Functional MRI of the Brainstem for Assessing Its Autonomic Functions: From Imaging Parameters and Analysis to Functional Atlas.

BACKGROUND: The brainstem is a crucial component of the central autonomic nervous (CAN) system. Functional MRI (fMRI) of the brainstem remains challenging due to a range of factors, including diverse imaging protocols, analysis, and interpretation. PURPOSE: To develop an fMRI protocol for establishing a functional atlas in the brainstem. STUDY TYPE: Prospective cross-sectional study. SUBJECTS: Ten healthy subjects (four males, six females). FIELD STRENGTH/SEQUENCE: Using a 3.0 Tesla MR scanner, we acquired T1-weighted images and three different fMRI scans using fMRI protocols of the optimized functional Imaging of Brainstem (FIBS), the Human Connectome Project (HCP), and the Adolescent Brain Cognitive Development (ABCD) project. ASSESSMENT: The temporal signal-to-noise-ratio (TSNR) of fMRI data was compared between the FIBS, HCP, and ABCD protocols. Additionally, the main normalization algorithms (i.e., FSL-FNIRT, SPM-DARTEL, and ANTS-SyN) were compared to identify the best approach to normalize brainstem data using root-mean-square (RMS) error computed based on manually defined reference points. Finally, a functional autonomic brainstem atlas that maps brainstem regions involved in the CAN system was defined using meta-analysis and data-driven approaches. STATISTICAL TESTS: ANOVA was used to compare the performance of different imaging and preprocessing pipelines with multiple comparison corrections (P ≤ 0.05). Dice coefficient estimated ROI overlap, with 50% overlap between ROIs identified in each approach considered significant. RESULTS: The optimized FIBS protocol showed significantly higher brainstem TSNR than the HCP and ABCD protocols (P ≤ 0.05). Furthermore, FSL-FNIRT RMS error (2.1 ± 1.22 mm; P ≤ 0.001) exceeded SPM (1.5 ± 0.75 mm; P ≤ 0.01) and ANTs (1.1 ± 0.54 mm). Finally, a set of 12 final brainstem ROIs with dice coefficient ≥0.50, as a step toward the development of a functional brainstem atlas. DATA CONCLUSION: The FIBS protocol yielded more robust brainstem CAN results and outperformed both the HCP and ABCD protocols. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

Medial prefrontal cortex deficits correlate with unrefreshing sleep in patients with chronic fatigue syndrome.

Unrefreshing sleep is a hallmark of chronic fatigue syndrome/myalgic encephalomyelitis (CFS). This study examined brain structure variations associated with sleep quality in patients with CFS. 38 patients with CFS (34.8 ± 10.1 years old) and 14 normal controls (NCs) (34.7 ± 8.4 years old) were recruited. All subjects completed the Hospital Anxiety and Depression Scale, Pittsburgh Sleep Quality Index (PSQI), and Chalder Fatigue Scale (CFQ) questionnaires. Brain MRI measures included global and regional grey and white matter volumes, magnetization transfer T1 weighted (MT-T1w) intensities, and T1 weighted (T1w) and T2 weighted spin echo signal intensities. We performed voxel based group comparisons of these regional brain MRI measures and regressions of these measures with the PSQI and CFQ scales adjusted for age, anxiety and depression, and the appropriate global measure. In CFS patients, negative correlations were observed in the medial prefrontal cortex (mPFC) between PSQI and MT-T1w intensities (family-wise error corrected cluster, PFWE  < 0.05) and between PSQI and T1w intensities (PFWE  < 0.05). In the same mPFC location, both MT and T1w intensities were lower in CFS patients compared with NCs (uncorrected voxel P < 0.001). This study is the first to report that brain structural differences are associated with unrefreshing sleep in CFS. This result refutes the suggestion that unrefreshing sleep is a misperception in CFS patients and further investigation of this symptom is warranted.

Progressive brain changes in patients with chronic fatigue syndrome: A longitudinal MRI study.

PURPOSE: To examine progressive brain changes associated with chronic fatigue syndrome (CFS). MATERIALS AND METHODS: We investigated progressive brain changes with longitudinal MRI in 15 CFS and 10 normal controls (NCs) scanned twice 6 years apart on the same 1.5 Tesla (T) scanner. MR images yielded gray matter (GM) volumes, white matter (WM) volumes, and T1- and T2-weighted signal intensities (T1w and T2w). Each participant was characterized with Bell disability scores, and somatic and neurological symptom scores. We tested for differences in longitudinal changes between CFS and NC groups, inter group differences between pooled CFS and pooled NC populations, and correlations between MRI and symptom scores using voxel based morphometry. The analysis methodologies were first optimized using simulated atrophy. RESULTS: We found a significant decrease in WM volumes in the left inferior fronto-occipital fasciculus (IFOF) in CFS while in NCs it was unchanged (family wise error adjusted cluster level P value, PFWE < 0.05). This longitudinal finding was consolidated by the group comparisons which detected significantly decreased regional WM volumes in adjacent regions (PFWE < 0.05) and decreased GM and blood volumes in contralateral regions (PFWE < 0.05). Moreover, the regional GM and WM volumes and T2w in those areas showed significant correlations with CFS symptom scores (PFWE < 0.05). CONCLUSION: The results suggested that CFS is associated with IFOF WM deficits which continue to deteriorate at an abnormal rate. J. Magn. Reson. Imaging 2016;44:1301-1311.

Evidence in chronic fatigue syndrome for severity-dependent upregulation of prefrontal myelination that is independent of anxiety and depression.

White matter (WM) involvement in chronic fatigue syndrome (CFS) was assessed using voxel-based regressions of brain MRI against CFS severity scores and CFS duration in 25 subjects with CFS and 25 normal controls (NCs). As well as voxel-based morphometry, a novel voxel-based quantitative analysis of T1 - and T2 -weighted spin-echo (T1w and T2w) MRI signal level was performed. Severity scores included the Bell CFS disability scale and scores based on the 10 most common CFS symptoms. Hospital Anxiety and Depression Scale (HADS) depression and anxiety scores were included as nuisance covariates. By relaxing the threshold for cluster formation, we showed that the T1w signal is elevated with increasing CFS severity in the ventrolateral thalamus, internal capsule and prefrontal WM. Earlier reports of WM volume losses and neuroinflammation in the midbrain, together with the upregulated prefrontal myelination suggested here, are consistent with the midbrain changes being associated with impaired nerve conduction which stimulates a plastic response on the cortical side of the thalamic relay in the same circuits. The T2w signal versus CFS duration and comparison of T2w signal in the CFS group with the NC group revealed changes in the right middle temporal lobe WM, where impaired communication can affect cognitive function. Adjustment for depression markedly strengthened cluster statistics and increased cluster size in both T1w severity regressions, but adjustment for anxiety less so. Thus, depression and anxiety are statistical confounders here, meaning that they contribute variance to the T1w signal in prefrontal WM but this does not correlate with the co-located variance from CFS severity. MRI regressions with depression itself only detected associations with WM volume, also located in prefrontal WM. We propose that impaired reciprocal brain-body and brain-brain communication through the midbrain provokes peripheral and central responses which contribute to CFS symptoms. Although anxiety, depression and CFS may share biological features, the present evidence indicates that CFS is a distinct disorder.

Community cardiovascular disease risk from cross-sectional general practice clinical data: a spatial analysis.

INTRODUCTION: Cardiovascular disease (CVD) continues to be a leading cause of illness and death among adults worldwide. The objective of this study was to calculate a CVD risk score from general practice (GP) clinical records and assess spatial variations of CVD risk in communities. METHODS: We used GP clinical data for 4,740 men and women aged 30 to 74 years with no history of CVD. A 10-year absolute CVD risk score was calculated based on the Framingham risk equation. The individual risk scores were aggregated within each Statistical Area Level One (SA1) to predict the level of CVD risk in that area. Finally, the pattern of CVD risk was visualized to highlight communities with high and low risk of CVD. RESULTS: The overall 10-year risk of CVD in our sample population was 14.6% (95% confidence interval [CI], 14.3%-14.9%). Of the 4,740 patients in our study, 26.7% were at high risk, 29.8% were at moderate risk, and 43.5% were at low risk for CVD over 10 years. The proportion of patients at high risk for CVD was significantly higher in the communities of low socioeconomic status. CONCLUSION: This study illustrates methods to further explore prevalence, location, and correlates of CVD to identify communities of high levels of unmet need for cardiovascular care and to enable geographic targeting of effective interventions for enhancing early and timely detection and management of CVD in those communities.

Absence of BOLD adaptation in chronic fatigue syndrome revealed by task functional MRI.

Neurological symptoms are central to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), yet its underlying neurophysiological mechanisms remain elusive. We examined a neglected aspect of task-based functional MRI, focusing on how blood oxygenation level-dependent (BOLD) signals alter during cognitive tasks in ME/CFS. This prospective observational study utilised MRI scans on ME/CFS participants and healthy controls (HCs) with sedentary lifestyles (ACTRN12622001095752). Participants completed two blocks of a Symbol Digit Modalities Test, with 30 trials per block split into two sets. The fMRI signal changes between blocks and sets were compared within and between groups. Thirty-four ME/CFS participants (38 years ± 10; 27 women) and 34 HCs (38 ± 10; 27 women), were evaluated. In the second task block, ME/CFS participants exhibited increased activation in the right postcentral gyrus, contrasting with decreased activation in multiple regions in HCs. These results were further confirmed by significantly higher bilateral dynamic changes (2nd vs 1st set) in the motor, sensory and cognitive cortex in ME/CFS compared to HCs and significant correlations between those changes in the left primary motor cortex with fatigue severities. BOLD adaptation, potentially improving energy economy, was absent in ME/CFS, which may provide an underlying neurophysiological process in ME/CFS.

Objective sleep measures in chronic fatigue syndrome patients: A systematic review and meta-analysis.

Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often report disrupted and unrefreshing sleep in association with worsened fatigue symptoms. However, the nature and magnitude of sleep architecture alteration in ME/CFS is not known, with studies using objective sleep measures in ME/CFS generating contradictory results. The current manuscript aimed to review and meta-analyse of case-control studies with objective sleep measures in ME/CSF. A search was conducted in PubMed, Scopus, Medline, Google Scholar, and Psychoinfo databases. After review, 24 studies were included in the meta-analysis, including 20 studies with 801 adults (ME/CFS = 426; controls = 375), and 4 studies with 477 adolescents (ME/CFS = 242; controls = 235), who underwent objective measurement of sleep. Adult ME/CFS patients spend longer time in bed, longer sleep onset latency, longer awake time after sleep onset, reduced sleep efficiency, decreased stage 2 sleep, more Stage 3, and longer rapid eye movement sleep latency. However, adolescent ME/CFS patients had longer time in bed, longer total sleep time, longer sleep onset latency, and reduced sleep efficiency. The meta-analysis results demonstrate that sleep is altered in ME/CFS, with changes seeming to differ between adolescent and adults, and suggesting sympathetic and parasympathetic nervous system alterations in ME/CFS.

Anti-Correlated Myelin-Sensitive MRI Levels in Humans Consistent with a Subcortical to Sensorimotor Regulatory Process-Multi-Cohort Multi-Modal Evidence.

Differential axonal myelination synchronises signalling over different axon lengths. The consequences of myelination processes described at the cellular level for the regulation of myelination at the macroscopic level are unknown. We analysed multiple cohorts of myelin-sensitive brain MRI. Our aim was to (i) confirm a previous report of anti-correlation between myelination in subcortical and sensorimotor areas in healthy subjects, (ii) and thereby test our hypothesis for a regulatory interaction between them. We analysed nine image-sets across three different human cohorts using six MRI modalities. Each image-set contained healthy controls (HC) and ME/CFS subjects. Subcortical and Sensorimotor regions of interest (ROI) were optimised for the detection of anti-correlations and the same ROIs were used to test the HC in all image-sets. For each cohort, median MRI values were computed in both regions for each subject and their correlation across the cohort was computed. We confirmed negative correlations in healthy controls between subcortical and sensorimotor regions in six image-sets: three T1wSE (p = 5 × 10-8, 5 × 10-7, 0.002), T2wSE (p =2 × 10-6), MTC (p = 0.01), and WM volume (p = 0.02). T1/T2 was the exception with a positive correlation (p = 0.01). This myelin regulation study is novel in several aspects: human subjects, cross-sectional design, ROI optimization, spin-echo MRI and reproducible across multiple independent image-sets. In multiple independent image-sets we confirmed an anti-correlation between subcortical and sensorimotor myelination which supports a previously unreported regulatory interaction. The subcortical region contained the brain's primary regulatory nuclei. We suggest a mechanism has evolved whereby relatively low subcortical myelination in an individual is compensated by upregulated sensorimotor myelination to maintain adequate sensorimotor performance.

Characterisation of the Australian Adult Population Living with Asthma: Severe - Exacerbation Frequency, Long-Term OCS Use and Adverse Effects.

Introduction: Asthma poses a significant burden for the Australian population. Understanding severe exacerbation rates, and steroid-related burden for adults diagnosed with asthma stands to offer insights into how this could be reduced. Methods: Electronic medical records (EMR) and questionnaires from the Optimum Patient Care Research Database Australia (OPCRDA) were utilised retrospectively. OPCRDA is a real-world database with >800,000 medical records from Australian primary care practices. Outcomes were severe asthma exacerbations in Australian adults, over a 12-month period, stratified by Global Initiative for Asthma (GINA) treatment intensity steps, and steroid associated comorbidities. Results: Of the 7868 adults treated for asthma, 19% experienced at least one severe exacerbation in the last 12-months. Severe exacerbation frequency increased with treatment intensity (≥1 severe exacerbation GINA 1 13%; GINA 4 23%; GINA 5a 33% and GINA 5b 28%). Questionnaire participants reported higher rates of severe exacerbations than suggested from their EMR (32% vs 23%) especially in steps 1, 4 and 5. Patients repeatedly exposed to steroids had an increased risk of osteoporosis (OR 1.95, 95% CI 1.43-2.66) and sleep apnoea (OR 1.78, 95% CI 1.30-2.46). Conclusion: The Australian population living with GINA 1, 4, 5a and 5b asthma have high severe exacerbation rates and steroid-related burden, especially when compared to other first world countries, with these patients needing alternative strategies or possibly specialist assessment to better manage their condition.

A brain MRI study of chronic fatigue syndrome: evidence of brainstem dysfunction and altered homeostasis.

To explore brain involvement in chronic fatigue syndrome (CFS), the statistical parametric mapping of brain MR images has been extended to voxel-based regressions against clinical scores. Using SPM5 we performed voxel-based morphometry (VBM) and analysed T(1) - and T(2) -weighted spin-echo MR signal levels in 25 CFS subjects and 25 normal controls (NC). Clinical scores included CFS fatigue duration, a score based on the 10 most common CFS symptoms, the Bell score, the hospital anxiety and depression scale (HADS) anxiety and depression, and hemodynamic parameters from 24-h blood pressure monitoring. We also performed group × hemodynamic score interaction regressions to detect locations where MR regressions were opposite for CFS and NC, thereby indicating abnormality in the CFS group. In the midbrain, white matter volume was observed to decrease with increasing fatigue duration. For T(1) -weighted MR and white matter volume, group × hemodynamic score interactions were detected in the brainstem [strongest in midbrain grey matter (GM)], deep prefrontal white matter (WM), the caudal basal pons and hypothalamus. A strong correlation in CFS between brainstem GM volume and pulse pressure suggested impaired cerebrovascular autoregulation. It can be argued that at least some of these changes could arise from astrocyte dysfunction. These results are consistent with an insult to the midbrain at fatigue onset that affects multiple feedback control loops to suppress cerebral motor and cognitive activity and disrupt local CNS homeostasis, including resetting of some elements of the autonomic nervous system (ANS).

Getting the most out of your practice--the Practice Health Atlas and business modelling opportunities.

BACKGROUND: The Practice Health Atlas (PHA) is a decision support tool for general practice, designed by the Adelaide Western Division of General Practice (AWDGP). OBJECTIVE: This article describes the features of the PHA and its potential role in enhancing health care. DISCUSSION: In developing the PHA, the AWDGP utilises a range of software tools and consults with a practice to understand its clinical data management approach. The PHA comprises three sections: epidemiology, business and clinical modelling systems, access to services. The objectives include developing a professional culture around quality health data and synthesis of aggregated de-identified general practice data at both practice and divisional level (and beyond) to assist with local health needs assessment, planning, and funding. Evaluation occurs through group feedback sessions and from the general practitioners and staff. It has demonstrated its potential to fulfill the objectives in outcome areas such as data quality and management, team based care, pro-active practice population health care, and business systems development, thereby contributing to improved patient health outcomes.

Autonomic correlations with MRI are abnormal in the brainstem vasomotor centre in Chronic Fatigue Syndrome.

Autonomic changes are often associated with the chronic fatigue syndrome (CFS), but their pathogenetic role is unclear and brain imaging investigations are lacking. The vasomotor centre and, through it, nuclei in the midbrain and hypothalamus play a key role in autonomic nervous system regulation of steady state blood pressure (BP) and heart rate (HR). In this exploratory cross-sectional study, BP and HR, as indicators of autonomic function, were correlated with volumetric and T1- and T2-weighted spin-echo (T1w and T2w) brain MRI in 25 CFS subjects and 25 normal controls (NC). Steady state BP (systolic, diastolic and pulse pressure) and HR in two postures were extracted from 24 h blood pressure monitoring. We performed (1) MRI versus autonomic score interaction-with-group regressions to detect locations where regression slopes differed in the CFS and NC groups (collectively indicating abnormality in CFS), and (2) MRI regressions in the CFS and NC groups alone to detect additional locations with abnormal correlations in CFS. Significant CFS regressions were repeated controlling for anxiety and depression (A&D). Abnormal regressions were detected in nuclei of the brainstem vasomotor centre, midbrain reticular formation and hypothalamus, but also in limbic nuclei involved in stress responses and in prefrontal white matter. Group comparisons of CFS and NC did not find MRI differences in these locations. We propose therefore that these regulatory nuclei are functioning correctly, but that two-way communication between them is impaired in CFS and this affects signalling to/from peripheral effectors/sensors, culminating in inverted or magnified correlations. This single explanation for the diverse abnormal correlations detected here consolidates the conclusion for a brainstem/midbrain nerve conduction deficit inferred earlier (Barnden et al., 2015). Strong correlations were also detected in isolated NC regressions.

Protecting the privacy of individual general practice patient electronic records for geospatial epidemiology research.

BACKGROUND: General practitioner (GP) practices in Australia are increasingly storing patient information in electronic databases. These practice databases can be accessed by clinical audit software to generate reports that inform clinical or population health decision making and public health surveillance. Many audit software applications also have the capacity to generate de-identified patient unit record data. However, the de-identified nature of the extracted data means that these records often lack geographic information. Without spatial references, it is impossible to build maps reflecting the spatial distribution of patients with particular conditions and needs. Links to socioeconomic, demographic, environmental or other geographically based information are also not possible. In some cases, relatively coarse geographies such as postcode are available, but these are of limited use and researchers cannot undertake precision spatial analyses such as calculating travel times. METHODS: We describe a method that allows researchers to implement meaningful mapping and spatial epidemiological analyses of practice level patient data while preserving privacy. RESULTS: This solution has been piloted in a diabetes risk research project in the patient population of a practice in Adelaide. CONCLUSIONS AND IMPLICATIONS: The method offers researchers a powerful means of analysing geographic clinic data in a privacy-protected manner.

Undiagnosed diabetes from cross-sectional GP practice data: an approach to identify communities with high likelihood of undiagnosed diabetes.

OBJECTIVES: To estimate undiagnosed diabetes prevalence from general practitioner (GP) practice data and identify areas with high levels of undiagnosed and diagnosed diabetes. DESIGN: Data from the North-West Adelaide Health Survey (NWAHS) were used to develop a model which predicts total diabetes at a small area. This model was then applied to cross-sectional data from general practices to predict the total level of expected diabetes. The difference between total expected and already diagnosed diabetes was defined as undiagnosed diabetes prevalence and was estimated for each small area. The patterns of diagnosed and undiagnosed diabetes were mapped to highlight the areas of high prevalence. SETTING: North-West Adelaide, Australia. PARTICIPANTS: This study used two population samples-one from the de-identified GP practice data (n=9327 active patients, aged 18 years and over) and another from NWAHS (n=4056, aged 18 years and over). MAIN OUTCOME MEASURES: Total diabetes prevalence, diagnosed and undiagnosed diabetes prevalence at GP practice and Statistical Area Level 1. RESULTS: Overall, it was estimated that there was one case of undiagnosed diabetes for every 3-4 diagnosed cases among the 9327 active patients analysed. The highest prevalence of diagnosed diabetes was seen in areas of lower socioeconomic status. However, the prevalence of undiagnosed diabetes was substantially higher in the least disadvantaged areas. CONCLUSIONS: The method can be used to estimate population prevalence of diabetes from general practices wherever these data are available. This approach both flags the possibility that undiagnosed diabetes may be a problem of less disadvantaged social groups, and provides a tool to identify areas with high levels of unmet need for diabetes care which would enable policy makers to apply geographic targeting of effective interventions.

The effectiveness of coordinated care for people with chronic respiratory disease.

OBJECTIVES: To evaluate the effectiveness of coordinated care for chronic respiratory disease. DESIGN AND SETTING: Community-based geographical control study, in western (intervention) and northern (comparison) metropolitan Adelaide (SA). PARTICIPANTS: 377 adults (223 intervention; 154 comparison) with chronic obstructive pulmonary disease, asthma or other chronic respiratory condition, July 1997 to December 1999. INTERVENTION: Coordinated care (includes care coordinator, care guidelines, service coordinator and care mentor). MAIN OUTCOME MEASURES: Hospital admissions (any, unplanned and respiratory), functionality (activities of daily living) and quality of life (SF-36 and Dartmouth COOP). RESULTS: At entry to the study, intervention and comparison subjects were dissimilar. The intervention group was 10 years older (P < 0.001), less likely to smoke (P = 0.014), had higher rates of hospitalisation in the previous 12 months (P < 0.001) and had worse self-reported quality of life (SF-36 physical component summary score [P < 0.001] and four of nine COOP domains [P = 0.002-0.013]). After adjustment for relevant baseline characteristics, coordinated care was not associated with any difference in hospitalisation, but was associated with some improvements in quality of life (SF-36 mental component summary score [P = 0.023] and three of nine COOP domains [P = 0.008-0.031]) compared with the comparison group. CONCLUSIONS: Coordinated care given to patients with chronic respiratory disease did not affect hospitalisation, but it was associated with an improvement in some quality-of-life measures.