Thesis (M.S.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / 2031-01-01

Schizophrenia is a complex and devastating illness with heterogeneous symptoms, late diagnosis, and excess early mortality. It is also associated with comorbidities including substance abuse, depression, anxiety, and sleep problems, that have adverse effects on the individual over the entire course of the disease. While effects of these comorbidities have been identified in the literature, few studies have involved longitudinal assessments and reproducible data collection in large populations. Recent smartphone research tools have been developed that provide better access to patients and can enable a real-world snapshot of a person’s mental state. In addition, these tools use the phone’s sensors to construct a digital phenotype of an individual, with the potential to detect changes in symptoms and cognition on a moment-by-moment basis. Previous studies report associations between anxiety and smartphone use, but most involve cross-sectional data and cohorts of healthy controls completing paper and pencil scales. A recent smartphone study collected day-to-day symptomatology, cognition, and phone usage data and discovered that the association between anxiety and smartphone use is more complex than originally thought.

Background: Inability to retain participants in a clinical trial poses a threat to clinical research as it can lead to a number of issues ultimately affecting generalisability, validity and reliability of the study. Patients with schizophrenia have been reported as particularly difficult to engage and retain in research and psychiatric treatment. This thesis aimed to improve the current understanding of the retention of people with schizophrenia in trials evaluating complex interventions. Methods: This thesis adopted a mixed method design. Quantitative methodology was used to identify the scale of attrition and to explore potential predictors of dropout. This included a systematic review and meta-analysis and a separate meta-analysis of individual patient data. Qualitative methodology was used in two studies to explore the perspectives of both trial staff and former trial participants on the factors important for retention and effective practices and strategies. Results: The results of the systematic review and meta-analysis demonstrated the rates of dropout from studies to be higher than from experimental interventions. Dropout from interventions significantly increased as the number of intervention sessions increased. The individual patient data meta-analysis found retention to be higher at the final follow-up assessment than at the penultimate one. The effect of arm allocation almost reached statistical significance pointing to the possibility of participants in the active arm having higher odds of completing the final follow-up than those in the control arm. Two qualitative studies identified barriers and facilitators to retention related to factors related to participant, researcher, study, and wider context. Some of the identified barriers were specific to schizophrenia. Conclusion: Attrition is a phenomenon that should be anticipated by trialists and prevented with the use of multiple strategies. The extent to which dropout can be minimised depends on a number of factors associated with the participant, researcher, study, and context.

Schizophrenia is the ninth leading cause of disability worldwide (e.g., Lopez et al., 2006), and is a devastating psychiatric illness. Although diagnosis is made based upon the occurrence of positive and negative symptoms (First, Spitzer, Gibbon & Williams, 1995), it is the cognitive symptoms that are most strongly associated with functional outcome (Green, 1996 ). Cognitive control, including the ability to appropriately update relevant information and resist interference from irrelevant information, is critical for flexible and adaptive goal-directed behavior, and is among the most frequently noted of the cognitive symptoms in schizoprenia (Barch, 2005; Barch & Smith, 2008). Despite this, deficits in cognitive control are unaffected by medications used to treat the clinical symptoms of the disorder (Greene et al, 2008). Understanding both the behavioral and the neural mechanisms that comprise this deficit is thus of paramount importance. Although deficits in cognitive control in schizoprenia have been extensively studied, a number of questions still remain. Here, I ask two main questions: First, is cognitive control impaired globally, or are only certain aspects of cognitive control impaired in schizophrenia? I found that that there are (at least) two different selection mechanisms, and that people with schizophrenia are impaired in only one of these: dysregulation in left posterior ventrolateral prefrontal cortex correlates with impaired behavioral performance on a working memory task, suggesting that deficits in inhibiting irrelevant information from working memory is the crux of the deficit. Second, I asked whether the nature of the information affects cognitive control. I found that people with schizophrenia are able to deploy cognitive control processes more effectively than healthy controls in cases in which salient, emotional information competes with active cognitive goals, suggesting specific underlying deficits in emotional processing.

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A literature review of the schizophrenia brain electrophysiology was undertaken with specific emphasis placed on the topographical distribution of evoked potentials (EPs). The outcomes of this review suggests that schizophrenia brain electrophysiology, demonstrate some differences, but with a variability reflective of the symptom heterogeneity. The literature associated with the use of attentional tasks while recording EPs, tended to demonstrate some consistency. The methodological issues associated with the EEG and EP recordings may also account for this variability. An evoked potential technique, which has been demonstrated to be sensitive to the changes in cognitive processes associated with attention, is the Steady State Probe Topography (SSPT) technique. The SSPT is a combination of both the Steady State Visual Evoked Potential (SSVEP) and the Probe-ERP paradigm. This technique allows the SSVEP to be measured continuously, is relatively insensitive to artifact, and can display the topographic distribution of the SSVEP measures during the attentional task. The technique employs the use of a sixty-four channel EEG recording system. This consists of a multichannel electrode helmet; multichannel amplifier/filter, task presentation computer and a computer controlled data acquisition system. Software was also developed to analyse the recorded brain electrical activity to produce the SSVEP magnitude and phase versus time series for each electrode site. The topographic distribution of the SSVEP measures associated with specific events during attentional tasks could also be displayed. At the time of the pilot study, this technique had not been applied previously to the study of schizophrenia and therefore warranted further study. Two separate studies are reported; an investigative pilot study and a chronic group study. The pilot SSVEP and schizophrenia study was designed to examine the changes in the SSVEP and its topography, during the performance of a number of attentional or activation tasks to examine the possibility of hypofrontality. The tasks selected for the study were those previously used for the examination of hypofrontality with metabolic imaging techniques; the Continuous Performance Task (CPT) and the Wisconsin Card Sort (WCS). The SSVEP was elicited by a superimposed 13Hz flicker on the visual field, while subjects performed computerised versions of the neuropsychological tasks. Topographical maps of the SSVEP magnitude distribution were then interpolated and displayed as an animated sequence synchronised with particular events occurring during the tasks. In comparison to the male control group, male schizophrenic patients exhibited differences in the SSVEP topography for all tasks, possibly reflecting the deficits in behavioural indices. Overall, the findings indicated that the technique demonstrated some merit for further examination of frontal SSVEP topography in schizophrenia. In a larger study of twenty chronic schizophrenia patients, the frontal topographical distribution of the SSVEP was examined. The earlier pilot study finding of reduced frontal SSVEP amplitude was replicated. The issue of hypofrontality in schizophrenia was applied as a possible interpretation.

Background: Schizophrenia is a serious disease with potential to implicate consequences on both the family and the sick. Nurses have a fundamental responsibility to relieve suffering, and also to offer support to both the individual and the family. Aim: To illuminate experiences of being a family member to a person with schizophrenia. Method: A systematic literature review was chosen. Nine articles were included. After having analyzed the results six categories were found. Result: The family members experienced the disease as fluctuating and stressful. Some felt ashamed for their sick family member and withdrew from the rest of the society. It was also common to grieve over the sick family member as they felt they had lost the person he/she ones was. Most studies showed that family members were disappointed with the psychiatric care. They felt excluded from the caring process and lack of information. Hopefully the result of this study leads to that nurses can offer increased support and understanding to the family. Conclusions: Disease and illness may affect on the whole life situation. To support a family in a crisis it is necessary to understand the person’s lifeworld and to be able to change their beliefs.

The pathophysiology of psychiatric disorders such as schizophrenia is not fully understood due, in part, to the shortcomings of available neurophysiological techniques. Previous studies have shown that patients with schizophrenia have deficits in dorsolateral prefrontal cortex (DLPFC). In this regard, two major deficits were observed: impairments in gamma-aminobutyric-acid (GABA) neurotransmission and cortical gamma (30-50Hz) oscillations. Previous in vitro and animal studies have linked the modulation of gamma oscillations with GABAB receptor mediated inhibition. Objectives: The first objective was to examine the effect of GABAB receptor mediated inhibition on cortical oscillations in the motor cortex and DLPFC in healthy subjects by using the novel technique of transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG) and through the TMS paradigm long interval cortical inhibition (LICI), which has been associated with GABAB receptor mediated inhibition. Second, to evaluate the psychometric properties of this neurophysiological paradigm, the validity and reliability of EEG indices of LICI were examined. Finally, the effect of LICI on cortical oscillations was examined in the DLPFC and motor cortex of patients with schizophrenia compared to healthy subjects and patients with bipolar disorder. Hypothesis: It was predicted that EEG measures of LICI would show validity and reliability, and it was hypothesized that patients with schizophrenia would show deficits in inhibition of gamma oscillations in DLPFC compared to healthy subjects and patients with bipolar disorder. Results: The first experiment showed that in healthy subjects LICI inhibited gamma oscillations in the DLPFC but not in the motor cortex. The second experiment demonstrated the validity and reliability of EEG indices of LICI were confirmed in healthy subjects. Finally, patients with schizophrenia had a selective deficit in inhibition of gamma oscillations in the DLPFC which appeared to be independent of illness duration or antipsychotic medication, and it was not observed in bipolar disorder. Conclusions: TMS combined with EEG allows for measuring modulatory effect of LICI on cortical oscillations. Inhibition of gamma oscillations in the DLPFC may be an essential neurophysiological process that may be impaired in schizophrenia. Future studies should ascertain the potential of gamma inhibition deficit as a biological marker for this illness.

The pathophysiology of psychiatric disorders such as schizophrenia is not fully understood due, in part, to the shortcomings of available neurophysiological techniques. Previous studies have shown that patients with schizophrenia have deficits in dorsolateral prefrontal cortex (DLPFC). In this regard, two major deficits were observed: impairments in gamma-aminobutyric-acid (GABA) neurotransmission and cortical gamma (30-50Hz) oscillations. Previous in vitro and animal studies have linked the modulation of gamma oscillations with GABAB receptor mediated inhibition. Objectives: The first objective was to examine the effect of GABAB receptor mediated inhibition on cortical oscillations in the motor cortex and DLPFC in healthy subjects by using the novel technique of transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG) and through the TMS paradigm long interval cortical inhibition (LICI), which has been associated with GABAB receptor mediated inhibition. Second, to evaluate the psychometric properties of this neurophysiological paradigm, the validity and reliability of EEG indices of LICI were examined. Finally, the effect of LICI on cortical oscillations was examined in the DLPFC and motor cortex of patients with schizophrenia compared to healthy subjects and patients with bipolar disorder. Hypothesis: It was predicted that EEG measures of LICI would show validity and reliability, and it was hypothesized that patients with schizophrenia would show deficits in inhibition of gamma oscillations in DLPFC compared to healthy subjects and patients with bipolar disorder. Results: The first experiment showed that in healthy subjects LICI inhibited gamma oscillations in the DLPFC but not in the motor cortex. The second experiment demonstrated the validity and reliability of EEG indices of LICI were confirmed in healthy subjects. Finally, patients with schizophrenia had a selective deficit in inhibition of gamma oscillations in the DLPFC which appeared to be independent of illness duration or antipsychotic medication, and it was not observed in bipolar disorder. Conclusions: TMS combined with EEG allows for measuring modulatory effect of LICI on cortical oscillations. Inhibition of gamma oscillations in the DLPFC may be an essential neurophysiological process that may be impaired in schizophrenia. Future studies should ascertain the potential of gamma inhibition deficit as a biological marker for this illness.