Dissociating variations in attention with schizotypy and anxiety

Establishing how cognitive abnormalities result in the signs and symptoms that define schizophrenia and anxiety disorders (and their co-morbidity) has become a prominent question in clinically, and sub-clinically, applied research. Abnormal performance in schizophrenia, schizotypy and anxiety has been observed in comparison to healthy individuals on a range of cognitive and behavioural tasks. For example, abnormal attention to irrelevant information has long been recognised by clinicians, which has since encouraged researchers to elucidate the nature of the relationship between schizophrenia, and anxiety more recently, with allocation of attention to stimuli in laboratory studies providing empirical evidence for an attentional view of these disorders. The pre-exposure effect (slower learning to a stimulus that has been rendered familiar by preexposure, relative to a novel cue), hereafter refered to as latent inhibition, has been shown to be inversely correlated with schizotypy, and abnormal in people with schizophrenia, but findings are inconsistent. One potential contributing factor to this inconsistency is that many tasks that purport to measure latent inhibition are confounded by alternative effects that also retard learning and co-vary with schizotypy, such as learned irrelevance (experience of a cue as irrelevant to the occurrence of an outcome due to inconsistent/uncorrelated presentations of a cue and a target). The general aim of this thesis is to address, or begin to address, some of the key questions and limitations with existing research that evaluate latent inhibition and learned irrelevance as potentially useful cognitive endophenotypes for schizophrenia and anxiety disorders. The current experiments separate out the effects of latent inhibition and learned irrelevance to assess the independent effects of these phenomena on schizotypy (and by extension schizophrenia) and anxiety. By teasing apart, the effects of latent inhibition and learned irrelevance the attempt is to disentangle, and improve understanding of attentional abnormalities observed in these sub-clinical traits and by extension, their related pathologies. Across Experiments 1-4, the purpose was two-fold. The first was to address the limitations of existing latent inhibition tasks by designing a paradigm that examines a purer effect of latent inhibition, by minimising the contribution of learned irrelevance, and assessing how this latent inhibition task co-varies with schizotypy and anxiety (Chapter 2: Experiments 1 and 2). The second was to examine the alternative, potentially less equivocal, learned attentional paradigm (learned irrelevance) and assess the relationship between this task with both schizotypy and anxiety (Chapter 3: Experiments 3 and 4). Based on the assumption that latent inhibition and learned irrelevance share similar psychological underpinnings (in this case, attentional), we anticipated the effect of schizotypy and anxiety to be comparable in the two types of attention tasks here. The results however indicate a double dissociation; an abnormally persistent latent inhibition effect in high positive schizotypy individuals (Experiments 1 and 2) and a reduced learned irrelevance effect in high state anxious individuals (Experiments 3 and 4). The possibility that latent inhibition is non-attentional and the implications of these findings for associative models of attention and learning are explored. The aim of Experiments 5 and 6 were to explore the causal relationship between induced variations in anxiety (stress, relaxation or neutral mood) and learned variations in attention, using a less ambiguous measure of attention (compared to latent inhibition): learned irrelevance. Based on the findings from Experiments 3 and 4, a reduced attentional bias towards previously established predictive cues was expected in individuals induced with an acute state of anxiousness, relative to individuals induced with either a relaxed or neutral mood state. This pattern of results was observed but to a weaker extent than the previous experiments, suggesting that induced variations in anxiety do not have the same relationship with learning as naturally occurring variations in anxiety, as observed in Experiments 3 and 4. Further analyses revealed that the relationship between reduced learned irrelevance and anxiety was mediated by individuals who were also characterised by high levels of schizotypy, and by extension vulnerability to schizophrenia. Given the potential common underlying cognitive processes to both anxiety and schizophrenia, it seems likely that therapies which target the symptoms of anxiety (e.g., Attentional Bias Modification Treatment; ABMT) would be beneficial to individuals who have also been diagnosed with a psychotic disorder. This work represents the first attempt to investigate the independent effects of latent inhibition and learned irrelevance on schizotypy and anxiety, using refined tasks that minimised the contribution of either learning phenomenon on each other. How these learning tasks co-vary in patients with schizophrenia and clinically diagnosed anxiety however remains for future research to determine . At this juncture, the current findings lend support to the potential cognitive endophenotype status of learned irrelevance (considering its status as a less ambiguous measure of attention) and its continued use to provide a base for the development of relevant attentional bias modification treatments

Dissociating variations in attention with schizotypy and anxiety

Establishing how cognitive abnormalities result in the signs and symptoms that define schizophrenia and anxiety disorders (and their co-morbidity) has become a prominent question in clinically, and sub-clinically, applied research. Abnormal performance in schizophrenia, schizotypy and anxiety has been observed in comparison to healthy individuals on a range of cognitive and behavioural tasks. For example, abnormal attention to irrelevant information has long been recognised by clinicians, which has since encouraged researchers to elucidate the nature of the relationship between schizophrenia, and anxiety more recently, with allocation of attention to stimuli in laboratory studies providing empirical evidence for an attentional view of these disorders. The pre-exposure effect (slower learning to a stimulus that has been rendered familiar by preexposure, relative to a novel cue), hereafter refered to as latent inhibition, has been shown to be inversely correlated with schizotypy, and abnormal in people with schizophrenia, but findings are inconsistent. One potential contributing factor to this inconsistency is that many tasks that purport to measure latent inhibition are confounded by alternative effects that also retard learning and co-vary with schizotypy, such as learned irrelevance (experience of a cue as irrelevant to the occurrence of an outcome due to inconsistent/uncorrelated presentations of a cue and a target). The general aim of this thesis is to address, or begin to address, some of the key questions and limitations with existing research that evaluate latent inhibition and learned irrelevance as potentially useful cognitive endophenotypes for schizophrenia and anxiety disorders. The current experiments separate out the effects of latent inhibition and learned irrelevance to assess the independent effects of these phenomena on schizotypy (and by extension schizophrenia) and anxiety. By teasing apart, the effects of latent inhibition and learned irrelevance the attempt is to disentangle, and improve understanding of attentional abnormalities observed in these sub-clinical traits and by extension, their related pathologies. Across Experiments 1-4, the purpose was two-fold. The first was to address the limitations of existing latent inhibition tasks by designing a paradigm that examines a purer effect of latent inhibition, by minimising the contribution of learned irrelevance, and assessing how this latent inhibition task co-varies with schizotypy and anxiety (Chapter 2: Experiments 1 and 2). The second was to examine the alternative, potentially less equivocal, learned attentional paradigm (learned irrelevance) and assess the relationship between this task with both schizotypy and anxiety (Chapter 3: Experiments 3 and 4). Based on the assumption that latent inhibition and learned irrelevance share similar psychological underpinnings (in this case, attentional), we anticipated the effect of schizotypy and anxiety to be comparable in the two types of attention tasks here. The results however indicate a double dissociation; an abnormally persistent latent inhibition effect in high positive schizotypy individuals (Experiments 1 and 2) and a reduced learned irrelevance effect in high state anxious individuals (Experiments 3 and 4). The possibility that latent inhibition is non-attentional and the implications of these findings for associative models of attention and learning are explored. The aim of Experiments 5 and 6 were to explore the causal relationship between induced variations in anxiety (stress, relaxation or neutral mood) and learned variations in attention, using a less ambiguous measure of attention (compared to latent inhibition): learned irrelevance. Based on the findings from Experiments 3 and 4, a reduced attentional bias towards previously established predictive cues was expected in individuals induced with an acute state of anxiousness, relative to individuals induced with either a relaxed or neutral mood state. This pattern of results was observed but to a weaker extent than the previous experiments, suggesting that induced variations in anxiety do not have the same relationship with learning as naturally occurring variations in anxiety, as observed in Experiments 3 and 4. Further analyses revealed that the relationship between reduced learned irrelevance and anxiety was mediated by individuals who were also characterised by high levels of schizotypy, and by extension vulnerability to schizophrenia. Given the potential common underlying cognitive processes to both anxiety and schizophrenia, it seems likely that therapies which target the symptoms of anxiety (e.g., Attentional Bias Modification Treatment; ABMT) would be beneficial to individuals who have also been diagnosed with a psychotic disorder. This work represents the first attempt to investigate the independent effects of latent inhibition and learned irrelevance on schizotypy and anxiety, using refined tasks that minimised the contribution of either learning phenomenon on each other. How these learning tasks co-vary in patients with schizophrenia and clinically diagnosed anxiety however remains for future research to determine . At this juncture, the current findings lend support to the potential cognitive endophenotype status of learned irrelevance (considering its status as a less ambiguous measure of attention) and its continued use to provide a base for the development of relevant attentional bias modification treatments

The Use of Cognitive Screening in Pharmacotherapy Trials for Cognitive Impairment Associated With Schizophrenia.

There are currently no regulatory approved pharmacological treatments for cognitive impairment associated with schizophrenia (CIAS). One possibility is that trial methodology itself is hindering their development. Emerging evidence suggests that patients with schizophrenia may show limited benefit from pro-cognitive interventions if they already exhibit intact cognitive performance, relative to normative thresholds. The aim of this report was to examine the extent to which objectively assessed cognitive performance has been used as an eligibility and/or stratification criterion in CIAS pharmacotherapy trials. On 16th January 2019, we conducted a systematic search of studies listed on ClinicalTrials.gov to identify randomized, double-blind, placebo-controlled, add-on pharmacotherapy trials conducted in patients with a diagnosis of schizophrenia, in which a paper-and-pencil or computerized cognitive task (or battery) was specified as a primary outcome measure. Of the 87 trials that met our inclusion criteria, 10 (11.5%) required the presence of an objectively assessed cognitive deficit as part of their patient eligibility criteria. No studies reported stratifying patients according to the presence or degree of cognitive impairment they exhibited. These results suggest that the vast majority of CIAS trials may have been underpowered due to the inclusion of cognitively "normal" patients. Purposive screening for cognitive impairment could increase CIAS trial success

Emotional bias training as a treatment for anxiety and depression:evidence from experimental medicine studies in healthy and medicated samples

BACKGROUND: Anxiety and depression are leading causes of disability worldwide, yet individuals are often unable to access appropriate treatment. There is a need to develop effective interventions that can be delivered remotely. Previous research has suggested that emotional processing biases are a potential target for intervention, and these may be altered through brief training programs. METHODS: We report two experimental medicine studies of emotional bias training in two samples: individuals from the general population (n = 522) and individuals currently taking antidepressants to treat anxiety or depression (n = 212). Participants, recruited online, completed four sessions of EBT from their own home. Mental health and cognitive functioning outcomes were assessed at baseline, immediately post-training, and at 2-week follow-up. RESULTS: In both studies, our intervention successfully trained participants to perceive ambiguous social information more positively. This persisted at a 2-week follow-up. There was no clear evidence that this change in emotional processing transferred to improvements in symptoms in the primary analyses. However, in both studies, there was weak evidence for improved quality of life following EBT amongst individuals with more depressive symptoms at baseline. No clear evidence of transfer effects was observed for self-reported daily stress, anhedonia or depressive symptoms. Exploratory analyses suggested that younger participants reported greater treatment gains. CONCLUSIONS: These studies demonstrate the effectiveness of delivering a multi-session online training program to promote lasting cognitive changes. Given the inconsistent evidence for transfer effects, EBT requires further development before it can be considered as a treatment for anxiety and depression

Effects of 7.5% Carbon Dioxide and Nicotine Administration on Latent Inhibition.

Stratified medicine approaches have potential to improve the efficacy of drug development for schizophrenia and other psychiatric conditions, as they have for oncology. Latent inhibition is a candidate biomarker as it demonstrates differential sensitivity to key symptoms and neurobiological abnormalities associated with schizophrenia. The aims of this research were to evaluate whether a novel latent inhibition task that is not confounded by alternative learning effects such as learned irrelevance, is sensitive to (1) an in-direct model relevant to psychosis [using 7.5% carbon dioxide (CO2) inhalations to induce dopamine release via somatic anxiety] and (2) a pro-cognitive pharmacological manipulation (via nicotine administration) for the treatment of cognitive impairment associated with schizophrenia. Experiment 1 used a 7.5% CO2 challenge as a model of anxiety-induced dopamine release to evaluate the sensitivity of latent inhibition during CO2 gas inhalation, compared to the inhalation of medical air. Experiment 2 examined the effect of 2 mg nicotine administration vs. placebo on latent inhibition to evaluate its sensitivity to a potential pro-cognitive drug treatment. Inhalation of 7.5% CO2 raised self-report and physiological measures of anxiety and impaired latent inhibition, relative to a medical air control; whereas administration of 2 mg nicotine, demonstrated increased latent inhibition relative to placebo control. Here, two complementary experimental studies suggest latent inhibition is modified by manipulations that are relevant to the detection and treatment of schizophrenia. These results suggest that this latent inhibition task merits further investigation in the context of neurobiological sub-groups suitable for novel treatment strategies

Emotional bias training as a treatment for anxiety and depression: Evidence from experimental medicine studies in healthy and medicated samples

Anxiety and depression are leading causes of disability worldwide, yet individuals are often unable to access appropriate treatment. There is a need to develop effective interventions that can be delivered remotely. Previous research has suggested that emotional processing biases are a potential target for intervention, and these may be altered through brief training programs. We report two experimental medicine studies of emotional bias training in two samples: individuals from the general population (n = 522) and individuals currently taking antidepressants to treat anxiety or depression (n = 212). Participants, recruited online, completed 4 sessions of EBT from their own home. Mental health and cognitive functioning outcomes were assessed at baseline, immediately post-training, and at two-week follow-up. In both studies, our intervention successfully trained participants to perceive ambiguous social information more positively. This persisted at two-week follow-up. There was inconsistent evidence that this change in emotional processing transferred to improvements in symptoms and functional outcomes. In both studies there was weak evidence for an improvement in quality of life following EBT amongst individuals with more depressive symptoms at baseline. No clear evidence of transfer effects was observed for self-reported daily stress, anhedonia or depressive symptoms. However, exploratory analyses suggested that younger participants reported greater treatment gains. These studies demonstrate the effectiveness of delivering a multi-session online training program to promote lasting cognitive changes. Given the inconsistent evidence for transfer effects, EBT requires further development before it can be recommended as a treatment for anxiety and depression

Online experimental medicine study of emotional bias training in healthy participants

This was an experimental study delivered online of emotional bias training (EBT) in a sample of healthy volunteers (n = 522), recruited via Prolific (prolific.co). The study aimed to investigate the effect of active EBT on a range of mental health and functional outcomes. The study protocol was pre-registered on the Open Science Framework (OSF) (osf.io/6xcu7)