Brain charts for the human lifespan.

Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.

Antenatal care of women who use opioids: a qualitative study of practitioners' perceptions of strengths and challenges of current service provision in Scotland.

BACKGROUND: The increasing rise of women using opioids during pregnancy across the world has warranted concern over the access and quality of antenatal care received by this group. Scotland has particularly high levels of opioid use, and correspondingly, pregnancies involving women who use opioids. The purpose of this study was to investigate the different models of antenatal care for women using opioids during pregnancy in three Scottish Health Board Areas, and to explore multi-disciplinary practitioners' perceptions of the strengths and challenges of working with women who use opioids through these specialist services. METHODS: Thirteen semi-structured interviews were conducted with health and social care workers who had experience of providing antenatal and postnatal care to women who use drugs across three Scottish Health Board Areas: NHS Greater Glasgow and Clyde, NHS Lothian, and NHS Tayside. Framework Analysis was used to analyse interview data. The five stages of framework analysis were undertaken: familiarisation, identifying the thematic framework, indexing, charting, and mapping and interpretation. RESULTS: Each area had a specialist antenatal pathway for women who used substances. Pathways varied, with some consisting of specialist midwives, and others comprising a multidisciplinary team (e.g. midwife, mental health nurse, social workers, and an obstetrician). Referral criteria for the specialist service differed between health board areas. These specialised pathways presented several key strengths: continuity of care with one midwife and a strong patient-practitioner relationship; increased number of appointments, support and scans; and highly specialised healthcare professionals with experience of working with substance use. In spite of this, there were a number of limitations to these pathways: a lack of additional psychological support for the mother; some staff not having the skills to engage with the complexity of patients who use substances; and problems with patient engagement. CONCLUSIONS: Across the three areas, there appears to be high-quality multi-disciplinary antenatal services for women who use opioids during pregnancy. However, referral criteria vary and some services appear more comprehensive than others. Further research is needed into the perceptions of women who use opioids on facilitators and barriers to antenatal care, and provision in rural regions of Scotland.

Developing a core outcome set for clinical trials in olfactory disorders: a COMET initiative.

STATEMENT OF PROBLEM: Evaluating the effectiveness of the management of Olfactory Dysfunction (OD) has been limited by a paucity of high-quality randomised and/or controlled trials. A major barrier is heterogeneity of outcomes in such studies. Core outcome sets (COS) - standardized sets of outcomes that should be measured/reported as determined by consensus-would help overcome this problem and facilitate future meta-analyses and/or systematic reviews (SRs). We set out to develop a COS for interventions for patients with OD. METHODS: A long-list of potential outcomes was identified by a steering group utilising a literature review, thematic analysis of a wide range of stakeholders' views and systematic analysis of currently available Patient Reported Outcome Measures (PROMs). A subsequent e-Delphi process allowed patients and healthcare practitioners to individually rate the outcomes in terms of importance on a 9-point Likert scale. RESULTS: After 2 rounds of the iterative eDelphi process, the initial outcomes were distilled down to a final COS including subjective questions (visual analogue scores, quantitative and qualitative), quality of life measures, psychophysical testing of smell, baseline psychophysical testing of taste, and presence of side effects along with the investigational medicine/device and patient's symptom log. CONCLUSIONS: Inclusion of these core outcomes in future trials will increase the value of research on clinical interventions for OD. We include recommendations regarding the outcomes that should be measured, although future work will be required to further develop and revalidate existing outcome measures.

Severe maternal morbidity in Scotland.

Using a cohort study design, we analysed 17 diagnoses and 9 interventions (including critical care admission) as a composite measure of severe maternal morbidity for pregnancies recorded over 14 years in Scotland. There were 762,918 pregnancies, of which 7947 (10 in 1000 pregnancies) recorded 9345 severe maternal morbidity events, 2802 episodes of puerperal sepsis being the most common (30%). Severe maternal morbidity incidence increased from 9 in 1000 pregnancies in 2012 to 17 in 1000 pregnancies in 2018, due in part to puerperal sepsis recording. The odds ratio (95%CI) for severe maternal morbidity was higher for: older women, for instance 1.22 (1.13-1.33) for women aged 35-39 years and 1.44 (1.27-1.63) for women aged > 40 years compared with those aged 25-29 years; obese women, for instance 1.13 (1.06-1.21) for BMI 30-40 kg.m-2 and 1.32 (1.15-1.51) for BMI > 40 kg.m-2 compared with BMI 18.5-24.9 kg.m-2 ; multiple pregnancy, 2.39 (2.09-2.74); and previous caesarean delivery, 1.52 (1.40-1.65). The median (IQR [range]) hospital stay was 3 (2-5 [1-8]) days with severe maternal morbidity and 2 (1-3 [1-5]) days without. Forty-one women died during pregnancy or up to 42 days after delivery, representing mortality rates per 100,000 pregnancies of about 365 with severe maternal morbidity and 1.6 without. There were 1449 women admitted to critical care, 807 (58%) for mechanical ventilation or support of at least two organs. We recorded an incidence of severe maternal morbidity higher than previously published, possibly because sepsis was coded inaccurately in our databases. Further research may determine the value of this composite measure of severe maternal morbidity.

The COVANOS trial - insight into post-COVID olfactory dysfunction and the role of smell training.

BACKGROUND: Olfactory dysfunction is a cardinal symptom of COVID-19 infection, however, studies assessing long-term olfactory dysfunction are limited and no randomised-controlled trials (RCTs) of early olfactory training have been conducted. METHODOLOGY: We conducted a prospective, multi-centre study consisting of baseline psychophysical measurements of smell and taste function. Eligible participants were further recruited into a 12-week RCT of olfactory training versus control (safety information). Patient-reported outcomes were measured using an electronic survey and BSIT at baseline and 12 weeks. An additional 1-year follow-up was open to all participants. RESULTS: 218 individuals with a sudden loss of sense of smell of at least 4-weeks were recruited. Psychophysical smell loss was observed in only 32.1%; 63 participants were recruited into the RCT. The absolute difference in BSIT improvement after 12 weeks was 0.45 higher in the intervention arm. 76 participants completed 1-year follow-up; 10/19 (52.6%) of participants with an abnormal baseline BSIT test scored below the normal threshold at 1-year, and 24/29 (82.8%) had persistent parosmia. CONCLUSIONS: Early olfactory training may be helpful, although our findings are inconclusive. Notably, a number of individuals who completed the 1-year assessment had persistent smell loss and parosmia at 1-year. As such, both should be considered important entities of long-Covid and further studies to improve management are highly warranted.

Invited Review: Factors associated with atypical brain development in preterm infants: insights from magnetic resonance imaging.

Preterm birth (PTB) is a leading cause of neurodevelopmental and neurocognitive impairment in childhood and is closely associated with psychiatric disease. The biological and environmental factors that confer risk and resilience for healthy brain development and long-term outcome after PTB are uncertain, which presents challenges for risk stratification and for the discovery and evaluation of neuroprotective strategies. Neonatal magnetic resonance imaging reveals a signature of PTB that includes dysconnectivity of neural networks and atypical development of cortical and deep grey matter structures. Here we provide a brief review of perinatal factors that are associated with the MRI signature of PTB. We consider maternal and foetal factors including chorioamnionitis, foetal growth restriction, socioeconomic deprivation and prenatal alcohol, drug and stress exposures; and neonatal factors including co-morbidities of PTB, nutrition, pain and medication during neonatal intensive care and variation conferred by the genome/epigenome. Association studies offer the first insights into pathways to adversity and resilience after PTB. Future challenges are to analyse quantitative brain MRI data with collateral biological and environmental data in study designs that support causal inference, and ultimately to use the output of such analyses to stratify infants for clinical trials of therapies designed to improve outcome.

Posterior reversible encephalopathy syndrome in liver transplant patients: clinical presentation, risk factors and initial management.

Posterior reversible encephalopathy syndrome (PRES) is an uncommon but well-known complication after transplantation diagnosed by characteristic radiological features. As limited data on this complex syndrome exist we sought to better define the incidence, clinical presentation and risk factors for PRES in liver transplant (LTx) patients. We conducted a retrospective analysis of 1923 adult LTx recipients transplanted between 2000 and 2010. PRES was diagnosed radiologically in 19 patients (1%), with 84% of cases occurring within 3 months post-LTX. We compared this cohort of PRES patients to 316 other LTx recipients also requiring radiographic imaging within 3 months after LTx for neurological symptoms. Seizure was the most common clinical manifestation in the PRES group (88% vs. 16%, p< 0.001) and 31% had an intracranial hemorrhage. Those with hemorrhage on imaging were more likely to be coagulopathic. PRES patients were significantly more likely to have had alcoholic liver disease and infection/sepsis. These factors may be related to a common pathway of vascular dysregulation/damage that appears to characterize this complex syndrome. Intracranial bleeding and seizures may be the end result of these phenomena. The relationship of these associated factors to the hypothesized pathophysiology of PRES is discussed.

A common neonatal image phenotype predicts adverse neurodevelopmental outcome in children born preterm.

Diffuse white matter injury is common in preterm infants and is a candidate substrate for later cognitive impairment. This injury pattern is associated with morphological changes in deep grey nuclei, the localization of which is uncertain. We test the hypotheses that diffuse white matter injury is associated with discrete focal tissue loss, and that this image phenotype is associated with impairment at 2years. We acquired magnetic resonance images from 80 preterm infants at term equivalent (mean gestational age 29(+6)weeks) and 20 control infants (mean GA 39(+2)weeks). Diffuse white matter injury was defined by abnormal apparent diffusion coefficient values in one or more white matter region (frontal, central or posterior white matter at the level of the centrum semiovale), and morphological difference between groups was calculated from 3D images using deformation based morphometry. Neurodevelopmental assessments were obtained from preterm infants at a mean chronological age of 27.5months, and from controls at a mean age of 31.1months. We identified a common image phenotype in 66 of 80 preterm infants at term equivalent comprising: diffuse white matter injury; and tissue volume reduction in the dorsomedial nucleus of the thalamus, the globus pallidus, periventricular white matter, the corona radiata and within the central region of the centrum semiovale (t=4.42 p<0.001 false discovery rate corrected). The abnormal image phenotype is associated with reduced median developmental quotient (DQ) at 2years (DQ=92) compared with control infants (DQ=112), p<0.001. These findings indicate that specific neural systems are susceptible to maldevelopment after preterm birth, and suggest that neonatal image phenotype may serve as a useful biomarker for studying mechanisms of injury and the effect of putative therapeutic interventions.

Provider bias as a function of patient genotype: polygenic score analysis among diabetics from the Health and Retirement Study.

OBJECTIVE: Poor patient-provider interactions due to provider bias are associated with worse physiological and behavioural health outcomes for patients. Prior research has shown that patients with obesity perceive less favourable interactions compared with those with lower weights. This paper explores whether this association depends on patients' cumulative polygenic score with respect to genes linked to obesity (i.e. a single variable quantifying the individual's genome-wide risk factors for high body mass index [BMI] or genetic liability) and whether providers react differentially to patients whose obesity is more genetic in nature compared with patients with diabetes caused by environmental factors. METHODS: The association between patients' BMI category, their polygenic score for high BMI and their interaction was assessed for two measures of the patient-provider interaction within a sample of 521 older patients with diabetes from the Health and Retirement Study. RESULTS: Particularly for patients with obesity, the quality of the patient-provider interaction depended on genetic liability for high BMI controlling for demographic and clinical covariates. Providers responded less favourably to patients with diabetes influenced by environmental factors compared with individuals with high genetic liability. CONCLUSIONS: Results of this study suggest that a patient's genotype may elicit particular responses from their healthcare provider. When a provider judges a patient's high BMI to be environmentally driven rather than genetically oriented, patients receive reduced quality of care.

Distinct imaging patterns and lesion distribution in posterior reversible encephalopathy syndrome.

BACKGROUND AND PURPOSE: Although the term posterior reversible encephalopathy syndrome (PRES) was popularized because of the typical presence of vasogenic edema in the parietal and occipital lobes, other regions of the brain are also frequently affected. We evaluated lesion distribution with CT and MR in a large cohort of patients who experienced PRES to comprehensively assess the imaging patterns identified. MATERIALS AND METHODS: The locations of the PRES lesion at toxicity were comprehensively identified and tabulated in 136 patients by CT (22 patients) and MR (114 patients) imaging including the hemispheric, basal ganglial, and infratentorial locations. Clinical associations along with presentation at toxicity including blood pressure were assessed. RESULTS: Vasogenic edema was consistently present in the parietal or occipital regions (98%), but other locations were common including the frontal lobes (68%), inferior temporal lobes (40%), and cerebellar hemispheres (30%). Involvement of the basal ganglia (14%), brain stem (13%), and deep white matter (18%) including the splenium (10%) was not rare. Three major patterns of PRES were noted: the holohemispheric watershed (23%), superior frontal sulcal (27%), and dominant parietal-occipital (22%), with additional common partial or asymmetric expression of these primary PRES patterns (28%). CONCLUSION: Involvement of the frontal lobe, temporal lobe, and cerebellar hemispheres is common in PRES, along with the occasional presence of lesions in the brain stem, basal ganglia, deep white matter, and splenium. Three primary PRES patterns are noted in the cerebral hemispheres, along with frequent partial or asymmetric expression of these PRES patterns. Awareness of these patterns and variations is important to recognize PRES neurotoxicity more accurately when present.

Brain Development in Fetuses of Mothers with Diabetes: A Case-Control MR Imaging Study.

BACKGROUND AND PURPOSE: Offspring exposed to maternal diabetes are at increased risk of neurocognitive impairment, but its origins are unknown. With MR imaging, we investigated the feasibility of comprehensive assessment of brain metabolism (1H-MRS), microstructure (DWI), and macrostructure (structural MRI) in third-trimester fetuses in women with diabetes and determined normal ranges for the MR imaging parameters measured. MATERIALS AND METHODS: Women with singleton pregnancies with diabetes (n = 26) and healthy controls (n = 26) were recruited prospectively for MR imaging studies between 34 and 38 weeks' gestation. RESULTS: Data suitable for postprocessing were obtained from 79%, 71%, and 46% of women for 1H-MRS, DWI, and structural MRI, respectively. There was no difference in the NAA/Cho and NAA/Cr ratios (mean [SD]) in the fetal brain in women with diabetes compared with controls (1.74 [0.79] versus 1.79 [0.64], P = .81; and 0.78 [0.28] versus 0.94 [0.36], P = .12, respectively), but the Cho/Cr ratio was marginally lower (0.46 [0.11] versus 0.53 [0.10], P = .04). There was no difference in mean [SD] anterior white, posterior white, and deep gray matter ADC between patients and controls (1.16 [0.12] versus 1.16 [0.08], P = .96; 1.54 [0.16] versus 1.59 [0.20], P = .56; and 1.49 [0.23] versus 1.52 [0.23], P = .89, respectively) or volume of the cerebrum (243.0 mL [22.7 mL] versus 253.8 mL [31.6 mL], P = .38). CONCLUSIONS: Acquiring multimodal MR imaging of the fetal brain at 3T from pregnant women with diabetes is feasible. Further study of fetal brain metabolism in maternal diabetes is warranted.

Posterior reversible encephalopathy syndrome in infection, sepsis, and shock.

BACKGROUND AND PURPOSE: The cause of "posterior reversible encephalopathy syndrome" (PRES) is not established. We recently encountered several patients who developed PRES in the setting of severe infection. In this study, we comprehensively reviewed the clinical and imaging features in a large cohort of patients who developed PRES, with particular attention to those with isolated infection, sepsis, or shock (I/S/S). METHODS: The clinical/imaging features of 106 patients who developed PRES were comprehensively evaluated. In 25 of these patients, PRES occurred in association with severe I/S/S separate from transplantation. The clinical/imaging features (computer tomography, MR imaging, and MR angiography [MRA]) of the patients with I/S/S were further evaluated, including organ/tissue/blood culture results, mean arterial blood pressure (MAP) at toxicity, extent of cerebral edema, and presence of vasospasm. RESULTS: PRES occurred in association with I/S/S in 25 of 106 patients (23.6%), in addition to 4 other major clinical settings, including cyclosporine/FK-506 (post-transplant) neurotoxicity (46.2%), autoimmune disease (10.4%), postchemotherapy (3.7%), and eclampsia (10.4%). In the 25 patients with I/S/S, available cultures demonstrated a predominance of gram-positive organisms (84%). Blood pressure was "normal" at toxicity in 10 patients (MAP, 95 mm Hg); "severe" hypertension was present in 15 patients (MAP, 137 mm Hg). Extent of brain edema graded on imaging studies was greater in the normal MAP group compared with the severe hypertension group (P < .05). MRA demonstrated vasospasm in patients with severe hypertension and vessel "pruning" in the normal MAP group. CONCLUSION: Infection/sepsis/shock may be an important cause of PRES, particularly in relation to infection with gram-positive organisms.

Smaller cerebellar volumes in very preterm infants at term-equivalent age are associated with the presence of supratentorial lesions.

BACKGROUND AND PURPOSE: Traditionally cerebellar functions are thought to be related to control of tone, posture, gait, and coordination of skilled motor activity. However, there is an increasing body of evidence implicating the cerebellum in cognition, language, memory, and motor learning. Preterm infants are at increased risk of neurodevelopmental delay, cognitive dysfunction, and behavioral and emotional disturbances. The role of the cerebellum in these adverse outcomes is unclear. OBJECTIVE: The objective of this study was to determine whether absolute cerebellar volumes differ between term-equivalent preterm infants and term-born control infants and to assess whether cerebellar volume is influenced by any possible antenatal, perinatal, and postnatal factors. METHODS: The study compared the MR imaging cerebellar volume by using a manual quantification program of 113 preterm infants at term-equivalent age and 15 term-born control infants. RESULTS: The median cerebellar volume of preterm at term-equivalent age was 25.4 cm3 and that of term-born control infants was 26.9 cm3. On initial analysis, there was a significant median difference of 2.0 cm3 (95% CI, 1.2 cm3 to 2.7 cm3) (2-sided P < .0001). However multiple regression analysis of perinatal variables showed that only infants with supratentorial lesions (P = .003) were significantly associated with the reduction in cerebellar volumes. The median cerebellar volumes were the following: supratentorial lesions, 18.9 cm3; no supratentorial lesions, 26.1 cm3; and term infants, 26.9 cm3 (analysis of variance, P < .0001). Hence, there was no significant difference in cerebellar volumes of preterm infants at term-equivalent age in the absence of supratentorial lesions. The median vermal volumes were 0.7 cm3 and were significantly related to cerebellar volumes both in preterm infants with and without lesions and in term-control infants. CONCLUSION: Premature infants at term-equivalent age have similar total cerebellar and vermal volumes compared with term infants in the presence of normal brain imaging. Reduced cerebellar volume in preterm infants at term-equivalent age is seen in association with supratentorial pathology such as hemorrhagic parenchymal infarction, intraventricular hemorrhage with dilation, and periventricular leukomalacia.

Epigenomic profiling of preterm infants reveals DNA methylation differences at sites associated with neural function.

DNA methylation (DNAm) plays a determining role in neural cell fate and provides a molecular link between early-life stress and neuropsychiatric disease. Preterm birth is a profound environmental stressor that is closely associated with alterations in connectivity of neural systems and long-term neuropsychiatric impairment. The aims of this study were to examine the relationship between preterm birth and DNAm, and to investigate factors that contribute to variance in DNAm. DNA was collected from preterm infants (birth<33 weeks gestation) and healthy controls (birth>37 weeks), and a genome-wide analysis of DNAm was performed; diffusion magnetic resonance imaging (dMRI) data were acquired from the preterm group. The major fasciculi were segmented, and fractional anisotropy, mean diffusivity and tract shape were calculated. Principal components (PC) analysis was used to investigate the contribution of MRI features and clinical variables to variance in DNAm. Differential methylation was found within 25 gene bodies and 58 promoters of protein-coding genes in preterm infants compared with controls; 10 of these have neural functions. Differences detected in the array were validated with pyrosequencing. Ninety-five percent of the variance in DNAm in preterm infants was explained by 23 PCs; corticospinal tract shape associated with 6th PC, and gender and early nutritional exposure associated with the 7th PC. Preterm birth is associated with alterations in the methylome at sites that influence neural development and function. Differential methylation analysis has identified several promising candidate genes for understanding the genetic/epigenetic basis of preterm brain injury.

Symptoms of obsessive-compulsive disorder.

OBJECTIVE: Obsessive-compulsive disorder encompasses a broad range of symptoms that represent multiple psychological domains, including perception, cognition, emotion, social relatedness, and diverse motor behaviors. The purpose of these analyses was to evaluate the correlational relationships of the symptoms of obsessive-compulsive disorder. METHOD: This study examined the 13 a priori categories used to group types of obsessions and compulsions in the Yale-Brown Obsessive Compulsive Scale symptom checklist in two independent groups of patients with obsessive-compulsive disorder (N = 208 and N = 98). A principal-components factor analysis with varimax rotation was performed, followed by a series of other exploratory analyses. RESULTS: The two data sets yielded nearly identical results. Four factors--obsessions and checking, symmetry and ordering, cleanliness and washing, and boarding--emerged in each data set, in total accounting for more than 60% of the variance. CONCLUSIONS: Obsessive-compulsive disorder is a multidimensional and etiologically heterogeneous condition. The four symptom dimensions identified in this study are largely congruent with those identified in earlier reports. These factors may be of value in future genetic, neurobiological, and treatment response studies.

Neighborhood disadvantage, stress, and drug use among adults.

This paper explores the relationships among neighborhood disadvantage, stress, and the likelihood of drug use in a sample of adults (N = 1,101). Using the 1995 Detroit Area Study in conjunction with tract-level data from the 1990 census, we find a positive relationship between neighborhood disadvantage and drug use, and this relationship remains statistically significant net of controls for individual-level socioeconomic status. Neighborhood disadvantage is moderately associated with drug related behaviors, indirectly through increased social stressors and higher levels of psychological distress among residents of disadvantaged neighborhoods. A residual effect of neighborhood disadvantage remains, net of a large number of socially relevant controls. Finally, results from interactive models suggest that the relationship between neighborhood disadvantage and drug use is most pronounced among individuals with lower incomes.