MS is a disease characterised by demyelination of the central nervous system resulting in decreased quality of life, increased anxiety, depression, fatigue, and cognitive dysfunction. Attention is frequently impaired in MS. A previous study demonstrated impairment specifically in the attentional alerting domain. However, this study did not establish whether the impairment was in intrinsic or extrinsic alertness, and did not examine the neural substrates associated with the impairment. To examine the alerting deficit in MS and establish the associated neural substrates, 40 female patients with MS and 40 age and gender match controls completed an alertness-motor paradigm designed to test both intrinsic and extrinsic alertness during functional magnetic resonance imaging. We found the MS group had a significant deficit in extrinsic alertness, which was associated with a lack of dorsal prefrontal cortex (DPFC) activation. In addition, reduced gray matter volume in the dorsal prefrontal cortex, thalamus, and basal ganglia were observed. Both fMRI and VBM correlations were observed between fatigue severity scale (FSS) scores and the DPFC. The combined results of our functional and structural MRI data analysis demonstrate that attention deficits in females with MS are a result of the complex relationship between brain tissue loss having a significant impact on functional brain regions subserving executive control of cognitive functions. Understanding the underlying mechanisms of cognitive performance and how they relate to fatigue are crucial to developing novel treatments for the symptoms of MS.

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.

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. To assess the effect of pump therapy on quality of life, mood, functional neuroimaging, behavioural/cognitive responses, sleep and metabolism. 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. 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. These findings support the administration of hormone therapy that mimics physiology.

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.

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.

Abstract Aims To investigate whether there are functional brain differences, or differences in global network measures, between patients with acute coronary syndrome (ACS) and non-obstructive coronary arteries and patients with an ST-elevation myocardial infarction (STEMI) and healthy controls. Methods and results In this single centre, prospective cohort study, all patients <80 years who presented to a tertiary cardiac centre with a suspected acute coronary syndrome and who had non-obstructive coronary arteries on invasive angiography were approached for inclusion. Age and sex matched patients presenting with a STEMI and a further group of healthy volunteers were recruited as control groups. All patients received routine clinical care and investigations and underwent additional psychological questionnaires, cardiac magnetic resonance imaging and functional brain imaging within 14 days of admission. Image pre-processing and analysis was undertaken in a blinded fashion. 72 participants, in addition to 27 STEMI controls and 28 healthy controls, were recruited. Median age in the participant group was 57 years (IQR 47–66 years) and patients were scanned 6 days (IQR 3–8 days) from admission. Patients with ACS and non-obstructive arteries had increased functional connectivity in the default mode network and reduced connectivity in the central executive network compared to controls (Figure 1). They also had higher anxiety scores compared to STEMI and healthy controls and higher depression and stress scores compared to healthy controls (Figure 2). There was no difference in any global network measure between participants and age and sex matched controls however high anxiety or stress scores were associated with lower global efficiency in patients with ACS and non-obstructive coronary arteries but not in controls (Figure 2). Conclusion Patients with ACS and non-obstructive coronary arteries are distinct from both the STEMI and healthy population in terms of their psychological and neurofunctional state and this may have important future therapeutic implications for patients. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): James Tudor FoundationRosetrees Trust

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.

Adrenal glucocorticoid secretion into the systematic circulation is characterised by a complex rhythm, composed of the diurnal variation, formed by changes in pulse amplitude of an underlying ultradian rhythm of short duration hormonal pulses. To elucidate the potential neurobiological significance of glucocorticoid pulsatility in man, we have conducted a randomised, double-blind, placebo-controlled, three-way crossover clinical trial on 15 healthy volunteers, investigating the impact of different glucocorticoid rhythms on measures of mood and neural activity under resting conditions by recruiting functional neuroimaging, computerised behavioural tests and ecological momentary assessments. Endogenous glucocorticoid biosynthesis was pharmacologically suppressed, and plasma levels of corticosteroid restored by hydrocortisone replacement in three different regimes, either mimicking the normal ultradian and circadian profile of the hormone, or retaining the normal circadian but abolishing the ultradian rhythm of the hormone, or by our current best oral replacement regime which results in a suboptimal circadian and ultradian rhythm. Our results indicate that changes in the temporal mode of glucocorticoid replacement impact (i) the morning levels of self-perceived vigour, fatigue and concentration, (ii) the diurnal pattern of mood variation, (iii) the within-network functional connectivity of various large-scale resting state networks of the human brain, (iv) the functional connectivity of the default-mode, salience and executive control networks with glucocorticoid-sensitive nodes of the corticolimbic system, and (v) the functional relationship between mood variation and underlying neural networks. The findings indicate that the pattern of the ultradian glucocorticoid rhythm could affect cognitive psychophysiology under non-stressful conditions and opens new pathways for our understanding on the neuropsychological effects of cortisol pulsatility with relevance to the goal of optimising glucocorticoid replacement strategies.

BackgroundDrugs 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.MethodsIn 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.FindingsBetween 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.Interpretation12 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.FundingEfficacy and Mechanism Evaluation Programme (UK Medical Research Council and National Institute for Health Research).

Background: Medications that modify the renin–angiotensin system may reduce Alzheimer’s disease pathology and reduce the rate of disease progression. Objective: This study investigated whether taking the antihypertensive drug losartan, in addition to normal care, would slow the progression of Alzheimer’s disease when compared with a placebo. Design: A double-blind multicentre randomised controlled trial, after a 4-week open-label phase, with follow-up at 14 days and at 3, 6, 9 and 12 months. The primary outcome was based on measured imaging differences in brain volume between baseline and 12 months. Setting: Twenty-three NHS hospital trusts across England, Scotland and Northern Ireland. Participants: Patients diagnosed with mild-to-moderate Alzheimer’s disease were eligible to participate if they met the following criteria: (1) aged ≥ 55 years; (2) a Mini Mental State Examination score of 15–28; (3) a modified Hachinski Ischaemic Score of ≤ 5; (4) a previous computerised tomography, single-photon emission computed tomography or magnetic resonance imaging scan consistent with a diagnosis of Alzheimer’s disease; (5) a study companion who was willing to participate in the study; and (6) capacity to consent for themselves. Patients were ineligible if they were (1) taking or intolerant to renin–angiotensin system-related medications, (2) unlikely to undergo magnetic resonance imaging or (3) unlikely to complete the trial protocol. People who had blood pressure outside the normal ranges, defined cardiovascular issues, impaired liver or renal function, or a primary neurodegenerative disease that was not Alzheimer’s disease were also excluded, as were women who had not reached menopause and were unwilling to take relevant protocol-specific safety precautions. Intervention: The intervention was either 100 mg of overencapsulated losartan (Teva Pharmaceuticals Industries Ltd, Petah Tikva, Israel) daily or a matched placebo for 12 months. Main outcome measures: Difference in brain atrophy, represented by measurement of whole-brain volume before and following 12 months of treatment post randomisation, was measured using volumetric MRI and determined by boundary shift interval analysis. Secondary outcomes included changes in rates of Alzheimer’s disease progression (as assessed using the ADAS-Cog, Mini Mental State Examination and Neuropsychiatric Inventory), the volume of white matter hyperintensities, cerebral blood flow (assessed by magnetic resonance imaging), blood pressure, magnetic resonance imaging measures of atrophy and association with measures of cognitive decline, and drug compliance and tolerability. Results: A total of 261 participants entered the open-label phase, of whom 211 were randomised to the intervention (n = 105) or placebo (n = 106) arms. Of the 197 people (93%) who completed the study, 81% (n = 171) had a valid primary outcome. The difference in brain volume between arms was consistent with chance (–2.79 ml, 95% confidence interval –6.46 to 0.89 ml; p = 0.19), and there was no evidence of benefit for any of the secondary outcome measures. Limitations: Our study had 82% power to detect treatment-based changes and, as a result, may have been underpowered or, more likely, the intervention, which may not have crossed the blood–brain barrier as much as expected, may have been given too late or for an insufficient amount of time in the disease process to influence the outcomes. Conclusions: Losartan administered over 12 months did not alter brain atrophy in Alzheimer’s disease. Future work: Other related ‘sartans’ could be tested in patient groups with mild cognitive impairment and for longer to fully test this hypothesis. Trial registration: Current Controlled Trials ISRCTN93682878 and EudraCT 2012-003641-15. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 19. See the NIHR Journals Library website for further project information.

The ceramic coatings on the surface of aluminum alloy substrates with micro-grooves have been successfully fabricated in the silicate solution via micro-arc oxidation (MAO) approach. Microstructure characterization showed that the larger main discharge channels were located in the center of micro-groove, the smaller secondary discharge channels were located on both sides of main discharge channel; and a few irregular micro-pores existed in the vicinity of all discharge channels, which were mainly cause by the rapid cooling and solidification of discharge channels hindering the removal of gases produced via reaction. Moreover, the growing direction of coating in the initial stage was mainly outward-growth and resulted in the formation of inverted triangle coating structure, which was due to the sharp-angled effect. But in the final growing stage, the inward-growth behavior played a key role owing to the spark transfer. According to above results and discussion, the formation of smooth, uniform and homogeneous ceramic coating on the surface of whole trapezoidal micro-groove substrate contained four stages: anodic oxidation growth, sharp corner rapid growth, coating homogenization and groove self-filling.

In this study, we employed a visuo-motor imagery task of alertness as a mental training to examine temporal processing of motor responses within healthy young adults. Participants were divided into two groups (group 1; n = 20 who performed the mental training before the real physical task and a control group who performed the physical task without mental training). We vary the time interval between the imperative stimulus and the preceding one (fore-period) in which temporal preparation and arousal increase briefly. Our behavioural results provide clear evidence that mental training reinforces both temporal preparation and arousal, by shortening reaction time (RT), especially for the shortest fore-periods (FP) within exogenous "FP 250 ms" (p = 0.008) and endogenous alertness "FP 650 ms" (p = 0.001). We investigated how the brain controls such small temporal changes. We focus our neural hypothesis on three brain regions: anterior insula, dorsolateral prefrontal cortex, and anterior cingulate cortex and three putative circuits: one top-down (from dorsolateral prefrontal cortex to anterior cingulate cortex) and two bottom-up (from anterior insula to dorsolateral prefrontal cortex and anterior cingulate cortex). In fMRI, effective connectivity is strengthened during exogenous alertness between anterior insula and dorsolateral prefrontal cortex (p = 0.001), between anterior insula and cingulate cortex (p = 0.01), and during endogenous alertness between dorsolateral prefrontal cortex and anterior cingulate cortex (p = 0.05). We suggest that attentional reinforcement induced by an intensive and short session of mental training induces a temporal deployment of attention and allow optimizing the time pressure by maintaining a high state of arousal and ameliorating temporal preparation.

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.

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.

Myocardial infarction with non-obstructive coronary arteries (MINOCA) is seen in 6–10% of patients presenting acutely with suspected myocardial infarction. Cardiac magnetic resonance imaging (CMR) can identify an underlying cause in ∼80% of patients. These patients are more likely to have a history of mental health illness or an emotional or stressful precipitant. Grey matter volume can be quantified in various anatomical regions of the brain and has been shown to be altered in common mental health conditions such as anxiety, stress and depression. This is the first prospective study investigating the acute structural brain, cardiac and psychological changes using MRI in patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) within 14 days of presentation compared to STEMI control patients. Patients meeting the 2017 ESC definition of MINOCA were prospectively recruited with STEMI control patients from February to December 2019. All participants underwent brain and comprehensive cardiac MRI, bloods and baseline psychological evaluation. We used voxel-based morphometry (VBM) to quantify grey matter volume and changes were compared between groups. 54 patients were included in this interim analysis (39 MINOCA, 15 STEMI controls). Demographics were largely similar but MINOCA patients were more likely to have a history of self-reported mental health disease (36% v 7%, p 0.03) and had significantly higher baseline anxiety (8.4 v 5.3, p 0.01) scores on the HADS questionnaire. We found that control patients have significantly greater grey matter volume in the orbitofrontal cortex (OFC) compared to MINOCA patients (pFWE-corr 0.002). The orbitofrontal cortex is involved in emotional processing and implicated in anxiety and depression. However, there was no association between grey matter volume in any brain region and anxiety, depression or perceived stress scale scores. Patients with MINOCA are more likely to have a history of mental health disease and have higher anxiety scores at presentation than STEMI controls. They have less grey matter volume in the orbitofrontal cortex compared to STEMI controls. Reduced Grey Matter Volume in the OFC Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Rosetrees Trust; James Tudor Foundation

Altered insight into disease or specific symptoms is a prominent clinical feature of frontotemporal dementia (FTD). Understanding the neural bases of insight is crucial to help improve FTD diagnosis, classification and management. A systematic review to explore the neural correlates of altered insight in FTD and associated syndromes was conducted. Insight was fractionated to examine whether altered insight into different neuropsychological/behavioural objects is underpinned by different or compatible neural correlates. 6 databases (Medline, Embase, PsycINFO, Web of Science, BIOSIS and ProQuest Dissertations & Theses Global) were interrogated between 1980 and August 2019. 15 relevant papers were found out of 660 titles screened. The studies included suggest that different objects of altered insight are associated with distinctive brain areas in FTD. For example, disease unawareness appears to predominantly correlate with right frontal involvement. In contrast, altered insight into social cognition potentially involves, in addition to frontal areas, the temporal gyrus, insula, parahippocampus and amygdala. Impaired insight into memory problems appears to be related to the frontal lobes, postcentral gyrus, parietal cortex and posterior cingulate. These results reflect to a certain extent those observed in other neurodegenerative conditions like Alzheimer's disease (AD) and also other brain disorders. Nevertheless, they should be cautiously interpreted due to variability in the methodological aspects used to reach those conclusions. Future work should triangulate different insight assessment approaches and brain imaging techniques to increase the understanding of this highly relevant clinical phenomenon in dementia.