Álvaro Díez

Background and Hypothesis: Altered brain activity preceding behavior may reflect a reduced ability to suppress the sensory consequences of self-generated actions in schizophrenia. The corollary discharge (CD) mechanism has been proposed to underlie this process. In the present study, we investigated CD by analyzing the readiness potential (RP) and its relationship to auditory N1 suppression in patients with schizophrenia compared to healthy controls (HCs). We also examined the association between RP activity and anomalous self-experiences (ASEs). Study Design: Event-related potentials were recorded from 48 patients with schizophrenia and 55 HCs during a vocalization paradigm including talk and listen conditions. RP amplitude and N1 suppression were quantified as the amplitude difference between listen and talk conditions. Regression analyses assessed the relationship between these components within each group and examined associations between RP and N1 amplitudes and ASEs, measured using the Inventory of Psychotic-Like Anomalous Self-Experiences (IPASE) scale, in the schizophrenia group. Study Results: In the talk condition, HCs showed greater RP amplitude compared with the listen condition, a difference that was absent in the schizophrenia group. In HCs, this RP increase was followed by suppression of the N1 component. A significant correlation between RP amplitude difference (talk minus listen) and N1 suppression was observed in HCs but not in patients. Importantly, reduced N1 suppression in patients with schizophrenia was associated with higher IPASE scores. Conclusions: These findings suggest that schizophrenia involves impairments in early cortical processes related to efference copy and corollary discharge mechanisms, reflected in reduced RP amplitude and the lack of coupling with N1 suppression. Such alterations may contribute to deficits in sensory prediction and to anomalous self-experiences in schizophrenia.

El proyecto humanizAS implementa la actividad "Entrevista a un Profesional Sanitario" como práctica obligatoria en el Grado en Medicina de la Universidad de Valladolid. Integrada en la asignatura de Psicología de segundo curso, facilitando el contacto asistencial temprano y la humanización. Esta actividad se ha realizado en el Grado en Medicina en los últimos cinco cursos académicos (2019-2024). La metodología exige colaboradores con un mínimo de cinco años de experiencia para obtener una perspectiva dilatada sobre la relación clínico-paciente y el manejo de la enfermedad. Los resultados muestran una alta satisfacción en estudiantes y profesionales participantes. El proyecto, apoyado por el ICOMVA y con enfoque multidisciplinar, se valida como una herramienta innovadora para introducir la reflexión humanística en la formación inicial del futuro médico.

Corollary discharge mechanism suppresses the conscious auditory sensory perception of self-generated speech and attenuates electrophysiological markers such as the auditory N1 Event-Related Potential (ERP) during Electroencephalographic (EEG) recordings. This phenomenon contributes to self-identification and seems to be altered in people with schizophrenia. Therefore, its alteration could be related to the anomalous self-experiences (ASEs) frequently found in these patients. To analyze corollary discharge dysfunction as a possible substrate of ASEs, we recorded EEG ERP from 43 participants with schizophrenia and 43 healthy controls and scored ASEs with the ‘Inventory of Psychotic-Like Anomalous Self-Experiences’ (IPASE). Positive and negative symptoms were also scored with the ‘Positive and Negative Syndrome Scale for Schizophrenia’ (PANSS) and with the ‘Brief Negative Symptom Scale’ (BNSS) respectively. The N1 components were elicited by two task conditions: (1) concurrent listening to self-pronounced vowels (talk condition) and (2) subsequent non-concurrent listening to the same previously self-uttered vowels (listen condition). The amplitude of the N1 component elicited by the talk condition was lower compared to the listen condition in people with schizophrenia and healthy controls. However, the difference in N1 amplitude between both conditions was significantly higher in controls than in schizophrenia patients. The values of these differences in patients correlated significantly and negatively with the IPASE, PANSS, and BNSS scores. These results corroborate previous data relating auditory N1 ERP amplitude with altered corollary discharge mechanisms in schizophrenia and support corollary discharge dysfunction as a possible underpinning of ASEs in this illness.

Aiming at discerning potential biotypes within the psychotic syndrome, we have recently reported the possible existence of two clusters or biotypes across schizophrenia and bipolar disorder characterized by their cognitive performance using the Brief Assessment of Cognition in Schizophrenia (BACS) instrument and validated with independent biological and clinical indexes (Fernández-Linsenbarth et al. in Schizophr Res 229:102–111, 2021). In this previous work, the group with larger cognitive deficits (N = 93, including 69 chronic schizophrenia, 17 first episodes (FE) of schizophrenia and 7 bipolar disorder patients) showed smaller thalamus and hippocampus volume and hyper-synchronic electroencephalogram than the group with milder deficits (N = 105, including 58 chronic schizophrenia, 25 FE and 22 bipolar disorder patients). We predicted that if these biotypes indeed corresponded to different cognitive and biological substrates, their adaptation to real life would be different. To this end, in the present work we have followed up the patients’ population included in that work at 1st and 3rd years after the date of inclusion in the 2021 study and we report on the statistical comparisons of each clinical and real-life outcomes between them. The first cluster, with larger cognitive deficits and more severe biological alterations, showed during that period a decreased capacity for job tenure (1st and 3rd years), more admissions to a psychiatric ward (1st year) and a higher likelihood for quitting psychiatric follow-up (3rd year). Patients in the second cluster, with moderate cognitive deficits, were less compliant with prescribed treatment at the 3rd year. The differences in real-life outcomes may give additional external validity to that yielded by biological measurements to the described biotypes based on neurocognition.

Introducción. La pandemia por COVID-19 ha motivado cambios en la sociedad, afectando a la salud mental de la población, particularmente en la infancia y adolescencia. Los menores con patología psiquiátrica previa pueden mostrar incrementos de su sintomatología (depresión, ansiedad o estrés) tanto durante el confinamiento como de forma persistente una vez concluido éste. Objetivo. Evaluar la sintomatología clínica y el impacto emocional en los menores que acuden a Hospital de día y en sus padres/cuidadores un año después de la finalización del confinamiento por COVID-19. Métodos: Se evaluó la sintomatología clínica (emocional y conductual) durante el confinamiento y/o un año después en 81 familias participantes. Se analizaron las diferencias clínicas entre ambos momentos temporales, en primer lugar, para dos grupos de menores y cuidadores independientes y, en segundo lugar, para un mismo grupo de menores y cuidadores evaluado en ambas ocasiones. Resultados. Los análisis longitudinales mostraron algunas tendencias de incrementos de la sintomatología en las dimensiones de depresión, ansiedad y de control afectivo y conductual en los menores. Sin embargo, estas diferencias significativas en ningún caso pasaron el corte de corrección por comparaciones múltiples. Sus familiares y cuidadores tampoco mostraron cambios significativos en la sintomatología evaluada entre ambos momentos temporales. Discusión: la sintomatología clínica de menores con patología psiquiátrica se ha mantenido un año después del fin del confinamiento por COVID-19. Se debería fomentar el seguimiento regular, una buena comunicación entre padres-hijos y un adecuado apoyo social sobre la díada menor-cuidador para favorecer un manejo emocional adecuado.

Background: There is increasing evidence for shared genetic susceptibility between schizophrenia and bipolar disorder. Although genetic variants only convey subtle increases in risk individually, their combination into a polygenic risk score constitutes a strong disease predictor.Aims: To investigate whether schizophrenia and bipolar disorder polygenic risk scores can distinguish people with broadly defined psychosis and their unaffected relatives from controls.Method: Using the latest Psychiatric Genomics Consortium data, we calculated schizophrenia and bipolar disorder polygenic risk scores for 1168 people with psychosis, 552 unaffected relatives and 1472 controls.Results: Patients with broadly defined psychosis had dramatic increases in schizophrenia and bipolar polygenic risk scores, as did their relatives, albeit to a lesser degree. However, the accuracy of predictive models was modest.Conclusions: Although polygenic risk scores are not ready for clinical use, it is hoped that as they are refined they could help towards risk reduction advice and early interventions for psychosis.Declaration of interest: R.M.M. has received honoraria for lectures from Janssen, Lundbeck, Lilly, Otsuka and Sunovian.

A range of endophenotypes characterise psychosis, however there has been limited work understanding if and how they are inter-related. This multi-centre study includes 8754 participants: 2212 people with a psychotic disorder, 1487 unaffected relatives of probands, and 5055 healthy controls. We investigated cognition [digit span (N = 3127), block design (N = 5491), and the Rey Auditory Verbal Learning Test (N = 3543)], electrophysiology [P300 amplitude and latency (N = 1102)], and neuroanatomy [lateral ventricular volume (N = 1721)]. We used linear regression to assess the interrelationships between endophenotypes. The P300 amplitude and latency were not associated (regression coef. −0.06, 95% CI −0.12 to 0.01, p = 0.060), and P300 amplitude was positively associated with block design (coef. 0.19, 95% CI 0.10–0.28, p < 0.001). There was no evidence of associations between lateral ventricular volume and the other measures (all p > 0.38). All the cognitive endophenotypes were associated with each other in the expected directions (all p < 0.001). Lastly, the relationships between pairs of endophenotypes were consistent in all three participant groups, differing for some of the cognitive pairings only in the strengths of the relationships. The P300 amplitude and latency are independent endophenotypes; the former indexing spatial visualisation and working memory, and the latter is hypothesised to index basic processing speed. Individuals with psychotic illnesses, their unaffected relatives, and healthy controls all show similar patterns of associations between endophenotypes, endorsing the theory of a continuum of psychosis liability across the population.

This large multi‐center study investigates the relationships between genetic risk for schizophrenia and bipolar disorder, and multi‐modal endophenotypes for psychosis. The sample included 4,242 individuals; 1,087 patients with psychosis, 822 unaffected first‐degree relatives of patients, and 2,333 controls. Endophenotypes included the P300 event‐related potential (N = 515), lateral ventricular volume (N = 798), and the cognitive measures block design (N = 3,089), digit span (N = 1,437), and the Ray Auditory Verbal Learning Task (N = 2,406). Data were collected across 11 sites in Europe and Australia; all genotyping and genetic analyses were done at the same laboratory in the United Kingdom. We calculated polygenic risk scores for schizophrenia and bipolar disorder separately, and used linear regression to test whether polygenic scores influenced the endophenotypes. Results showed that higher polygenic scores for schizophrenia were associated with poorer performance on the block design task and explained 0.2% (p = 0.009) of the variance. Associations in the same direction were found for bipolar disorder scores, but this was not statistically significant at the 1% level (p = 0.02). The schizophrenia score explained 0.4% of variance in lateral ventricular volumes, the largest across all phenotypes examined, although this was not significant (p = 0.063). None of the remaining associations reached significance after correction for multiple testing (with alpha at 1%). These results indicate that common genetic variants associated with schizophrenia predict performance in spatial visualization, providing additional evidence that this measure is an endophenotype for the disorder with shared genetic risk variants. The use of endophenotypes such as this will help to characterize the effects of common genetic variation in psychosis.

The “dysconnection hypothesis” of psychosis suggests that a disruption of functional integration underlies cognitive deficits and clinical symptoms. Impairments in the P300 potential are well documented in psychosis. Intrinsic (self‐)connectivity in a frontoparietal cortical hierarchy during a P300 experiment was investigated. Dynamic Causal Modeling was used to estimate how evoked activity results from the dynamics of coupled neural populations and how neural coupling changes with the experimental factors. Twenty‐four patients with psychotic disorder, twenty‐four unaffected relatives, and twenty‐five controls underwent EEG recordings during an auditory oddball paradigm. Sixteen frontoparietal network models (including primary auditory, superior parietal, and superior frontal sources) were analyzed and an optimal model of neural coupling, explaining diagnosis and genetic risk effects, as well as their interactions with task condition were identified. The winning model included changes in connectivity at all three hierarchical levels. Patients showed decreased self‐inhibition—that is, increased cortical excitability—in left superior frontal gyrus across task conditions, compared with unaffected participants. Relatives had similar increases in excitability in left superior frontal and right superior parietal sources, and a reversal of the normal synaptic gain changes in response to targets relative to standard tones. It was confirmed that both subjects with psychotic disorder and their relatives show a context‐independent loss of synaptic gain control at the highest hierarchy levels. The relatives also showed abnormal gain modulation responses to task‐relevant stimuli. These may be caused by NMDA‐receptor and/or GABAergic pathologies that change the excitability of superficial pyramidal cells and may be a potential biological marker for psychosis. Hum Brain Mapp 38:3262–3276, 2017. © 2017 Wiley Periodicals, Inc.