Childhood adversity, the brain and psychosis: Abstracts

Childhood trauma is associated with an increased risk of psychosis, but the mechanisms that mediate this relationship are unknown. Research suggests that people with first-episode psychosis (FEP) report more childhood traumas and have lower metacognitive abilities than non-clinical controls. Cognitive (information-processing) biases have been posited as a mechanism by which exposure to trauma can lead to the development of psychotic phenomena such as hallucinations and delusional beliefs, and can be broadly categorized as biases in causal attribution, interpretation, and inference. The effects from childhood adversity seem not to be specific to one disease. Rather childhood adversity seems to be a common risk factor for psychiatric disorder and depending on subsequent alterations in information processing and on preexisting genetic factors the vulnerability will be more to the one or the other psychiatric disorder. For example, childhood adversity was also found to be associated with cognitive bias and particular negative emotion processing in patients with major depressive disorder. In a series of studies, it was explored whether and how childhood adversity is associated with alterations in the stress hormone system and in turn with structural, functional and metabolic brain changes depending on genetic factors in key regions of interest in patients with major depressive disorders. 

Although multiple lines of evidence implicate glutamate dysfunction in schizophrenia / psychosis there is some indication that the extent or nature of glutamate dysfunction may differ across individuals. For example, while recent meta-analysis of case-control studies measuring brain glutamate using proton magnetic resonance spectroscopy (1H-MRS) have found overall reductions in glutamate metabolites in the medial frontal cortex (mFC) (1) and elevations in the basal ganglia in schizophrenia (1,2) individual studies have reported both increases, decreases and no change. Indeed, our recent meta-analysis of variability finds that patients demonstrate greater variability in glutamate metabolite levels than controls (3).   

This talk will discuss the potential clinical consequences of heterogeneity in glutamate dysfunction, with a focus on clinical and functional response to antipsychotic treatment. Higher glutamate metabolite levels are associated with more severe symptom severity and worse functioning in schizophrenia (3). Although not all results are consistent, some cross-sectional have shown higher glutamate metabolite levels in the mFC in groups showing a poor response to treatment, including non-remission in first episode psychosis, treatment resistant or clozapine-resistant schizophrenia, compared to individuals with a good antipsychotic response (4-8). Prospective studies have also indicated that higher glutamate levels are associated with a subsequently poorer response to antipsychotic treatment (9,10). Further understanding may ultimately aid prediction of outcome in psychosis or the targeting of glutamate-acting therapeutics to patient subgroups.  

 References 

1. Nakahara et al. Mol Psychiatry. 2021  

2. Merritt K, et al. JAMA Psychiatry. 2016;73(7). 

3. Merritt et al., under review. Preprint: https://www.researchsquare.com/article/rs-2057436/v1  

4. Egerton et al., Neuropsychopharmacology 2012;37:2515–21. 

5. Egerton et al., Schizophr Bull. 2021;47:505–16. 

6. Iwata et al., Biol Psychiatry. 2019;85:596–605. 

7. Mouchlianitis et al., Schizophr Bull. 2016;42:744–52. 

8. Tarumi et al., Neuropsychopharmacology. 2019;45:632–40. 

9. Egerton et al., Mol Psychiatry. 2018;23:2145–55 

10. Egerton et al., Neuropsychopharmacology. 2022 https://doi.org/10.1038/s41386-022-01508-w  

Childhood adversity has been associated with earlier onset and greater severity of psychotic disorders. Such experiences are known to negatively impact on a range of functions, including cognitive and interpersonal difficulties. One of the proposed mechanisms through which childhood adversity affects these problems in psychosis is when childhood adversity disrupts typical cognitive and brain development during childhood and adolescence. In this talk, I will provide findings on the role of childhood adversity on cognitive problems and related brain alterations presenting functional Magnetic Resonance Imaging (fMRI) and Magnetic Resonance Spectroscopy (MRS) findings. Finally, I will discuss how such an approach may optimise early identification, prevention and treatment in individuals with psychosis. 

In trauma-exposed individuals with a diagnosis of schizophrenia, existing neuroimaging studies have highlighted the involvement of stress-sensitive frontolimbic pathways among others with regional approaches. Examining patterns of anatomical connectivity may inform integrative aspects of the brain’s distributed network structure. Trauma-exposure was assessed retrospectively using the 28-item Childhood Trauma Questionnaire. High levels of trauma-exposure were defined by the presence of moderate-severe abuse and/or neglect. Structural networks were constructed from ‘nodes’ (AAL) derived from T1-weighted structural and diffusion-weighted MRI (32 directions, b= 1000 s/mm2, 3T) based ‘edges’ using non-tensor based tractography (constrained spherical deconvolution; CSD). Covarying for age and sex, group differences in whole-brain topology and permutation-based statistics were examined across weighted (fractional anisotropy; FA, number-of-streamlines; NOS) and unweighted measures of connectivity. Having a diagnosis of schizophrenia (DSM-IV, n=51, mean age±SD 44±11 years), relative to controls (n=140, 34.0±12 years), was associated with whole-brain impairments in network topology, characterised by lower efficiency, strength, clustering, density and increases in path length and betweenness; and hypoconnectivity within frontotemporal, frontoparietal and occipital connections (FA/NOS-weighted). Irrespective of diagnosis, trauma-exposure did not relate to any structural network differences (n=55, 40±13 years, p>0.05), nor was there any significant diagnosis by trauma interaction across any whole-brain or subnetwork measures of topology examined (n=17, 47±13 years, p>0.05). Using a graph-theoretical connectome approach, we did not detect a distinguishable impact of trauma-exposure on topological or structural connectivity impairments observed in schizophrenia, nor did trauma-exposure irrespective of diagnosis confer any generalised changes in network topology the latter being inconsistent with regional-approach studies. We confirm that schizophrenia is characterised by abnormal and inefficient communication among frontoparietal, frontotemporal and occipital connection involving the default mode network. These anatomical findings do not preclude the potential for an impact of trauma independently or differentially in schizophrenia on functional patterns or dynamic connectivity patterns.  

Immune dysfunction is implicated in the aetiology of schizophrenia with elevation of peripherally measured cytokines prior to the onset of disorder and causality suggested in genomic studies. However, the efficacy of immunomodulatory drugs is mixed, and it is not clear how we should target new and repurposed agents to better effect. There is considerable heterogeneity in the potential clinical profile of immune active psychosis; with negative, cognitive and acute symptoms variably implicated. Identifying valid, reproducible inflammation subgroups of patients with schizophrenia based on their inflammatory profile could help elucidate illness mechanisms and stratification of potential candidates of novel treatments. This presentation will rehearse existing and recently published data demonstrating the importance of affective symptoms in early stages of psychosis and potential phenotypic and neuroanatomical profile that may aid better targeted treatments.

Rachel is Professor of Psychiatry and Youth Mental Health at the University of Birmingham, and Consultant Psychiatrist in the Birmingham Early Intervention Services. She trained in Medicine at the Royal Free Hospital, University of London and Psychiatry in Birmingham. She completed her PhD at the University of Birmingham, investigating depression and suicidality in first episode psychosis. Her recent research is identifying novel treatments for early stages of schizophrenia, and she leads the Psychosis Immune Mechanism Stratified Medicine Study, a collaborative multi-stage project investigating inflammatory mechanisms and immune-phenotypic profile of psychosis. Other current funded studies are also taking translational research into practice, including the NIHR funded Early Psychosis Informatics into Care (EPICare) study. She is chief investigator and co-investigator on a number of RCTs for repurposed and targeted treatments. Rachel is Deputy Chair of the NIHR Mental Health Translational Research Consortium, Honorary General Secretary of the British Association for Psychopharmacology and Deputy Editor for the British Journal of Psychiatry. 

Schizophrenia and bipolar disorder show similar clinical, cognitive and neurobiological features and share genetic and environmental risk factors. In particular, childhood trauma exposure can shape the developmental trajectories of the brain and larger neurobiological systems (e.g., stress, inflammation). These aberrant neurodevelopmental features can lead to more severe forms and earlier diagnoses of these disorders, as well as more severe cognitive and affective dysfunctions. Despite an increasing interest on the identification of long-term neurobiological and clinical consequences of childhood trauma exposure, its interactions with the other risk factors in the development of schizophrenia and bipolar disorder remain unclear. This presentation will first highlight the common and/or disorder-specific impacts of childhood trauma on brain function/morphology and neurobiological systems in adult patients with schizophrenia or bipolar disorder, as well as in healthy adults. Then interactions between childhood trauma and other risk factors for psychosis (e.g., genetic, schizotypy, socio-demographic) or aberrant neurobiological features, on brain function/morphology and associated behaviours in these populations will be explored. Future multi-modal and integrative studies are needed to better understand the complex relationships existing between risk factors implicated in the development of disorders from the mood-psychosis spectrum. This knowledge will be fundamental in the optimisation of therapeutic approaches for these conditions. 

Yann Quidé

1 School of Psychology, University of New South Wales (UNSW) Sydney, Sydney, NSW, Australia 

2 Neuroscience Research Australia, Randwick, NSW, Australia 

Oxidative stress has been proposed to occur in several patients with psychosis. Several observations suggest that this could be a key defect that may precede the onset of illness. In our brain, the primary antioxidant is a molecule called glutathione (GSH), which is present primarily in astrocytes. There are two good reasons to focus on GSH when studying the oxidative stress status in mental illnesses: firstly, with neurochemical imaging techniques such as Magnetic Resonance Spectroscopy (MRS), we can estimate the quantity of GSH in a given region of the brain; second, there are many well tolerated antioxidant modulators that can be used to boost GSH levels in the brain. Together, this makes a perfect recipe to identify those who have low levels of GSH and give them interventions to improve it. Over the last 5 years we have been closely looking at the levels of GSH in a region of the brain called the anterior cingulate cortex, from where reliable measurements can be made using MRS using a 7-Tesla MRI scanner. The story of the central antioxidant system in psychosis provides a roadmap for leveraging adaptive brain changes to effective interventions.