Ultradian hydrocortisone replacement alters neuronal processing, emotional ambiguity, affect and fatigue in adrenal insufficiency: The PULSES trial.

BACKGROUND: Primary adrenal insufficiency (PAI) mortality and morbidity remain unacceptably high, possibly arising as glucocorticoid replacement does not replicate natural physiology. A pulsatile subcutaneous pump can closely replicate cortisol's circadian and ultradian rhythm. OBJECTIVES: To assess the effect of pump therapy on quality of life, mood, functional neuroimaging, behavioural/cognitive responses, sleep and metabolism. METHODS: A 6-week randomised, crossover, double-blinded and placebo-controlled feasibility study of usual dose hydrocortisone in PAI administered as either pulsed subcutaneous or standard care in Bristol, United Kingdom (ISRCTN67193733). Participants were stratified by adrenal insufficiency type. All participants who received study drugs are included in the analysis. The primary outcome, the facial expression recognition task (FERT), occurred at week 6. RESULTS: Between December 2014 and 2017, 22 participants were recruited - 20 completed both arms, and 21 were analysed. The pump was well-tolerated. No change was seen in the FERT primary outcome; however, there were subjective improvements in fatigue and mood. Additionally, functional magnetic resonance imaging revealed differential neural processing to emotional cues and visual stimulation. Region of interest analysis identified the left amygdala and insula, key glucocorticoid-sensitive regions involved in emotional ambiguity. FERT post hoc analysis confirmed this response. There were four serious adverse events (AE): three intercurrent illnesses requiring hospitalisation (1/3, 33.3% pump) and a planned procedure (1/1, 100% pump). There was a small number of expected AEs: infusion site bruising/itching (3/5, 60% pump), intercurrent illness requiring extra (3/7, 42% pump) and no extra (4/6, 66% pump) steroid. CONCLUSIONS: These findings support the administration of hormone therapy that mimics physiology.

Dysfunction of basal ganglia functional connectivity associated with subjective and cognitive fatigue in multiple sclerosis.

Objectives: Central fatigue is one of the most common symptoms in multiple sclerosis (MS). It has a profound impact on quality of life and a negative effect on cognition. Despite its widespread impact, fatigue is poorly understood and very difficult to measure. Whilst the basal ganglia has been implicated in fatigue the nature of its role and involvement with fatigue is still unclear. The aim of the present study was to establish the role of the basal ganglia in MS fatigue using functional connectivity measures. Methods: The present study examined the functional connectivity (FC) of the basal ganglia in a functional MRI study with 40 female participants with MS (mean age = 49.98 (SD = 9.65) years) and 40 female age-matched (mean age = 49.95 (SD = 9.59) years) healthy controls (HC). To measure fatigue the study employed the subjective self-report Fatigue Severity Scale and a performance measure of cognitive fatigue using an alertness-motor paradigm. To distinguish physical and central fatigue force measurements were also recorded. Results: The results suggest that decreased local FC within the basal ganglia plays a key role in cognitive fatigue in MS. Increased global FC between the basal ganglia and the cortex may sub serve a compensatory mechanism to reduce the impact of fatigue in MS. Conclusion: The current study is the first to show that basal ganglia functional connectivity is associated with both subjective and objective fatigue in MS. In addition, the local FC of the basal ganglia during fatigue inducing tasks could provide a neurophysiological biomarker of fatigue.

Fidelity of 3D Printed Brains from MRI Scan in Children with Pathology (Prior Hypoxic Ischemic Injury).

Cortical injury on the surface of the brain in children with hypoxic ischemic injury (HII) can be difficult to demonstrate to non-radiologists and lay people using brain images alone. Three-dimensional (3D) printing is helpful to communicate the volume loss and pathology due to HII in children's brains. 3D printed models represent the brain to scale and can be held up against models of normal brains for appreciation of volume loss. If 3D printed brains are to be used for formal communication, e.g., with medical colleagues or in court, they should have high fidelity of reproduction of the actual size of patients' brains. Here, we evaluate the size fidelity of 3D printed models from MRI scans of the brain, in children with prior HII. Twelve 3D prints of the brain were created from MRI scans of children with HII and selected to represent a variety of cortical pathologies. Specific predetermined measures of the 3D prints were made and compared to measures in matched planes on MRI. Fronto-occipital length (FOL) and bi-temporal/bi-parietal diameters (BTD/BPD) demonstrated high interclass correlations (ICC). Correlations were moderate to weak for hemispheric height, temporal height, and pons-cerebellar thickness. The average standard error of measurement (SEM) was 0.48 cm. Our results demonstrate high correlations in overall measurements of each 3D printed model derived from brain MRI scans versus the original MRI, evidenced by high ICC values for FOL and BTD/BPD. Measures with low correlation values can be explained by variability in matching the plane of measurement to the MRI slice orientation.

Voxel-based map of the inter-arterial watershed zones in children.

PURPOSE: To create a voxel-based map of the inter-arterial watershed derived from children who have sustained a hypoxic-ischemic injury involving this region at term. MATERIALS AND METHODS: Patients 0-18 years of age diagnosed with a hypoxic-ischemic injury of the watershed on magnetic resonance imaging (MRI) were included. Two pediatric neuroradiologists segmented the lesions as visualized on the T2-weighted sequence. All lesion maps were normalized to a brain template and overlapped to create a frequency map in order to highlight the frequency of involvement of portions of the cortical watershed. RESULTS: A total of 47 patients (35 boys) were included in the final sample. Their mean age was 7.6 ± 3.6 years. The cortical watershed was successfully mapped. Three watershed regions were defined: the anterior, peri-Sylvian, and posterior watershed zones. The anterior and peri-Sylvian watershed zones are connected through the involvement of the middle frontal gyrus. The peri-Sylvian and the posterior watershed zones are connected through the involvement of the inferior parietal lobule, the posterior aspect of the superior temporal gyrus, and the angular gyrus with the occipital lobe. The temporal lobe and orbital part of the frontal lobe are largely spared in all patients. CONCLUSION: A voxel-based lesion map of children with watershed hypoxic ischemic injury at term was created and three inter-arterial watershed zones defined: anterior, peri-Sylvian, and posterior watersheds.

Safety and efficacy of losartan for the reduction of brain atrophy in clinically diagnosed Alzheimer's disease (the RADAR trial): a double-blind, randomised, placebo-controlled, phase 2 trial.

BACKGROUND: Drugs modifying angiotensin II signalling could reduce Alzheimer's disease pathology, thus decreasing the rate of disease progression. We investigated whether the angiotensin II receptor antagonist losartan, compared with placebo, could reduce brain volume loss, as a measure of disease progression, in clinically diagnosed mild-to-moderate Alzheimer's disease. METHODS: In this double-blind, multicentre, randomised controlled trial, eligible patients aged 55 years or older, previously untreated with angiotensin II drugs and diagnosed (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria) with mild-to-moderate Alzheimer's disease, and who had capacity to consent, were recruited from 23 UK National Health Service hospital trusts. After undergoing a 4-week, open-label phase of active treatment then washout, participants were randomly assigned (1:1) oral over-encapsulated preparations of either 100 mg losartan (after an initial two-dose titration stage) or matched placebo daily for 12 months. Randomisation, minimised by age and baseline medial temporal lobe atrophy score, was undertaken online or via pin-access service by telephone. Participants, their study companions, and study personnel were masked to group assignment. The primary outcome, analysed by the intention-to-treat principle (ie, participants analysed in the group to which they were randomised, without imputation for missing data), was change in whole brain volume between baseline and 12 months, measured using volumetric MRI and determined by boundary shift interval (BSI) analysis. The trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN93682878) and the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT 2012-003641-15), and is completed. FINDINGS: Between July 22, 2014, and May 17, 2018, 261 participants entered the open-label phase. 211 were randomly assigned losartan (n=105) or placebo (n=106). Of 197 (93%) participants who completed the study, 171 (81%) had complete primary outcome data. The mean brain volume (BSI) reduction was 19·1 mL (SD 10·3) in the losartan group and 20·0 mL (10·8) in the placebo group. The difference in total volume reduction between groups was -2·29 mL (95% CI -6·46 to 0·89; p=0·14). The number of adverse events was low (22 in the losartan group and 20 in the placebo group) with no differences between treatment groups. There was one treatment-related death per treatment group. INTERPRETATION: 12 months of treatment with losartan was well tolerated but was not effective in reducing the rate of brain atrophy in individuals with clinically diagnosed mild-to-moderate Alzheimer's disease. Further research is needed to assess the potential therapeutic benefit from earlier treatment in patients with milder cognitive impairment or from longer treatment periods. FUNDING: Efficacy and Mechanism Evaluation Programme (UK Medical Research Council and National Institute for Health Research).

Accuracy of radiologists, nonradiologists, and laypeople for identifying children with cerebral cortical atrophy from "Mercator map" curved reconstructions of MRIs of the brain.

BACKGROUND: Using text reports to communicate bilateral, symmetric, and zonal cortical brain atrophy in children with term hypoxic ischemic injury (HII) to parents and legal professionals contesting compensation rights can be difficult. Using standard cross-sectional images for explaining bilateral, regional brain imaging to laypeople is also challenging. A single flattened image of the brain surface, much like a map of the earth is derived from a globe, can be generated from curved reconstruction of magnetic resonance imaging (MRI) scans, i.e., a Mercator map. Laypeople's ability to identify abnormal "Mercator brain maps," without prior training, requires evaluation before use in nonmedical settings. AIM: To determine the sensitivity and specificity of laypeople in detecting abnormal pediatric Mercator flat-earth maps of the brain, without prior training. METHODS AND MATERIALS: 10 Mercator brain maps were provided to 111 participants individually. The maps comprised 5 HII, 1 cortical dysplasia, and 4 normal cases. Participants were required to identify the abnormal scans. Sensitivity and specificity overall and for participants' subgroups were calculated. RESULTS: Overall sensitivity and specificity were 67% and 80%, respectively. General radiologists (n = 12) had sensitivity and specificity of 91.2% and 94.6%, respectively. Laypeople (n = 54) had a sensitivity of 67% and specificity of 80%. CONCLUSION: The high specificity and sensitivity of radiologists validated the technique for distinguishing abnormal scans, regarding cortical pathology. High specificity of laypeople for identifying abnormal brains using Mercator maps indicates that this is a viable communication tool for demonstrating cortical MRI abnormalities of HII in children to laypersons.

Using structural and functional MRI as a neuroimaging technique to investigate chronic fatigue syndrome/myalgic encephalopathy: a systematic review.

OBJECTIVE: This systematic review aims to synthesise and evaluate structural MRI (sMRI) and functional MRI (fMRI) studies in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). METHODS: We systematically searched Medline and Ovid and included articles from 1991 (date of Oxford diagnostic criteria for CFS/ME) to first April 2019. Studies were selected by predefined inclusion and exclusion criteria. Two reviewers independently reviewed the titles and abstracts to determine articles for inclusion, full text and quality assessment for risk of bias. RESULTS: sMRI studies report differences in CFS/ME brain anatomy in grey and white matter volume, ventricular enlargement and hyperintensities. Three studies report no neuroanatomical differences between CFS/ME and healthy controls. Task-based fMRI investigated working memory, attention, reward and motivation, sensory information processing and emotional conflict. The most consistent finding was CFS/ME exhibited increased activations and recruited additional brain regions. Tasks with increasing load or complexity produced decreased activation in task-specific brain regions. CONCLUSIONS: There were insufficient data to define a unique neural profile or biomarker of CFS/ME. This may be due to inconsistencies in finding neuroanatomical differences in CFS/ME and the variety of different tasks employed by fMRI studies. But there are also limitations with neuroimaging. All brain region specific volumetric differences in CFS/ME were derived from voxel-based statistics that are biased towards group differences that are highly localised in space. fMRI studies demonstrated both increases and decreases in activation patterns in CFS/ME, this may be related to task demand. However, fMRI signal cannot differentiate between neural excitation and inhibition or function-specific neural processing. Many studies have small sample sizes and did not control for the heterogeneity of this clinical population. We suggest that with robust study design, subgrouping and larger sample sizes, future neuroimaging studies could potentially lead to a breakthrough in our understanding of the disease.

Cortical ischaemic patterns in term partial-prolonged hypoxic-ischaemic injury-the inter-arterial watershed demonstrated through atrophy, ulegyria and signal change on delayed MRI scans in children with cerebral palsy.

The inter-arterial watershed zone in neonates is a geographic area without discernible anatomic boundaries and difficult to demarcate and usually not featured in atlases. Schematics currently used to depict the areas are not based on any prior anatomic mapping, compared to adults.Magnetic resonance imaging (MRI) of neonates in the acute to subacute phase with suspected hypoxic-ischaemic injury (HII) can demonstrate signal abnormality and restricted diffusion in the cortical and subcortical parenchyma of the watershed regions.In the chronic stage of partial-prolonged hypoxic-ischaemic injury, atrophy and ulegyria can make the watershed zone more conspicuous as a region. Our aim is to use images extracted from a sizable medicolegal database (approximately 2000 cases), of delayed MRI scans in children with cerebral palsy, to demonstrate the watershed region.To achieve this, we have selected cases diagnosed on imaging as having sustained a term pattern of partial-prolonged HII affecting the hemispheric cortex, based on the presence of bilateral, symmetric atrophy with ulegyria. From these, we have identified those patients demonstrating injury along the whole watershed continuum as well as those demonstrating selective anterior or posterior watershed predominant injury for demonstration.Recognition of this zone is essential for diagnosing partial-prolonged hypoxic-ischaemic injury sustained in term neonates. The images presented in this pictorial review provide a template for identifying the cortical watershed distribution when there is milder regional (anterior, parasagittal, peri-Sylvian and posterior) watershed injury and for more severe injury where multiple regions are injured in combination or as a continuum.

Technical report: 3D printing of the brain for use as a visual-aid tool to communicate MR imaging features of hypoxic ischaemic injury at term with non-physicians.

3D printing has been used in several medical applications. There are no reports however of 3D printing of the brain in children for demonstrating pathology to non-medical professionals such as lawyers. We printed 3D models of the paediatric brain from volumetric MRI in cases of severe and moderate hypoxic ischaemic injury as well as a normal age matched control, as follows: MRI DICOM data was converted to NifTI (Neuroimaging Informatics Technology Initiative) format; segmentation of the brain into CSF, grey, and white matter was performed; the segmented data was converted to STL format and printed on a commercially available scanner. The characteristic volume loss and surface features of hypoxic ischaemic injury are visible in these models, which could be of value in the communication of the nature and severity of such an insult in a court setting as they can be handled and viewed from up close.

Determination of retinal surface area.

Previous attempts at determining retinal surface area and surface area of the whole eye have been based upon mathematical calculations derived from retinal photographs, schematic eyes and retinal biopsies of donor eyes. 3-dimensional (3-D) ocular magnetic resonance imaging (MRI) allows a more direct measurement, it can be used to image the eye in vivo, and there is no risk of tissue shrinkage. The primary purpose of this study is to compare, using T2-weighted 3D MRI, retinal surface areas for superior-temporal (ST), inferior-temporal (IT), superior-nasal (SN) and inferior-nasal (IN) retinal quadrants. An ancillary aim is to examine whether inter-quadrant variations in area are concordant with reported inter-quadrant patterns of susceptibility to retinal breaks associated with posterior vitreous detachment (PVD). Seventy-three adult participants presenting without retinal pathology (mean age 26.25 ± 6.06 years) were scanned using a Siemens 3-Tesla MRI scanner to provide T2-weighted MR images that demarcate fluid-filled internal structures for the whole eye and provide high-contrast delineation of the vitreous-retina interface. Integrated MRI software generated total internal ocular surface area (TSA). The second nodal point was used to demarcate the origin of the peripheral retina in order to calculate total retinal surface area (RSA) and quadrant retinal surface areas (QRSA) for ST, IT, SN, and IN quadrants. Mean spherical error (MSE) was -2.50 ± 4.03D and mean axial length (AL) 24.51 ± 1.57 mm. Mean TSA and RSA for the RE were 2058 ± 189 and 1363 ± 160 mm2 , respectively. Repeated measures anova for QRSA data indicated a significant difference within-quadrants (P < 0.01) which, contrasted with ST (365 ± 43 mm2 ), was significant for IT (340 ± 40 mm2 P < 0.01), SN (337 ± 40 mm2 P < 0.01) and IN (321 ± 39 mm2 P < 0.01) quadrants. For all quadrants, QRSA was significantly correlated with AL (P < 0.01) and exhibited equivalent increases in retinal area/mm increase in AL. Although the differences between QRSAs are relatively small, there was evidence of concordance with reported inter-quadrant patterns of susceptibility to retinal breaks associated with PVD. The data allow AL to be converted to QRSAs, which will assist further work on inter-quadrant structural variation.

Curved reformat of the paediatric brain MRI into a 'flat-earth map' - standardised method for demonstrating cortical surface atrophy resulting from hypoxic-ischaemic encephalopathy.

Hypoxic-ischaemic encephalopathy is optimally imaged with brain MRI in the neonatal period. However neuroimaging is often also performed later in childhood (e.g., when parents seek compensation in cases of alleged birth asphyxia). We describe a standardised technique for creating two curved reconstructions of the cortical surface to show the characteristic surface changes of hypoxic-ischaemic encephalopathy in children imaged after the neonatal period. The technique was applied for 10 cases of hypoxic-ischaemic encephalopathy and also for age-matched healthy children to assess the visibility of characteristic features of hypoxic-ischaemic encephalopathy. In the abnormal brains, fissural or sulcal widening was seen in all cases and ulegyria was identifiable in 7/10. These images could be used as a visual aid for communicating MRI findings to clinicians and other interested parties.

Contradictory reasoning network: an EEG and FMRI study.

Contradiction is a cornerstone of human rationality, essential for everyday life and communication. We investigated electroencephalographic (EEG) and functional magnetic resonance imaging (fMRI) in separate recording sessions during contradictory judgments, using a logical structure based on categorical propositions of the Aristotelian Square of Opposition (ASoO). The use of ASoO propositions, while controlling for potential linguistic or semantic confounds, enabled us to observe the spatial temporal unfolding of this contradictory reasoning. The processing started with the inversion of the logical operators corresponding to right middle frontal gyrus (rMFG-BA11) activation, followed by identification of contradictory statement associated with in the right inferior frontal gyrus (rIFG-BA47) activation. Right medial frontal gyrus (rMeFG, BA10) and anterior cingulate cortex (ACC, BA32) contributed to the later stages of process. We observed a correlation between the delayed latency of rBA11 response and the reaction time delay during inductive vs. deductive reasoning. This supports the notion that rBA11 is crucial for manipulating the logical operators. Slower processing time and stronger brain responses for inductive logic suggested that examples are easier to process than general principles and are more likely to simplify communication.

Dynamic facial expressions evoke distinct activation in the face perception network: a connectivity analysis study.

Very little is known about the neural structures involved in the perception of realistic dynamic facial expressions. In the present study, a unique set of naturalistic dynamic facial emotional expressions was created. Through fMRI and connectivity analysis, a dynamic face perception network was identified, which is demonstrated to extend Haxby et al.'s [Haxby, J. V., Hoffman, E. A., & Gobbini, M. I. The distributed human neural system for face perception. Trends in Cognitive Science, 4, 223-233, 2000] distributed neural system for face perception. This network includes early visual regions, such as the inferior occipital gyrus, which is identified as insensitive to motion or affect but sensitive to the visual stimulus, the STS, identified as specifically sensitive to motion, and the amygdala, recruited to process affect. Measures of effective connectivity between these regions revealed that dynamic facial stimuli were associated with specific increases in connectivity between early visual regions, such as the inferior occipital gyrus and the STS, along with coupling between the STS and the amygdala, as well as the inferior frontal gyrus. These findings support the presence of a distributed network of cortical regions that mediate the perception of different dynamic facial expressions.

Disconnected brains: what is the role of fMRI in connectivity research?

In this paper we consider how functional Magnetic Resonance Imaging (fMRI) has been used to study cortical connectivity in autism and autistic spectrum disorders (ASD). We discuss those studies that have contributed to the evidence supporting a model of disordered cortical connectivity in autism and (ASD), with a focusing emphasis on the application to research into the underconnectivity model. We note that the analytical techniques employed are limited and do not allow interpretation in terms of effective, or directional connectivity, nor do they provide information about the temporal or spectral characteristics of the functional networks being studied. We highlight how currently the features of neural generators that are being assessed by functional connectivity in fMRI are unclear. In addition, we note the importance in clinical studies of considering the consequences of task choice for the nature of the imaging data that can be collected and also of individual differences in participant state and trait characteristics for the accurate interpretation of imaging data. We discuss how alternative techniques such as EEG/MEG may address the limitations of fMRI in assessing brain connectivity, and additionally consider the potential of multimodal approaches. We conclude that fMRI has made significant contributions towards our understanding of the brain in terms of neural systems but that the conclusions drawn from its application in the sphere of autism research need to be approached with caution. It is important in research of this kind that we are aware of the need to examine the methodological and analytical techniques closely when applying findings in clinical populations, not only when they are used to support the development of theoretical models but also to inform diagnostic or treatment decisions.

Interhemispheric differences of spectral power in expressive language: a MEG study with clinical applications.

In the last decade we have seen an exponential growth of functional imaging studies investigating multiple aspects of language processing. These studies have sparked an interest in applying some of the paradigms to various clinically relevant questions, such as the identification of the cortical regions mediating language function in surgical candidates for refractory epilepsy. Here we present data from a group of adult control participants in order to investigate the potential of using frequency specific spectral power changes in MEG activation patterns to establish lateralisation of language function using expressive language tasks. In addition, we report on a paediatric patient whose language function was assessed before and after a left hemisphere amygdalo-hippocampectomy. Our verb generation task produced left hemisphere decreases in beta-band power accompanied by right hemisphere increases in low beta-band power in the majority of the control group, a previously unreported phenomenon. This pattern of spectral power was also found in the patient's post-surgery data, though not her pre-surgery data. Comparison of pre and post-operative results also provided some evidence of reorganisation in language related cortex both inter- and intra-hemispherically following surgery. The differences were not limited to changes in localisation of language specific cortex but also changes in the spectral and temporal profile of frontal brain regions during verb generation. While further investigation is required to establish concordance with invasive measures, our data suggest that the methods described may serve as a reliable lateralisation marker for clinical assessment. Furthermore, our findings highlight the potential utility of MEG for the investigation of cortical language functioning in both healthy development and pathology.