Periodic Reporting for period 4 - iRELaTE (Immune Response and Social Cognition in Schizophrenia)
Periodo di rendicontazione: 2021-01-01 al 2021-12-31
What is the problem/issue being addressed?
This project seeks to address the question: ‘Can difficulties with social thinking (known as social cognition) in schizophrenia be explained by an abnormal immune response that is caused by genetic risk factors and moderated by environmental risk factors?’
Why is it important for society?
Schizophrenia, affecting 0.5-1% of the population, is ranked by the World Health Organisation as more disabling than paraplegia or blindness in 18-34 year olds. Current treatments, developed over 50 years ago, are only partly effective in treating this disability, and new treatments are lacking. This is partly because the biological and environmental factors that contribute to the social disability experiences by patients is only partly understood. To address this treatment impasse, this project aims to develop and test a novel immune based model of deficits in social cognition – the set of mental operations that underlie social interactions (e.g. emotion recognition, theory of mind) and strongly predict social disability in schizophrenia. By validating an immune based model of schizophrenia, this project has the potential to move beyond current treatments focused on the neurochemical known as dopamine, and suggest ground-breaking alternatives for understanding and treating social disability in this and other neurodevelopmental disorders.
Why is it important for society?
This project has two parts. The overall objectives of part A (human studies) focuses on neuropsychological and neuroimaging studies of social cognition in patients and healthy adults so as to (1) provide an innovative characterisation of the effects of inflammatory markers (e.g. pro-/anti- inflammatory cytokines) on social cognition, (2) establish whether these markers mediate the effects of recently identified genetic risk loci on schizophrenia, and (3) identify to what extent early social environment (e.g. parental relationships, childhood trauma) moderates this relationship. The objectives of Part B (mice studies), focusing on behavioural and pharmacological studies in mice, are to (1) establish the causal effects of early immune challenge and early social environment on social cognition, and (2) test the translational benefits of anti-inflammatory treatment to normalize the resulting deficits.
This project seeks to address the question: ‘Can difficulties with social thinking (known as social cognition) in schizophrenia be explained by an abnormal immune response that is caused by genetic risk factors and moderated by environmental risk factors?’
Why is it important for society?
Schizophrenia, affecting 0.5-1% of the population, is ranked by the World Health Organisation as more disabling than paraplegia or blindness in 18-34 year olds. Current treatments, developed over 50 years ago, are only partly effective in treating this disability, and new treatments are lacking. This is partly because the biological and environmental factors that contribute to the social disability experiences by patients is only partly understood. To address this treatment impasse, this project aims to develop and test a novel immune based model of deficits in social cognition – the set of mental operations that underlie social interactions (e.g. emotion recognition, theory of mind) and strongly predict social disability in schizophrenia. By validating an immune based model of schizophrenia, this project has the potential to move beyond current treatments focused on the neurochemical known as dopamine, and suggest ground-breaking alternatives for understanding and treating social disability in this and other neurodevelopmental disorders.
Why is it important for society?
This project has two parts. The overall objectives of part A (human studies) focuses on neuropsychological and neuroimaging studies of social cognition in patients and healthy adults so as to (1) provide an innovative characterisation of the effects of inflammatory markers (e.g. pro-/anti- inflammatory cytokines) on social cognition, (2) establish whether these markers mediate the effects of recently identified genetic risk loci on schizophrenia, and (3) identify to what extent early social environment (e.g. parental relationships, childhood trauma) moderates this relationship. The objectives of Part B (mice studies), focusing on behavioural and pharmacological studies in mice, are to (1) establish the causal effects of early immune challenge and early social environment on social cognition, and (2) test the translational benefits of anti-inflammatory treatment to normalize the resulting deficits.
The work undertaken during this reporting period has consisted of the following:
1. Securing the ethical approval and service level agreements required to undertake the project.
2. Recruiting and training of staff working on the project, consisting of 3 postdoctoral researchers, two PhD students, two research assistants, and two clinical research nurses. Over the life of the project this further resulted in training of replacement staff (e.g. at postdoctoral and research assistant level, PhD students who joined the project for part of their projects, etc.).
3. Establishing all necessary protocols for participant recruitment and assessment.
4. Recruiting and screening all human participants and for inclusion in the study and animals for animal studies.
4. Undertaking clinical, neuropsychological, and neuroimaging (MRI) assessments, and phlebotomy on patients and healthy participants. This has resulted in a rich dataset of ~330 participants, consisting of ~100 patients and ~230 health participants.
5. Carrying out husbandry, assessments, training, intervention and data collection on animal involved in the study (~300 mice across both arms of the animal studies).5. Stimulating, and analysing bloods for all participants for immune markers of interest, beginning with IL-6.
6. Data QA/QC and entry to Redcap database and transfer of this data to statistical software for the purposes of data analysis (all now completed).
7. Neuroimaging preprocessing completed. This is based on over 230 participants (see publications)
8. Analysis of existing datasets to carrying out genetic analysis of cognitive performance focusing on on immune related genes (see publications).
9. Analysis of existing datasets to carry out an analysis of the effects of early adversity on cognition and social cognition (see publications).
10. Systematic reviews of the literature on the effects of early social environment on cognition in schizophrenia and other psychiatric disorders (see publications).
11. Analysis of behavioural phenotypes in mouse model (see publications).
12. Other dissemination activities related to the project (see dissemination activities below), and notably highlighting of the iRELATE project on National television via the documentary "Hearing Voices".
1. Securing the ethical approval and service level agreements required to undertake the project.
2. Recruiting and training of staff working on the project, consisting of 3 postdoctoral researchers, two PhD students, two research assistants, and two clinical research nurses. Over the life of the project this further resulted in training of replacement staff (e.g. at postdoctoral and research assistant level, PhD students who joined the project for part of their projects, etc.).
3. Establishing all necessary protocols for participant recruitment and assessment.
4. Recruiting and screening all human participants and for inclusion in the study and animals for animal studies.
4. Undertaking clinical, neuropsychological, and neuroimaging (MRI) assessments, and phlebotomy on patients and healthy participants. This has resulted in a rich dataset of ~330 participants, consisting of ~100 patients and ~230 health participants.
5. Carrying out husbandry, assessments, training, intervention and data collection on animal involved in the study (~300 mice across both arms of the animal studies).5. Stimulating, and analysing bloods for all participants for immune markers of interest, beginning with IL-6.
6. Data QA/QC and entry to Redcap database and transfer of this data to statistical software for the purposes of data analysis (all now completed).
7. Neuroimaging preprocessing completed. This is based on over 230 participants (see publications)
8. Analysis of existing datasets to carrying out genetic analysis of cognitive performance focusing on on immune related genes (see publications).
9. Analysis of existing datasets to carry out an analysis of the effects of early adversity on cognition and social cognition (see publications).
10. Systematic reviews of the literature on the effects of early social environment on cognition in schizophrenia and other psychiatric disorders (see publications).
11. Analysis of behavioural phenotypes in mouse model (see publications).
12. Other dissemination activities related to the project (see dissemination activities below), and notably highlighting of the iRELATE project on National television via the documentary "Hearing Voices".
This study has, during the reporting period, already progressed our knowledge beyond the state of the art by showing that
(1) Immune related genes, specifically those related to the complement system, explain variation in cognitive and social cognitive performance in both patients and in healthy performance.
(2) Early social environment, even 'mild' adversity such as physical parental disciplining, has deleterious effects on cognitive performance. Variation in immune function are also association with both early environment and cognitive performance.
During the next phase of the study until the end of the project, the following results are expected:
1. To use the human data (patients and healthy participant data) to model the effects of early environment and genetic background on cognition as mediated via immune response.
2. To ascertain the degree to which this relationship is modelled in a mice model, and test whether the effects of maternal immune activation +/- social isolation can be rescued using an immune based treatment.
3. Doing so is expected to shed light on whether immune activity is a viable target for pharmacological or psychological interventions aimed at improving cognitive function.
In addition to these primary outcomes, a number of secondary outcomes/results are also anticipated, including:
1. Determining how the Trier social stress can be optimised for use in clinical studies (e.g. number of testers required).
2. Examining the relationship between MRI derived metics of brain connectivity (both structural and functional) and cognitive performance.
3. Establishing novel approaches to characterising the relationship between genetic variation and cognition.
(1) Immune related genes, specifically those related to the complement system, explain variation in cognitive and social cognitive performance in both patients and in healthy performance.
(2) Early social environment, even 'mild' adversity such as physical parental disciplining, has deleterious effects on cognitive performance. Variation in immune function are also association with both early environment and cognitive performance.
During the next phase of the study until the end of the project, the following results are expected:
1. To use the human data (patients and healthy participant data) to model the effects of early environment and genetic background on cognition as mediated via immune response.
2. To ascertain the degree to which this relationship is modelled in a mice model, and test whether the effects of maternal immune activation +/- social isolation can be rescued using an immune based treatment.
3. Doing so is expected to shed light on whether immune activity is a viable target for pharmacological or psychological interventions aimed at improving cognitive function.
In addition to these primary outcomes, a number of secondary outcomes/results are also anticipated, including:
1. Determining how the Trier social stress can be optimised for use in clinical studies (e.g. number of testers required).
2. Examining the relationship between MRI derived metics of brain connectivity (both structural and functional) and cognitive performance.
3. Establishing novel approaches to characterising the relationship between genetic variation and cognition.