Sleep Spindles as Biomarker for Early Detection of Neurodegenerative Disorders

The present invention relates to the use of sleep spindles as a novel biomarker for early diagnosis of synucleinopathies, in particular Parkinson's disease (PD). The method is based on automatic detection of sleep spindles. The method may be combined with measurements of one or more further biomarkers derived from polysomnographic recordings.</p

Using a statistical learning approach to identify sociodemographic and clinical predictors of response to clozapine

Background: A proportion of people with treatment-resistant schizophrenia fail to show improvement on clozapine treatment. Knowledge of the sociodemographic and clinical factors predicting clozapine response may be useful in developing personalised approaches to treatment. Methods: This retrospective cohort study used data from the electronic health records of the South London and Maudsley (SLaM) hospital between 2007 and 2011. Using the Least Absolute Shrinkage and Selection Operator (LASSO) regression statistical learning approach, we examined 35 sociodemographic and clinical factors’ predictive ability of response to clozapine at 3 months of treatment. Response was assessed by the level of change in the severity of the symptoms using the Clinical Global Impression (CGI) scale. Results: We identified 242 service-users with a treatment-resistant psychotic disorder who had their first trial of clozapine and continued the treatment for at least 3 months. The LASSO regression identified three predictors of response to clozapine: higher severity of illness at baseline, female gender and having a comorbid mood disorder. These factors are estimated to explain 18% of the variance in clozapine response. The model’s optimism-corrected calibration slope was 1.37, suggesting that the model will underfit when applied to new data. Conclusions: These findings suggest that women, people with a comorbid mood disorder and those who are most ill at baseline respond better to clozapine. However, the accuracy of the internally validated and recalibrated model was low. Therefore, future research should indicate whether a prediction model developed by including routinely collected data, in combination with biological information, presents adequate predictive ability to be applied in clinical settings

A predictor model of treatment resistance in schizophrenia using data from electronic health records

Objectives: To develop a prognostic tool of treatment resistant schizophrenia (TRS) in a large and diverse clinical cohort, with comprehensive coverage of patients using mental health services in four London boroughs. Methods: We used the Least Absolute Shrinkage and Selection Operator (LASSO) for time-to-event data, to develop a risk prediction model from the first antipsychotic prescription to the development of TRS, using data from electronic health records. Results: We reviewed the clinical records of 1,515 patients with a schizophrenia spectrum disorder and observed that 253 (17%) developed TRS. The Cox LASSO survival model produced an internally validated Harrel’s C index of 0.60. A Kaplan-Meier curve indicated that the hazard of developing TRS remained constant over the observation period. Predictors of TRS were: having more inpatient days in the three months before and after the first antipsychotic, more community face-to-face clinical contact in the three months before the first antipsychotic, minor cognitive problems, and younger age at the time of the first antipsychotic. Conclusions: Routinely collected information, readily available at the start of treatment, gives some indication of TRS but is unlikely to be adequate alone. These results provide further evidence that earlier onset is a risk factor for TRS

Clinical correlates of early onset antipsychotic treatment resistance

Background:: There is evidence of heterogeneity within treatment-resistant schizophrenia (TRS), with some people not responding to antipsychotic treatment from illness onset and others becoming treatment-resistant after an initial response period. These groups may have different aetiologies. Aim:: This study investigates sociodemographic and clinical correlates of early onset of TRS. Method:: Employing a retrospective cohort design, we do a secondary analysis of data from a cohort of people with TRS attending the South London and Maudsley. Regression analyses were conducted to identify the correlates of the length of treatment to TRS. Predictors included the following: gender, age, ethnicity, problems with positive symptoms, problems with activities of daily living, psychiatric comorbidities, involuntary hospitalisation and treatment with long-acting injectable antipsychotics. Results:: In a cohort of 164 people with TRS (60% were men), the median length of treatment to TRS was 3 years and 8 months. We observed no cut-off on the length of treatment until TRS presentation differentiating between early and late TRS (i.e. no bimodal distribution). Having mild to very severe problems with hallucinations and delusions at the treatment start was associated with earlier TRS (~19 months earlier). In sensitivity analyses, including only complete cases (subject to selection bias), treatment with a long-acting injectable antipsychotic was additionally associated with later TRS (~15 months later). Conclusion:: Our findings do not support a clear separation between early and late TRS but rather a continuum of the length of treatment before TRS onset. Having mild to very severe problems with positive symptoms at treatment start predicts earlier onset of TRS

Synaptic integration and dendritic excitability in cerebellar Purkinje neurons

Dendrites receive most of the synaptic input to the neuron, but their contribution to synaptic integration is not well understood. In this thesis I investigate synaptic integration in Purkinje neurons in cerebellar slices, focusing on the contribution of dendritic excitability using simultaneous somatic and dendritic patch-clamp recordings. I first investigated the ionic conductances underlying intrinsic bistability in Purkinje cell action potential firing. The hyperpolarisation-activated mixed cation current Ih promotes the tonically firing state, with the firing rate being limited by the calcium-activated potassium current. Physiological modulation of Ih by serotonin is shown to enhance bistability triggered by inhibitory synaptic inputs. I next explored the interaction between excitatory postsynaptic potentials (EPSPs) and voltage-gated channels. Near action potential threshold, parallel fibre (PF) EPSPs are non-linearly amplified. Application of the sodium channel blocker TTX abolishes this subthreshold EPSP "boosting". Strong depolarisation reveals an additional boosting mechanism which is mediated by calcium channel activation. Sodium channel-mediated boosting is perisomatic in origin, while calcium channel-mediated boosting is dendritic. The potassium channel blocker 4-aminopyridine abolishes the somato-dendritic polarity of calcium boosting and also hyperpolarises the voltage threshold of both sodium and calcium boosting. Blocking Ih, increases the time constant of EPSP decay, thereby augmenting EPSP boosting. These results indicate that EPSPs are shaped by a complex interplay of several channel types depending on stimulus intensity and membrane potential. I demonstrate that the very powerful synaptic input provided by the climbing fibre (CF) triggers an EPSP which depolarises the entire dendritic membrane to near zero mV. Pairing the CF with depolarisation or PF input triggered secondary calcium spikes which could be confined to dendritic branches and depended on the relative timing of CF and PF input. Inhibitory GABAergic synaptic input mimicked using dynamic clamp could completely suppress or delay CF-evoked dendritic calcium spikes in a temporally and spatially precise manner

Clinical correlates of early onset antipsychotic treatment resistance

Background:: There is evidence of heterogeneity within treatment-resistant schizophrenia (TRS), with some people not responding to antipsychotic treatment from illness onset and others becoming treatment-resistant after an initial response period. These groups may have different aetiologies. Aim:: This study investigates sociodemographic and clinical correlates of early onset of TRS. Method:: Employing a retrospective cohort design, we do a secondary analysis of data from a cohort of people with TRS attending the South London and Maudsley. Regression analyses were conducted to identify the correlates of the length of treatment to TRS. Predictors included the following: gender, age, ethnicity, problems with positive symptoms, problems with activities of daily living, psychiatric comorbidities, involuntary hospitalisation and treatment with long-acting injectable antipsychotics. Results:: In a cohort of 164 people with TRS (60% were men), the median length of treatment to TRS was 3 years and 8 months. We observed no cut-off on the length of treatment until TRS presentation differentiating between early and late TRS (i.e. no bimodal distribution). Having mild to very severe problems with hallucinations and delusions at the treatment start was associated with earlier TRS (~19 months earlier). In sensitivity analyses, including only complete cases (subject to selection bias), treatment with a long-acting injectable antipsychotic was additionally associated with later TRS (~15 months later). Conclusion:: Our findings do not support a clear separation between early and late TRS but rather a continuum of the length of treatment before TRS onset. Having mild to very severe problems with positive symptoms at treatment start predicts earlier onset of TRS