Neuropsychological assessment and functional magnetic resonance imaging of verbal declarative memory performance in relatives of schizophrenia patients and controls

BACKGROUND: While the aetiology of schizophrenia has yet to be established, genetic liability is currently the most robust determinant of propensity for the development of schizophrenia, with a risk rate of between 15 and 20% in first-degree relatives of schizophrenia patients. Unaffected relatives of schizophrenics have shown similar, but less severe neuropsychological impairments, to those seen in schizophrenia patients, which are stable over time in individuals beyond the age of risk for the disorder. Such deficits may be reflective of a genetic vulnerability to the disorder (Byrne et al 2003; (Faraone et al 1999). Declarative memory has emerged as a core cognitive impairment in schizophrenia (Cirillo and Seidman 2002) and evidence shows functional brain response differences between patients and controls in frontal, temporal, and parietal areas during tests of memory (Ragland et al 2004). Nonetheless, it is unclear how far behavioural and functional deficits reflect increased risk, at what stage, if at all, these deteriorate in those who develop the disorder, or whether pre-morbid impairments in those who go on to develop schizophrenia could be predictive of psychosis. The Edinburgh High Risk Study recruited 162 individuals (16-25 years) with at least one first or second degree relative with schizophrenia and 43 closely matched controls. A broad neuropsychological and clinical assessment battery was administered every 18-24 months over 10 years, while participants underwent between 1 and 3 functional magnetic resonance imaging (fMRI) scans during a verbal memory and executive function task over 5 years. | | METHODS: Baseline predictors of schizophrenia, performance changes over 2 neuropsychological assessments, and the influence of genetic liability were examined in high risk participants with (HR+) and without psychotic symptoms (HR-), those who are now ill (Scz) and controls (C), using one-way ANOVAs and repeated measures ANCOVAs. Aspects of verbal and non-verbal learning and memory were also compared between the HR and C in the first 100 participants to undergo a functional MRI scan using one-way ANOVAs. In the same participants, differences between groups in blood oxygen level dependent (BOLD) fMRI brain responses during an event related verbal encoding (word classification) and retrieval task were investigated using fixed and random effects general linear models. | | RESULTS: On a test of verbal learning at baseline, Scz performed significantly less well than HR However, there were no significant interactions of time by group, and HR showed stable impairments relative to controls on immediate and delayed prose recall, delayed list recall and response suppression across both assessments before and after controlling for IQ. A measure of quantitative genetic liability was inversely correlated with delayed prose recall over time. HR showed poorer cued delayed recall, and less word retention between short and long delay recall trials on a verbal learning test. A visual recognition test also significantly discriminated between HR and C. Behavioural analysis of the fMRI verbal encoding and retrieval task revealed no differences between groups in reaction time or accuracy. However, during a word classification task (encoding) there was a greater BOLD response in the right inferior frontal lobe (BA45/44) in HR relative to C and in the right inferior parietal lobule (BA7/40) in HR+ relative to C and HR-. A greater bilateral cerebellar and left inferior frontal response was also apparent in HR relative to C, and an increased ventral anterior thalamus response in HR- relative to HR+, during correct recognition compared to correct rejection responses. | | CONCLUSIONS: Stable differences in NP performance over time suggest a trait deficit, which is relatively unaffected by the presence of psychotic symptoms and schizophrenia onset, although small numbers might have precluded detection of significant time by group interactions. Poorer verbal memory performance overall in Scz suggests that this deficit is more pronounced in those who go on to develop schizophrenia. Non-verbal learning impairments reflect encoding deficits, while verbal learning impairments reflect encoding and retention difficulties in the HR group. Increased BOLD response in frontal and cerebellar areas in the HR group could be due to a requirement for greater effort to perform the task equivalently to C, and may reflect a biological trait deficit in the brains of relatives of schizophrenia patients. Subtle differences in the inferior parietal lobe between HR+ and HR- and C may be indicative of state related functional abnormalities, which possibly herald the onset of schizophrenia

A comparison of specific positive future expectancies and global hopelessness as predictors of suicidal ideation in a prospective study of repeat self-harmers

Background. Hopelessness and the lack of positive future expectancies have been related to suicidality. This is the first study to compare the power of positive future expectancies and global hopelessness in the prediction of suicidal ideation. In short, are specific positive expectancies or global hopelessness attitudes more closely related to suicidality? Method. One hundred and forty four adults hospitalized following a suicidal self-harm episode completed a range of clinical and psychological measures in hospital and were followed up approximately 2.5 months after discharge. All participants reported at least one other self-harm episode in addition to the index episode. Results. Hierarchical regression analyses confirmed that specific positive future expectancies were better predictors of Time 2 suicidal ideation than global hopelessness. In addition, as hypothesized, negative future thinking was not independently associated with suicidal ideation. Limitations. Short-term follow-up. Conclusions. Specific, idiographic expectancies for positive events (i.e., positive future thinking) are more important predictors of suicidal ideation than global attitudes of hopelessness. Unlike global hopelessness, they provide more options for intervention (e.g., identifying life goals and plans). These findings are particularly noteworthy given the widespread use of measures of global hopelessness. The theoretical and clinical implications are discussed

Correlations between fMRI activation and individual psychotic symptoms in un-medicated subjects at high genetic risk of schizophrenia

<p>Abstract</p> <p>Background:</p> <p>It has been proposed that different types of psychopathology in schizophrenia may reflect distinguishable pathological processes. In the current study we aimed to address such associations in the absence of confounders such as medication and disease chronicity by examining specific relationships between fMRI activation and individual symptom severity scores in un-medicated subjects at high genetic risk of schizophrenia.</p> <p>Methods:</p> <p>Associations were examined across two functional imaging paradigms: the Hayling sentence completion task, and an encoding/retrieval task, comprising encoding (at word classification) and retrieval (old word/new word judgement). Symptom severity was assessed using the positive and negative syndrome scale (PANSS). Items examined were hallucinations, delusions, and suspiciousness/persecution.</p> <p>Results:</p> <p>Associations were seen in the anterior middle temporal gyrus in relation to hallucination scores during the sentence completion task, and in the medial temporal lobe in association with suspiciousness/persecution scores in the encoding/retrieval task. Cerebellar activation was associated with delusions and suspiciousness/persecution scores across both tasks with differing patterns of laterality.</p> <p>Conclusion:</p> <p>These results support a role for the lateral temporal cortex in hallucinations and medial temporal lobe in positive psychotic symptoms. They also highlight the potential role of the cerebellum in the formation of delusions. That the current results are seen in un-medicated high risk subjects indicates these associations are not specific to the established illness and are not related to medication effects.</p

Self-regulation of unattainable goals in suicide attempters: the relationship between goal disengagement, goal reengagement and suicidal ideation

There is growing interest in models of adaptive self-regulation. Recent research suggests that goal disengagement and goal reengagement (i.e., goal adjustment) are implicated in the self-regulation of emotion. This study extends the self-regulation research to investigate the utility of goal adjustment in understanding suicidal risk. To this end, two hundred adults hospitalised following a suicidal episode completed a range of clinical and psychological measures in hospital and were followed up approximately 2.5 months after discharge (Time 2). Hierarchical regression analyses showed that goal reengagement predicted suicidal ideation at Time 2. In addition, the lack of goal reengagement was especially pernicious when reported concomitantly with high disengagement. These predictive effects were independent of baseline mood, attempt status and suicidal intent. The theoretical and clinical implications are discussed

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

Predicting short-term outcome in well-being following suicidal behaviour: The conjoint effects of social perfectionism and positive future thinking

This study investigated an integrative, psychological model of suicidality involving the relationship between perfectionism and future thinking to predict short-term outcome in well-being following a suicidal episode. Two hundred and sixty-seven adults hospitalized following a self-harm episode completed a range of clinical and psychological measures in hospital and were followed up approximately two months after discharge. Hierarchical regression analyses confirmed that, among the suicidal self-harmers who had a history of repetitive self-harm (n = 65), outcome among low social perfectionists changed as a function of positive future thinking such that outcome was better for those high on positive thoughts compared with those low on positive future thoughts. There was no such positive change in outcome among the high social perfectionists. There were also no significant interactive effects evident among the non-repetitive self-harmers (n = 61). These findings extend recent research to suggest that socially prescribed perfectionism and positive future thinking (but not negative future thinking) are implicated in outcome following repetitive suicidality. Implications for theory and clinical practice are discussed