activation and de-activation in acute schizomanic or schizodepressive schizoaffective patients. Compared to controls, the schizoaffective patients showed a reduced activation in the DLPFC and also a failure of de-activation in the medial frontal cortex. This latter area corresponds to the anterior node of the DMN. In the second study the same patients were reassessed after at least two months of clinical remission. The subgroup of schizomanic patients were found to show a reversible frontal hypoactivation during n-back performance when compared to clinical remission, while no changes in the brain response to the task were seen in schizodepressive patients in comparison to clinical remission. The whole group of schizoaffective patients in clinical remission showed a failure of de-activation in the medial frontal cortex compared to the healthy controls. The cognitive assessment in the second study showed that schizomanic patients improved in memory but not in executive functioning from active illness to remission, while schizodepressive patients did not show changes in either domain. All schizoaffective patients in clinical remission continued to show memory and executive impairment compared to the controls. Overall, the present thesis suggests that DLPFC hypoactivation is a state feature of schizoaffective disorder. This finding aligns it with schizophrenia but also with bipolar disorder, where reduced DLPFC activity has also been described. Failure of de-activation, and by extension DMN dysfunction, appeared across all different phases of the disorder, as a trait feature of the illness. DMN dysfunction has also been described in a range of psychiatric disorders, including schizophrenia and bipolar disorder. Cognitive impairment was a further finding of this thesis. There was some evidence of memory improvement in euthymic schizomanic patients, but this was partial and the patients still showed deficits in remission, in particular executive dysfunction

Brain structural changes in schizoaffective disorder compared to schizophrenia and bipolar disorder

Brain structural changes in schizoaffective disorder, and how far they resemble those seen in schizophrenia and bipolar disorder, have only been studied to a limited extent. Forty-five patients meeting - and criteria for schizoaffective disorder, groups of patients with 45 matched schizophrenia and bipolar disorder, and 45 matched healthy controls were examined using voxel-based morphometry (). Analyses comparing each patient group with the healthy control subjects found that the patients with schizoaffective disorder and the patients with schizophrenia showed widespread and overlapping areas of significant volume reduction, but the patients with bipolar disorder did not. A subsequent analysis compared the combined group of patients with the controls followed by extraction of clusters. In regions where the patients differed significantly from the controls, no significant differences in mean volume between patients with schizoaffective disorder and patients with schizophrenia in any of five regions of volume reduction were found, but mean volumes in the patients with bipolar disorder were significantly smaller in three of five. The findings provide evidence that, in terms of structural gray matter brain abnormality, schizoaffective disorder resembles schizophrenia more than bipolar disorder