Shubulade Smith

Non-invasive mapping of connections between human thalamus and cortex using diffusion imaging

Evidence concerning anatomical connectivities in the human brain is sparse and based largely on limited post-mortem observations. Diffusion tensor imaging has previously been used to define large white-matter tracts in the living human brain, but this technique has had limited success in tracing pathways into gray matter. Here we identified specific connections between human thalamus and cortex using a novel probabilistic tractography algorithm with diffusion imaging data. Classification of thalamic gray matter based on cortical connectivity patterns revealed distinct subregions whose locations correspond to nuclei described previously in histological studies. The connections that we found between thalamus and cortex were similar to those reported for non-human primates and were reproducible between individuals. Our results provide the first quantitative demonstration of reliable inference of anatomical connectivity between human gray matter structures using diffusion data and the first connectivity-based segmentation of gray matter.

Normalized accurate measurement of longitudinal brain change.

Purpose Quantitative measurement of change in brain size and shape (e.g., to estimate atrophy) is an important current area of research. New methods of change analysis attempt to improve robustness, accuracy, and extent of automation. A fully automated method has been developed that achieves high estimation accuracy. Method A fully automated method of longitudinal change analysis is presented here, which automatically segments brain from nonbrain in each image, registers the two brain images while using estimated skull images to constrain scaling and skew, and finally estimates brain surface motion by tracking surface points to subvoxel accuracy. Results and Conclusion The method described has been shown to be accurate (≈0.2% brain volume change error) and to achieve high robustness (no failures in several hundred analyses over a range of different data sets).

Risk factors for progression of brain atrophy in aging Six-year follow-up of normal subjects

Objectives: To determine the rate of brain atrophy in neurologically asymptomatic elderly and to investigate the impact of baseline variables including conventional cerebrovascular risk factors, APOE ε4, and white matter hyperintensity (WMH) on its progression. Methods: We assessed the brain parenchymal fraction at baseline and subsequent annual brain volume changes over 6 years for 201 participants (F/M = 96/105; 59.8 ± 5.9 years) in the Austrian Stroke Prevention Study from 1.5-T MRI scans using SIENA (structural image evaluation using normalization of atrophy)/SIENAX (an adaptation of SIENA for cross-sectional measurement)(www.fmrib.ox.ac.uk/fsl). Hypertension, cardiac disease, diabetes mellitus, smoking, and regular alcohol intake were present in 64 (31.8%), 60 (29.9%), 5 (2.5%), 70 (39.3%), and 40 (20.7%) subjects, respectively. Plasma levels of fasting glucose (93.7 ± 18.6 mg/dL), glycated hemoglobin A (HbA1c; 5.6 ± 0.7%), total cholesterol (228.3 ± 40.3 mg/dL), and triglycerides (127.0 ± 75.2 mg/dL) were determined. WMH was rated as absent (n = 56), punctate (n = 120), early confluent (n = 14), and confluent (n = 11). Results: The baseline brain parenchymal fraction of the entire cohort was 0.80 ± 0.02 with a mean annual brain volume change of −0.40 ± 0.29%. Univariate analysis demonstrated a higher rate of brain atrophy in older subjects (p = 0.0001), in those with higher HbA1c (p = 0.0001), higher body mass index (p = 0.02), high alcohol intake (p = 0.04), severe WMH (p = 0.03), and in APOE ε4 carriers (p = 0.07). Multivariate analysis suggested that baseline brain parenchymal fraction, HbA1c, and WMH score explain a major proportion of variance in the rates of brain atrophy in the cohort (corrected R2 = 0.27; p = 0.0001). Conclusions: Neurologically asymptomatic elderly experience continuing brain volume loss, which appears to accelerate with age. Glycated hemoglobin A (HbA1c) was identified as a risk factor for a greater rate of brain atrophy. Clustering of factors associated with the so-called metabolic syndrome in subjects with high HbA1c suggests a link between this syndrome and late-life brain tissue loss.

The effects of antipsychotic-induced hyperprolactinaemia on the hypothalamic-pituitary-gonadal axis.

Hyperprolactinaemia is commonly induced by antipsychotic medications that have dopamine-blockade as their main mechanism of action. The purpose of this study was to assess the effect of antipsychotic-induced hyperprolactinaemia on hypothalamic-pituitary-gonadal axis (HPG) function. HPG axis function was assessed in 67 consecutive outpatients who were diagnosed with schizophrenia and stabilized for a period of not less than 2 years on typical antipsychotic medication, by means of clinical history, relevant questionnaires and measurement of plasma prolactin, estradiol, progesterone, testosterone, LH, FSH, sex hormone binding globulin, and TSH levels. Normative laboratory data were used to assess whether hormone levels fell within the reference range for a normal population. There was a significant correlation between dose of medication and plasma prolactin levels for the total group (P <0.001). Prolactin levels were significantly negatively associated with sex hormone levels in females (P <0.05). Males taking antipsychotic medication had a mean prolactin level of 404.1m/IU and mean gonadotrophin and sex hormone levels that fell within normal limits. The results of this study indicate that neuroleptic-induced prolactin secretion is a dose-related side effect and, in females, the level of hyperprolactinaemia is correlated with the degree of suppression of the HPG axis. Women taking long-term prolactin-raising antipsychotic medications are likely to be hyperprolactinaemic and have an associated hypogonadal state. In males, prolactin levels remain within normal limits, but at the upper end, with no apparent disturbance of reproductive hormones.

Determining the common medical presenting problems to an accident and emergency department

All accident and emergency (A&E) attendances over a one year period were prospectively studied in order to determine common medical presenting problems. Data were collected on children (0–15 years) attending a paediatric A&E department in Nottingham between February 1997 and February 1998. A total of 38 982 children were seen. The diagnoses of 26 756 (69%) were classified as trauma or surgical, and 10 369 (27%) as medical; 1857 (4%) could not be classified. The commonest presenting problems reported for “medical” children were breathing difficulty (31%), febrile illness (20%), diarrhoea with or without vomiting (16%), abdominal pain (6%), seizure (5%), and rash (5%). The most senior doctor seeing these patients in A&E was a senior house officer (intern or junior resident) in 78% of cases, paediatric registrar (senior resident) in 19%, consultant (attending physician) in 1.4%, and “other” in 2.6%. Guidelines developed for A&E should target the commonest presenting problem categories, six of which account for 83% of all medical attendances, and be directed towards senior house officers.

Altered cerebellar functional connectivity mediates potential adaptive plasticity in patients with multiple sclerosis

Background: The cerebellum is of potential interest for understanding adaptive responses in motor control in patients with multiple sclerosis because of the high intrinsic synaptic plasticity of this brain region. Objective: To assess the relative roles of interactions between the neocortex and the cerebellum using measures of functional connectivity. Methods: A role for altered neocortical–cerebellar functional connectivity in adaptive responses to injury from multiple sclerosis was tested using 1.5 T functional magnetic resonance imaging (fMRI) during figure writing with the dominant right hand in patients with predominantly early relapsing-remitting multiple sclerosis. Results: Patients (n = 14) showed a more bihemispheric pattern of activation in motor cortex than healthy controls (n = 11). Correlations between task related signal changes in neocortical and cerebellar regions of interest were used as a measure of functional connectivity. Healthy controls showed strong functional connectivity between the left motor cortex and the right cerebellar dentate nucleus. Significant connectivity between the left primary motor cortex and the right dentate was not found in patients. However, patients had significant connectivity between the left premotor neocortex and the ipsilateral (left) cerebellar cortex (crus I), which was not found in healthy controls. Conclusions: Changes in apparent cerebellar–neocortical functional connectivity may mediate potentially adaptive changes in brain motor control in patients with multiple sclerosis. Similar changes in the cerebellum and premotor cortex have been reported in the healthy brain during motor learning, suggesting that common mechanisms may contribute to normal motor learning and motor recovery after injury from multiple sclerosis.

Bone mineral density and its relationship to prolactin levels in patients taking antipsychotic treatment.

Abstract: Antipsychotic treatment is frequently associated with elevated prolactin levels. Raised prolactin levels have been linked with osteoporosis. The objective of this study is to determine whether patients taking antipsychotics show reduced bone mineral density (BMD), and whether this is associated with prolactin levels. BMD (standardized as z scores) was compared using dual x-ray absorptiometry of the lumbar spine and hip in patients taking antipsychotics (n = 102, mean age: 46.0, SD: 13.1, 47% male, median treatment duration: 3.0 years) to matched reference controls. Levels of prolactin, markers of bone metabolism, and risk factors for osteoporosis were measured. Mean BMD was not significantly reduced, other than the total spine score for black males (mean z score: −0.88, P = 0.00001). BMD was correlated with body mass index but there was no correlation with prolactin. BMD was not correlated with prolactin levels and showed no clinically significant reduction. The low BMD in black males warrants further investigation.

Vitamin D deficiency in first episode psychosis: A case–control study

BACKGROUND Vitamin D deficiency is seen in a high proportion of people with established psychotic disorders, but it is not known if this is present at onset of the illness. We set out to examine vitamin D levels in people with their first episode of psychosis (FEP). METHOD We conducted a matched case-control study to examine vitamin D levels and rates of vitamin D deficiency in sixty nine patients presenting with their FEP and sixty nine controls matched for age, sex and ethnicity. Differences between groups were tested using students-t tests, paired t-tests and odds ratios for further analysis. RESULTS Vitamin D levels were significantly lower in cases than in controls (p<0.001). The odds ratio of being vitamin D deficient was 2.99 in the FEP group relative to the control group. There was no correlation between vitamin D levels and length of hospitalisation in the patient group (r=-0.027, p=0.827). CONCLUSIONS We found higher rates of vitamin D deficiency in people with FEP compared to matched controls. Given that vitamin D is neuroprotective; that developmental vitamin D deficiency may be a risk factor for psychosis, and that incipient psychosis may affect lifestyle factors and diet, future studies are required to examine this association further. In the meantime, there is a need for more widespread testing of vitamin D levels in FEP and for the development of appropriate management strategies.

An evidence and consensus based guideline for the management of a child after a seizure

Structured in the format recommended by Hayward et al1 for guideline reports. Objective: An evidence and consensus based guideline for the management of the child who presents to hospital having had a seizure. It does not deal with the child who is still seizing. The guideline is intended for use by junior doctors, and was developed for this common problem (5% of all paediatric medical attenders) where variation in practice occurs. Options: Assessment, investigations (biochemistry, lumbar puncture, serum anticonvulsant levels, EEG in particular), and/or admission are examined. Outcomes: The guideline aims to direct junior doctors in recognising those children who are at higher risk of serious intracranial pathology including infection, and conversely to recognise those children at low risk who are safe to go home. Evidence: A systematic review of the literature was performed. Articles were identified using the electronic data bases Medline (from 1966 to June 1998), Embase (from 1980 to June 1998) and Cochrane (to June 1998), and selected if they investigated the specified clinical question. Personal reviews were excluded. Selected articles were appraised, graded, and synthesised qualitatively. Statements of recommendation were made. Consensus: An anonymous, postal Delphi consensus development was used. A national panel of 30 medical and nursing staff regularly caring for these children were asked to grade their agreement with the statements generated. They were sent the relevant original publications, the appraisals, and literature review. On the second and third rounds they were asked whether they wished to re-grade their agreement in the light of other panellists’ responses. Consensus was defined as 83% of panellists agreeing with the statement. Recommendations in brief: For afebrile seizures all children should have their blood pressure recorded, but no other investigations are routine although a seizing or somnolent child should have blood glucose measured; all children under 1 year should be admitted. For seizures with fever, clinical signs indicating the need to treat as meningitis are given. Children should be admitted if they are under 18 months old, have had a complex seizure, or after pretreatment with antibiotics. Validation: The guideline has undergone implementation and evaluation in a paediatric accident and emergency department, the results of which will be published separately. Only one alteration was made to the guideline as a result of this validation process, which is included here.

Cardiovascular risk factors and metabolic syndrome in people with established psychotic illnesses: baseline data from the IMPaCT randomized controlled trial.

Background The aims of the study were to determine the prevalence of cardiometabolic risk factors and establish the proportion of people with psychosis meeting criteria for the metabolic syndrome (MetS). The study also aimed to identify the key lifestyle behaviours associated with increased risk of the MetS and to investigate whether the MetS is associated with illness severity and degree of functional impairment. Method Baseline data were collected as part of a large randomized controlled trial (IMPaCT RCT). The study took place within community mental health teams in five Mental Health NHS Trusts in urban and rural locations across England. A total of 450 randomly selected out-patients, aged 18–65 years, with an established psychotic illness were recruited. We ascertained the prevalence rates of cardiometabolic risk factors, illness severity and functional impairment and calculated rates of the MetS, using International Diabetes Federation (IDF) and National Cholesterol Education Program Third Adult Treatment Panel criteria. Results High rates of cardiometabolic risk factors were found. Nearly all women and most men had waist circumference exceeding the IDF threshold for central obesity. Half the sample was obese (body mass index ≥ 30 kg/m2) and a fifth met the criteria for type 2 diabetes mellitus. Females were more likely to be obese than males (61% v. 42%, p < 0.001). Of the 308 patients with complete laboratory measures, 57% (n = 175) met the IDF criteria for the MetS. Conclusions In the UK, the prevalence of cardiometabolic risk factors in individuals with psychotic illnesses is much higher than that observed in national general population studies as well as in most international studies of patients with psychosis.