Macro- and micro-structural insights into primary dystonia: a UK Biobank study.

BACKGROUND: Dystonia is a hyperkinetic movement disorder with key motor network dysfunction implicated in pathophysiology. The UK Biobank encompasses > 500,000 participants, of whom 42,565 underwent brain MRI scanning. This study applied an optimized pre-processing pipeline, aimed at better accounting for artifact and improving data reliability, to assess for grey and white matter structural MRI changes between individuals diagnosed with primary dystonia and an unaffected control cohort. METHODS: Individuals with dystonia (n = 76) were identified from the UK Biobank using published algorithms, alongside an age- and sex-matched unaffected control cohort (n = 311). Grey matter morphometric and diffusion measures were assessed, together with white matter diffusion tensor and diffusion kurtosis metrics using tractography and tractometry. Post-hoc Neurite Orientation and Density Distribution Imaging (NODDI) was also undertaken for tracts in which significant differences were observed. RESULTS: Grey matter tremor-specific striatal differences were observed, with higher radial kurtosis. Tractography identified no white matter differences, however segmental tractometry identified localised differences, particularly in the superior cerebellar peduncles and anterior thalamic radiations, including higher fractional anisotropy and lower orientation distribution index in dystonia, compared to controls. Additional tremor-specific changes included lower neurite density index in the anterior thalamic radiations. CONCLUSIONS: Analysis of imaging data from one of the largest dystonia cohorts to date demonstrates microstructural differences in cerebellar and thalamic white matter connections, with architectural differences such as less orientation dispersion potentially being a component of the morphological structural changes implicated in dystonia. Distinct tremor-related imaging features are also implicated in both grey and white matter.

The impact of cumulative obstetric complications and childhood trauma on brain volume in young people with psychotic experiences.

Psychotic experiences (PEs) occur in 5-10% of the general population and are associated with exposure to childhood trauma and obstetric complications. However, the neurobiological mechanisms underlying these associations are unclear. Using the Avon Longitudinal Study of Parents and Children (ALSPAC), we studied 138 young people aged 20 with PEs (n = 49 suspected, n = 53 definite, n = 36 psychotic disorder) and 275 controls. Voxel-based morphometry assessed whether MRI measures of grey matter volume were associated with (i) PEs, (ii) cumulative childhood psychological trauma (weighted summary score of 6 trauma types), (iii) cumulative pre/peri-natal risk factors for psychosis (weighted summary score of 16 risk factors), and (iv) the interaction between PEs and cumulative trauma or pre/peri-natal risk. PEs were associated with smaller left posterior cingulate (pFWE < 0.001, Z = 4.19) and thalamus volumes (pFWE = 0.006, Z = 3.91). Cumulative pre/perinatal risk was associated with smaller left subgenual cingulate volume (pFWE < 0.001, Z = 4.54). A significant interaction between PEs and cumulative pre/perinatal risk found larger striatum (pFWE = 0.04, Z = 3.89) and smaller right insula volume extending into the supramarginal gyrus and superior temporal gyrus (pFWE = 0.002, Z = 4.79), specifically in those with definite PEs and psychotic disorder. Cumulative childhood trauma was associated with larger left dorsal striatum (pFWE = 0.002, Z = 3.65), right prefrontal cortex (pFWE < 0.001, Z = 4.63) and smaller left insula volume in all participants (pFWE = 0.03, Z = 3.60), and there was no interaction with PEs group. In summary, pre/peri-natal risk factors and childhood psychological trauma impact similar brain pathways, namely smaller insula and larger striatum volumes. The effect of pre/perinatal risk was greatest in those with more severe PEs, whereas effects of trauma were seen in all participants. In conclusion, environmental risk factors affect brain networks implicated in schizophrenia, which may increase an individual's propensity to develop later psychotic disorders.

Mutation-related magnetization-transfer, not axon density, drives white matter differences in premanifest Huntington disease: Evidence from in vivo ultra-strong gradient MRI.

White matter (WM) alterations have been observed in Huntington disease (HD) but their role in the disease-pathophysiology remains unknown. We assessed WM changes in premanifest HD by exploiting ultra-strong-gradient magnetic resonance imaging (MRI). This allowed to separately quantify magnetization transfer ratio (MTR) and hindered and restricted diffusion-weighted signal fractions, and assess how they drove WM microstructure differences between patients and controls. We used tractometry to investigate region-specific alterations across callosal segments with well-characterized early- and late-myelinating axon populations, while brain-wise differences were explored with tract-based cluster analysis (TBCA). Behavioral measures were included to explore disease-associated brain-function relationships. We detected lower MTR in patients' callosal rostrum (tractometry: p = .03; TBCA: p = .03), but higher MTR in their splenium (tractometry: p = .02). Importantly, patients' mutation-size and MTR were positively correlated (all p-values < .01), indicating that MTR alterations may directly result from the mutation. Further, MTR was higher in younger, but lower in older patients relative to controls (p = .003), suggesting that MTR increases are detrimental later in the disease. Finally, patients showed higher restricted diffusion signal fraction (FR) from the composite hindered and restricted model of diffusion (CHARMED) in the cortico-spinal tract (p = .03), which correlated positively with MTR in the posterior callosum (p = .033), potentially reflecting compensatory mechanisms. In summary, this first comprehensive, ultra-strong gradient MRI study in HD provides novel evidence of mutation-driven MTR alterations at the premanifest disease stage which may reflect neurodevelopmental changes in iron, myelin, or a combination of these.

Longitudinal Structural MRI Findings in Individuals at Genetic and Clinical High Risk for Psychosis: A Systematic Review.

Background: Several cross-sectional studies report brain structure differences between healthy volunteers and subjects at genetic or clinical high risk of developing schizophrenia. However, longitudinal studies are important to determine whether altered trajectories of brain development precede psychosis onset. Methods: We conducted a systematic review to determine if brain trajectories differ between (i) those with psychotic experiences (PE), genetic (GHR) or clinical high risk (CHR), compared to healthy volunteers, and (ii) those who transition to psychosis compared to those who do not. Results: Thirty-eight studies measured gray matter and 18 studies measured white matter in 2,473 high risk subjects and 990 healthy volunteers. GHR, CHR, and PE subjects show an accelerated decline in gray matter primarily in temporal, and also frontal, cingulate and parietal cortex. In those who remain symptomatic or transition to psychosis, gray matter loss is more pronounced in these brain regions. White matter volume and fractional anisotropy, which typically increase until early adulthood, did not change or reduced in high risk subjects in the cingulum, thalamic radiation, cerebellum, retrolenticular part of internal capsule, and hippocampal-thalamic tracts. In those who transitioned, white matter volume and fractional anisotropy reduced over time in the inferior and superior fronto-occipital fasciculus, corpus callosum, anterior limb of the internal capsule, superior corona radiate, and calcarine cortex. Conclusion: High risk subjects show deficits in white matter maturation and an accelerated decline in gray matter. Gray matter loss is more pronounced in those who transition to psychosis, but may normalize by early adulthood in remitters.

Drum training induces long-term plasticity in the cerebellum and connected cortical thickness.

It is unclear to what extent cerebellar networks show long-term plasticity and accompanied changes in cortical structures. Using drumming as a demanding multimodal motor training, we compared cerebellar lobular volume and white matter microstructure, as well as cortical thickness of 15 healthy non-musicians before and after learning to drum, and 16 age matched novice control participants. After 8 weeks of group drumming instruction, 3 ×30 minutes per week, we observed the cerebellum significantly changing its grey (volume increase of left VIIIa, relative decrease of VIIIb and vermis Crus I volume) and white matter microstructure in the inferior cerebellar peduncle. These plastic cerebellar changes were complemented by changes in cortical thickness (increase in left paracentral, right precuneus and right but not left superior frontal thickness), suggesting an interplay of cerebellar learning with cortical structures enabled through cerebellar pathways.

Anatomical evidence of an indirect pathway for word repetition.

OBJECTIVE: To combine MRI-based cortical morphometry and diffusion white matter tractography to describe the anatomical correlates of repetition deficits in patients with primary progressive aphasia (PPA). METHODS: The traditional anatomical model of language identifies a network for word repetition that includes Wernicke and Broca regions directly connected via the arcuate fasciculus. Recent tractography findings of an indirect pathway between Wernicke and Broca regions suggest a critical role of the inferior parietal lobe for repetition. To test whether repetition deficits are associated with damage to the direct or indirect pathway between both regions, tractography analysis was performed in 30 patients with PPA (64.27 ± 8.51 years) and 22 healthy controls. Cortical volume measurements were also extracted from 8 perisylvian language areas connected by the direct and indirect pathways. RESULTS: Compared to healthy controls, patients with PPA presented with reduced performance in repetition tasks and increased damage to most of the perisylvian cortical regions and their connections through the indirect pathway. Repetition deficits were prominent in patients with cortical atrophy of the temporo-parietal region with volumetric reductions of the indirect pathway. CONCLUSIONS: The results suggest that in PPA, deficits in repetition are due to damage to the temporo-parietal cortex and its connections to Wernicke and Broca regions. We therefore propose a revised language model that also includes an indirect pathway for repetition, which has important clinical implications for the functional mapping and treatment of neurologic patients.

Epidemiological characteristics and diagnostic approach in patients admitted to the emergency room for transient loss of consciousness: Group for Syncope Study in the Emergency Room (GESINUR) study.

AIMS: To assess the clinical presentation and acute management of patients with transient loss of consciousness (T-LOC) in the emergency department (ED). METHODS AND RESULTS: A multi-centre prospective observational study was carried out in 19 Spanish hospitals over 1 month. The patients included were > or =14 years old and were admitted to the ED because of an episode of T-LOC. Questionnaires and corresponding electrocardiograms (ECGs) were reviewed by a Steering Committee (SC) to unify diagnostic criteria, evaluate adherence to guidelines, and diagnose correctly the ECGs. We included 1419 patients (prevalence, 1.14%). ECG was performed in 1335 patients (94%) in the ED: 498 (37.3%) ECGs were classified as abnormal. The positive diagnostic yield ranged from 0% for the chest X-ray to 12% for the orthostatic test. In the ED, 1217 (86%) patients received a final diagnosis of syncope, whereas the remaining 202 (14%) were diagnosed of non-syncopal transient loss of consciousness (NST-LOC). After final review by the SC, 1080 patients (76%) were diagnosed of syncope, whereas 339 (24%) were diagnosed of NST-LOC (P < 0.001). Syncope was diagnosed correctly in 84% of patients. Only 25% of patients with T-LOC were admitted to hospitals. CONCLUSION: Adherence to clinical guidelines for syncope management was low; many diagnostic tests were performed with low diagnostic yield. Important differences were observed between syncope diagnoses at the ED and by SC decision.

Analysis of current management of atrial fibrillation in the acute setting: GEFAUR-1 study.

STUDY OBJECTIVE: Limited information relative to the management of atrial fibrillation in the emergency department (ED) daily practice is available. This study evaluates current management of atrial fibrillation in this setting to identify areas for practice improvement. METHODS: This was a prospective multicenter observational study carried out in 12 EDs. Adults in whom atrial fibrillation was demonstrated in an ECG obtained in the ED were included. Clinical variables and atrial fibrillation management in the ED were prospectively collected by the treating physicians using a standardized questionnaire. Patients with rapid ventricular response (>100 beats/min) were considered eligible for rate control, and patients with recent-onset episodes (<48 hours) were eligible for rhythm control. RESULTS: Of 1,178 patients, 41% presented with a rapid ventricular response and 21% had recent-onset episodes. Rhythm control was attempted in 42% of eligible patients, with antiarrhythmic drugs in 88% of cases (I-C drugs in 44% of patients; amiodarone in 43% of patients). Overall effectiveness of pharmacologic cardioversion was 63% (amiodarone 54.5%, flecainide 93%), whereas electrocardioversion was effective in 87.5% of cases. Rate control was performed in 68.3% of eligible patients (overall effectiveness 47.8%); digoxin was used in 67% of cases (effectiveness 45%). Both strategies were selected in 4.5% of cases, whereas no treatment for atrial fibrillation was performed in 60% of patients. CONCLUSION: In our ED population, rate-control effectiveness is poor and rhythm control is not attempted in most recent-onset episodes. Methods to improve rate-control effectiveness, the selection of patients for rhythm control, and the use of electrocardioversion appear warranted.

Differences among clinical classification schemes for predicting stroke in atrial fibrillation: implications for therapy in daily practice.

BACKGROUND: Several clinical classification schemes (CCSs) for predicting stroke in nonvalvular atrial fibrillation (NVAF) have been developed to help identify patients eligible for anticoagulation. OBJECTIVES: To estimate the agreement in predicting the risk of stroke among four widespread CCSs, and to determine their implications for thromboprophylaxis in clinical practice. METHODS: The authors conducted a prospective, multicenter, observational study of adults with NVAF in 12 emergency departments (EDs) in July 2000 and February 2001. The proportions of patients classified as having high, moderate, and low risk of stroke among the following CCSs were compared: the Atrial Fibrillation Investigators (AFI), the Stroke Prevention in Atrial Fibrillation (SPAF), the CHADS(2) (an acronym for congestive heart failure, hypertension, age >75 years, diabetes mellitus, and prior stroke or transient ischemic attack), and the American College of Chest Physicians (ACCP). RESULTS: One thousand two hundred twenty patients were included. The proportions of patients stratified as having high/moderate/low risk of stroke according to each CCS were: 70%/22%/8% (AFI), 38%/41%/21% (SPAF), 13%/45%/42% (CHADS(2)), and 86%/7%/7% (ACCP). The agreement was medium between AFI and ACCP (kappa = 0.52) and poor among the rest of them (AFI/SPAF, kappa = 0.01; AFI/CHADS(2), kappa = 0.02; SPAF/CHADS(2), kappa = 0.18; SPAF/ACCP, kappa = 0.11; CHADS(2)/ACCP, kappa = 0.03). The agreements in selecting patients as eligible for antiplatelet therapy or anticoagulation were: AFI/SPAF, kappa = 0.45; AFI/CHADS(2), kappa = 0.22; AFI/ACCP, kappa = 0.91; SPAF/CHADS(2), kappa = 0.47; SPAF/ACCP, kappa = 0.11; CHADS(2)/ACCP, kappa = 0.03. CONCLUSIONS: In the ED population studied, these CCSs showed relevant differences in the risk of stroke stratification and, therefore, in the identification of patients with NVAF eligible for anticoagulation.

Risk factors for stroke and thromboprophylaxis in atrial fibrillation: what happens in daily clinical practice? The GEFAUR-1 study.

STUDY OBJECTIVES: We determine the risk for stroke of patients with atrial fibrillation in the emergency department (ED) and analyze the use of stroke prophylaxis in this setting. METHODS: This was a cross-sectional study carried out in 12 EDs. Clinical variables, risk factors for stroke, the prophylaxis prescribed, and the reasons for not initiating anticoagulation were collected. Risk factors and indications for therapy were evaluated according to the American College of Chest Physicians' 1998 recommendations. RESULTS: Of 1,178 patients included, 69% were not taking anticoagulants. Of the latter, 89% patients had indications for anticoagulation (age >75 years 59%, hypertension 56%, cardiac disorders 29%, heart failure 22%, diabetes 22%, previous embolism 14%), and 63% of the patients had 2 or more risk factors. Anticoagulation was prescribed in the ED to 27% of patients (67% with warfarin, 33% low-weight heparin plus warfarin), antiplatelets to 20% of patients, and no thromboprophylaxis to 53% of these eligible patients. Anticoagulants were prescribed in only 9% of patients with risk factors and current prophylaxis with antiplatelet agents. The main reasons for not prescribing anticoagulation in the presence of risk factors were advanced age (11%), contraindication for anticoagulation (27%), or because it was not considered to be indicated by the physicians (23%). CONCLUSION: Most patients seen in the ED with atrial fibrillation are at high risk of stroke. Despite this risk, anticoagulation is underused in this setting, mainly because of the influence of advanced age on medical decisions and the reluctance to change current antiplatelet therapy.

[Consensus document for the management of patients with atrial fibrillation in hospital emergency departments]. / Documento de consenso sobre el tratamiento de la fibrilación auricular en los servicios de urgencias hospitalarios.

Atrial fibrillation (AF) is the most prevalent arrhythmia in hospital emergency departments and is a serious disease associated with a twofold increase in morbidity and a high mortality rate. However, the management of AF in this scenario is variable and frequently inadequate. This is probably a consequence of the diverse clinical aspects and therapeutic options to consider in the management of patients with AF. Therefore, implementation of specific, coordinated management strategies by the different care providers involved is needed to improve the quality of care and optimize the use of human and material resources. This document presents the guidelines recommended by the Spanish Society of Cardiology (SEC) and the Spanish Society of Emergency Medicine (SEMES) for the management of AF in hospital emergency departments. These guidelines are based on published scientific evidence and are applicable to most emergency departments in Spain. Specific management strategies are proposed for the conversion and maintenance of sinus rhythm, heart rate control during AF, prophylaxis for thrombi and emboli, and hospital admission and discharge protocols.

Documento de consenso sobre el tratamiento de la fibrilación auricular en los servicios de urgencias hospitalarios / Consensus document for the management of patients with atrial fibrillation in hospital emergency departments

La fibrilación auricular (FA) es la arritmia más prevalente en los servicios de urgencias hospitalarios (SUH) y es una enfermedad grave que duplica la mortalidad y que conlleva una elevada morbilidad. Sin embargo, a pesar de estas consideraciones, en nuestro medio se realiza un manejo heterogéneo y con frecuencia inadecuado de la FA en los SUH. Probablemente, esto es una consecuencia de la diversidad de aspectos clínicos que deben considerarse en los pacientes con FA, así como del elevado número de opciones terapéuticas posibles, lo que justifica la implementación de estrategias concretas y coordinadas de actuación entre los diversos profesionales implicados en el manejo de los pacientes con FA, con el fin de mejorar su tratamiento y optimizar los recursos humanos y materiales. Este documento recoge las guías recomendadas por la Sociedad Española de Cardiología (SEC) y la Sociedad Española de Medicina de Urgencias y Emergencias (SEMES) para el manejo de la FA en los SUH, donde se proponen unas pautas generales basadas en la evidencia científica publicada hasta el momento y aplicables a la mayoría de los SUH de nuestro país. De esta forma, se proponen estrategias concretas de manejo de los pacientes con FA en los aspectos de recuperación y mantenimiento del ritmo sinusal, control de la frecuencia cardíaca durante FA, profilaxis tromboembólica e ingreso o alta hospitalaria, todo ello con el objetivo de promover una mejor atención a los pacientes con un uso más adecuado de los recursos disponibles en nuestro medio (AU)