The project aims to explore changes in brain chemistry in individuals who have recently experienced psychosis. Recent research suggests that chemicals in the brain, specifically one called glutamate, may behave differently in people who have experienced psychosis compared to those who have not. It is also known that some individuals with psychosis can find tasks involving memory and attention more challenging. This study aims at understanding how brain chemistry is linked to memory and attention, and if this is different between people who have and have not experienced psychosis.

The study will also investigate how a commonly used brain stimulation technique might help people with psychosis and other conditions by altering brain chemistry for a very short period. Non-invasive brain stimulation using very weak electrical stimulation has been used to help improve symptoms in individuals with psychosis and many other conditions, and has been shown to alter brain chemistry for a few hours after stimulation. However, it does not work for everyone. It will be investigated if levels of glutamate can predict whether brain stimulation will help an individual or not. In other words, the study investigates if glutamate can be used as a marker for tailoring treatments.

This project also aims to collect personal experiences or challenges that individuals with psychosis face. This information will be gathered through interviews. This will help to understand what specific difficulties individuals have, such as with certain aspects of memory and attention. The interview will also gather opinions and concerns about brain imaging and brain stimulation and current understandings of chemicals in the brain. For example, the study will explore why individuals may not want to take part in brain imaging or brain stimulation.

TRIAL / STUDY BACKGROUND INFORMATION AND RATIONALE

Cognitive impairment in psychosis:

Cognitive impairments occur in up to 80% of people living with psychosis. The recent landscape report, commissioned by the Wellcome Trust, highlighted that cognitive impairments are an "area of concern for people with psychosis" (p.36) and, furthermore, that "personalising the intervention approach...is desirable" (p.39). Specific cognitive symptoms are variable across individuals, but they are relevant for the individual as they predict day-to-day functioning and quality of life. Current interventions aiming at cognitive improvements are effective for some, but not all, individuals with psychosis. To increase the amount of viable and effective treatment options, a personalised approach based on improved understanding into the variability in cognitive impairments in psychosis is needed.

This project aims to explore perceptions of cognitive impairment & treatment from those with first-hand experience (Study 2); to explore a potential neurochemical marker (glutamate levels, in particular) for cognitive functioning with a focus on working memory (WM) (Study 1a); and to assess how this marker may predict changes in response to a single 'accelerated' session of non-invasive brain stimulation using transcranial direct current stimulation (tDCS) (Study 1a). Additionally, the study aims to explore the effects of accelerated tDCS on neurochemistry in individuals with first-episode psychosis (FEP; Study 1b). This 'accelerated' approach involves applying two stimulations in proximity during one testing session as recommended by several authors to safely maximise potential stimulation effects. The investigators chose tDCS as intervention method due to its potential for influencing glutamate levels (see below). Through these three interconnected studies using functional magnetic resonance spectroscopy (fMRS), transcranial direct current stimulation (tDCS) and interview approaches, the study aims at better understanding and informing potential future treatment options for cognitive impairment in psychosis.

It is important to note that while this study will use tDCS as part of this project, this is not an interventional study, in the respect that it is not assessing the impact of tDCS directly on symptoms or quality of life. In study 1a, the investigators will explore statistical relationships between changes in neurochemistry during the cognitive task, and changes in task performance during and following tDCS. In study 1b, the study will explore how neurochemistry is temporarily altered following accelerated tDCS in a subset of FEP participants. This will allow to validate previous work in healthy controls showing changes in Glu following tDCS, and to assess relationships between task performance and neurometabolite change. Thus, study 1a aims at establishing a link between neurochemical changes and subsequent responses to tDCS, while study 1b, aims to corroborate that tDCS has indeed influenced neurochemical changes in FEP individuals. Further details in the sections below.

Experience of cognitive impairment and perceptions of interventions in psychosis:

There is relatively little research exploring the subjective impact of cognitive impairments experienced through psychosis. Yet, impairments in cognitive functioning are experienced by 75-80% of people living with psychosis, and any future intervention that is designed to alleviate these impairments will have to target the most salient concerns of individuals with lived experiences to enhance uptake and engagement with the intervention. Past research that has interviewed individuals with psychosis has found impairments in cognitive functioning negatively impact on individuals daily functioning, including vocational performance, and on their self-concept, and relationships with others. Further interviews have shown that the notion of future interventions designed to enhance cognitive strengths has been received positively by individuals with psychosis. However, except for these studies little is known about this area, and these studies focused on young people (aged 18-26) receiving treatment in Australia. Additionally, relatively little is known about the perceptions of this demographic about views towards non-invasive brain stimulation approaches and use of magnetic resonance imaging in potential treatment plans. Study 2 will use semi-structured interviews to improve insights into the subjective impact of cognitive impairment and perceptions of non-invasive brain stimulation/ imaging among NHS patients in the UK. These will give valuable insights into what matters to patients and how potential interventions are perceived.

Working memory (WM) and psychosis:

Although several different cognitive functions can be affected in individuals with psychosis (perceptions of which will be explored in study 2), some cognitive domains seem particularly vulnerable, including associative processes in episodic and working memory (WM). WM is a crucial component of goal-directed behaviour. For instance, in a conversation we need to keep our semantic goals (the main message we want to convey) active in WM as well as a representation of what has been said already. Similarly, if we want to evaluate whether our actions have been successful and in line with our goals, i.e. monitoring our own performance, we need to keep a representation of the context and relevant information active in WM. These monitoring processes are often compromised in individuals with schizophrenia, thereby impacting goal-directed behaviour. Thus, impairments in WM are linked to impairments in goal-directed behaviour and will impact on a range of everyday life tasks.

Evidence from brain imaging studies using magnetic resonance spectroscopy (MRS) have given recent insights into the neurochemistry which underlies our ability to perform WM tasks and potential differences between those with and without psychosis. MRS is a specialised form of magnetic resonance imaging (MRI) which allows for quantification of neuro-metabolites, including glutamate (Glu) and GABA, which play a key role in regulating activity within the brain. Recent work has revealed a link between cognitive functions in schizophrenia and MRS measures of glutamate acquired at rest. In more dynamic measures taken during a cognitive task using fMRS, Jelen et al (2019) found that levels of Glu increase when transitioning from low to high WM conditions in healthy controls but not in individuals with psychosis. In Study 1a, we will build on the previous literature by using fMRS to explore how neurometabolites, including Glu, vary during a WM task between individuals with first episode psychosis and controls and how these modulations in task-dependent Glu-level modulations are related to the individual's WM performance.

Modulating glutamate using tDCS:

There is some evidence that Glu levels in the brain may be related to treatment outcome. A recent meta-analysis showed increased medial frontal Glu levels in treatment-resistant psychosis but decreased Glu levels in treatment responders, indicating a preliminary association between Glu levels and treatment outcome. Therefore, it seems to be promising to further investigate the relationship between Glu levels, cognitive functions, and treatment outcomes.

After establishing how Glu changes in response to a WM task in both first episode psychosis (FEP) individuals and health controls, the study aims to evaluate if this natural flexibility in Glu is related to changes in Glu driven by external means which could be developed into robust therapies in the future. Specifically, Study 1a will explore the potential relationship between Glu change during the WM task and behavioural change attributed to transcranial direct current stimulation (tDCS). The investigators will then extend this in Study 1b to corroborate if Glu levels have indeed been modulated by exposure to tDCS.

Transcranial direct-current stimulation (tDCS) is a non-invasive brain stimulation method which can modulate Glu levels in stimulated brain areas. A weak current is applied to the scalp influencing the underlying cortex by altering the membrane potential of neurons proximal to the surface electrode. Anodal stimulation is frequently reported to increase the cortical excitability which can induce increased neural plasticity and thereby lead to functional changes that last longer than the actual stimulation. TDCS has the advantage that it can modulate Glu levels in targeted brain areas and, compared to many pharmacological interventions, has relatively mild and short-lasting side effects (e.g. tingling sensations), has demonstrated good tolerability within the majority of patient groups and has the potential to develop for home use in the future.

TDCS has already been used in individuals with schizophrenia to improve executive functions and learning as well as working memory and clinical symptoms. Although the effect sizes of tDCS stimulations are often noted to be variable within healthy individuals, studies in several different brain regions have shown links between relevant task performance and tDCS response.

The investigators propose that task-related Glu changes (measured with fMRS) predict more precisely who will benefit most from tDCS stimulation. The investigators will assess this in Study 1a through evaluating the relationship between fMRS measured Glu change during a WM task and performance change in the same take following tDCS. In a subset of participants (Study 1b), the study will additionally explore any change in fMRS measured Glu immediately following tDCS. Thus, the study will investigate the relationship between pre- and post-tDCS Glu modulations, within-task Glu modulations and behavioural task performance.

The aim in Study 1b is not to evaluate the effectiveness of tDCS (this would need to be tested in a follow-up RCT), but to establish the relationship between Glu dynamics in a cognitive task and the effect of an intervention that modulates the Glu system. The study involves a CE marked device which has been used extensively for research purposes.

The investigators do not anticipate that any of our results will affect future clinical practice directly, however, the information gathered form the various sub-studies will provide valuable knowledge that could provide the foundation for future intervention developments.

Inclusion Criteria for FEP Group (studies 1a and 1b):

Eligibility criteria for first episode psychosis group are as follows:

1. Aged 18-55 years.
2. Ability to understand and willing to give written informed consent.
3. Fluent in English to be able to understand all cognitive task instructions and questionnaires.
4. Current psychotic disorder of less than 5yrs total duration. Defined as meeting DSM-5 criteria consistent with a diagnosis of schizophrenia, schizoaffective disorder, bipolar affective disorder, or severe depression with psychosis.
5. At least 8 weeks of stable treatment.
6. Ability to travel to the University of Nottingham for in-person testing.

Exclusion Criteria for FEP Group (Studies 1a and 1b):

1. Clinically significant neurological or comorbid psychiatric disorder in the opinion of the investigator.
2. History of clinically significant head injury
3. Current harmful use of, or dependence on, psychoactive substances (excluding nicotine) in the opinion of the investigator
4. Current use of any medication which may interfere with the study in the opinion of the investigator, i.e. any medication that might affect the neurochemicals of interest
5. Contraindications for MR scanning as assessed by SPMIC screening form and trained scanner operator (e.g. claustrophobia, pregnancy, metal implants, etc.)
6. Contraindications for transcranial direct current stimulation as assessed by standard screening form (e.g. cardiac pacemaker or other implanted devices, seizures, epilepsy, open head wound, etc.)
7. Having taken part within the previous month as a participant in a clinical trial that involved taking a drug or having an invasive procedure.

Inclusion Criteria for Healthy Matched Controls (Studies 1a and 1b):

Matched healthy control participants will be recruited from a local database of volunteers, from posters and online advertisements.

Inclusion criteria (matched controls):

1. Aged 18 - 55 years.
2. Ability to understand and willing to give written informed consent.
3. English as first language or fluent in English.
4. Ability to travel to the University of Nottingham for in-person testing.

Exclusion criteria for Health Matched Controls (Studies 1a and 1b):

1. Personal or family history of psychosis.
2. Clinically significant neurological or psychiatric disorder.
3. History of clinically significant head injury.
4. Current harmful use of, or dependence on, psychoactive substances (excluding nicotine and caffeine) in the opinion of the investigator.
5. Current use of any medication, which may interfere with the study in the opinion of the investigator i.e. any medication that might affect the neurochemicals of interest.
6. Contraindications for MR scanning as assessed by SPMIC screening form and trained scanner operator (e.g. claustrophobia, pregnancy etc).
7. Contraindications for transcranial direct current stimulation as assessed by standard screening form (e.g. cardiac pacemaker or other implanted devices, seizures, epilepsy, open head wound, etc.)
8. Having taken part within the previous month as a participant in a clinical trial that involved taking a drug, being paid an inconvenience allowance, or having an invasive procedure (e.g. venepuncture >50ml, endoscopy).

Inclusion Criteria for participants with lived experiences of psychosis (Study 2):

1. Aged 18+ years.
2. Ability to understand and willing to give written informed consent.
3. Fluent in English to be able to understand and answer all questions.
4. History of psychotic disorder defined as DSM-5 criteria for diagnosis of schizophrenia, schizoaffective disorder, bipolar affective disorder, or severe depression with psychosis. No limit of time since first episode.
5. At least 8 weeks of stable treatment.
6. Ability to travel to the University of Nottingham for in-person testing.

Exclusion Criteria for participants with lived experiences of psychosis (Study 2):

1. Clinically significant neurological or comorbid psychiatric disorder.
2. Current harmful use of, or dependence on, psychoactive substances (excluding nicotine) in the opinion of the investigator.
3. Having taken part within the previous month as a participant in a clinical trial that involved taking a drug or having an invasive procedure.
4. Lived experience where psychosis symptoms have not been directly experienced by the individual (e.g., support or carer role to someone else).

Magnetic resonance spectroscopy (MRS/fMRS) data functional MRI data Performance on cognitive assessments at different study time points QoL and other questionnaire data interview transcripts or summarised interview data (depending on participant consent)

Data will be shared after publication of the study results. Data shared in OSF and UK Data Service do not have a time limitation.

IPD from study 1a and b will be uploaded to OSF. Interview data will be deposited with the UK data service.