ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries.

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors

Effects of Social Networks and Caregiver Characteristics on Loneliness in Caregivers to Older Adults with Chronic Conditions

Caregivers to older adults with chronic conditions may experience physical and mental health issues, such as depression and loneliness, due to the stressful nature of providing daily care. Loneliness levels also may be affected by caregiving characteristics (e.g., time spent on caregiving per week), as well as differing levels of social support. Yet, few studies have specifically examined the relationship between loneliness, caregiving characteristics and social support in caregivers to older adults with chronic conditions. Understanding the risk factors for loneliness among caregivers may provide insights into ways to improve caregiver well-being. This study aims to investigate differences in loneliness between caregivers and non-caregivers and associations with caregiving and social network characteristics. In this study, participants will include healthy adult caregivers and non-caregivers who will complete a series of measures assessing loneliness, social support, social networks and caregiving characteristics. This information will be used to map social networks, social interaction frequency, and examine relationships with loneliness among caregivers and non-caregivers

Brain structural covariance networks in obsessive-compulsive disorder: a graph analysis from the ENIGMA Consortium.

Brain structural covariance networks reflect covariation in morphology of different brain areas and are thought to reflect common trajectories in brain development and maturation. Large-scale investigation of structural covariance networks in obsessive-compulsive disorder (OCD) may provide clues to the pathophysiology of this neurodevelopmental disorder. Using T1-weighted MRI scans acquired from 1616 individuals with OCD and 1463 healthy controls across 37 datasets participating in the ENIGMA-OCD Working Group, we calculated intra-individual brain structural covariance networks (using the bilaterally-averaged values of 33 cortical surface areas, 33 cortical thickness values, and six subcortical volumes), in which edge weights were proportional to the similarity between two brain morphological features in terms of deviation from healthy controls (i.e. z-score transformed). Global networks were characterized using measures of network segregation (clustering and modularity), network integration (global efficiency), and their balance (small-worldness), and their community membership was assessed. Hub profiling of regional networks was undertaken using measures of betweenness, closeness, and eigenvector centrality. Individually calculated network measures were integrated across the 37 datasets using a meta-analytical approach. These network measures were summated across the network density range of K = 0.10-0.25 per participant, and were integrated across the 37 datasets using a meta-analytical approach. Compared with healthy controls, at a global level, the structural covariance networks of OCD showed lower clustering (P < 0.0001), lower modularity (P < 0.0001), and lower small-worldness (P = 0.017). Detection of community membership emphasized lower network segregation in OCD compared to healthy controls. At the regional level, there were lower (rank-transformed) centrality values in OCD for volume of caudate nucleus and thalamus, and surface area of paracentral cortex, indicative of altered distribution of brain hubs. Centrality of cingulate and orbito-frontal as well as other brain areas was associated with OCD illness duration, suggesting greater involvement of these brain areas with illness chronicity. In summary, the findings of this study, the largest brain structural covariance study of OCD to date, point to a less segregated organization of structural covariance networks in OCD, and reorganization of brain hubs. The segregation findings suggest a possible signature of altered brain morphometry in OCD, while the hub findings point to OCD-related alterations in trajectories of brain development and maturation, particularly in cingulate and orbitofrontal regions

Surfactant proteins SP-A and SP-D modulate uterine contractile events in ULTR myometrial cell line

Pulmonary surfactant proteins SP-A and SP-D are pattern recognition innate immune molecules. However, there is extrapulmonary existence, especially in the amniotic fluid and at the feto-maternal interface. There is sufficient evidence to suggest that SP-A and SP-D are involved in the initiation of labour. This is of great importance given that preterm birth is associated with increased mortality and morbidity. In this study, we investigated the effects of recombinant forms of SP-A and SP-D (rhSP-A and rhSP-D, the comprising of trimeric lectin domain) on contractile events in vitro, using a human myometrial cell line (ULTR) as an experimental model. Treatment with rhSP-A or rhSP-D increased the cell velocity, distance travelled and displacement by ULTR cells. rhSP-A and rhSP-D also affected the contractile response of ULTRs when grown on collagen matrices showing reduced surface area. We investigated this effect further by measuring contractility-associated protein (CAP) genes. Treatment with rhSP-A and rhSP-D induced expression of oxytocin receptor (OXTR) and connexin 43 (CX43). In addition, rhSP-A and rhSP-D were able to induce secretion of GROα and IL-8. rhSP-D also induced the expression of IL-6 and IL-6 Ra. We provide evidence that SP-A and SP-D play a key role in modulating events prior to labour by reconditioning the human myometrium and in inducing CAP genes and pro-inflammatory cytokines thus shifting the uterus from a quiescent state to a contractile one

Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex

The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders

Antioxidant, acetylcholinesterase inhibitory activity and cytotoxicity assessment of the crude extracts of Boophane disticha

1. IntroductionAlzheimer’s disease (AD) is the most commonneurodegenerative disease and is characterized bymemory impairment, cognitive dysfunction, behavioraldisturbances and deficits in daily living (Konrath et al,2012). Approaches to enhance cholinergic function inAD have included stimulation of cholinergic receptorsor prolonging the availability of acetylcholine (ACh)released into the neuronal synaptic cleft by inhibitingACh hydrolysis through the use of acetylcholinesterase(AChE) inhibitors (Howes and Houghton, 2003). Tacrinewas the first widely used AChE inhibitor (Summers,2006). Second generation AChE inhibitors with longerhalf-lives than tacrine, such as donepezil, galanthamineand rivastigmine, have since been developed and arecurrently in use (Shah et al, 2008). In addition, severallines of evidence indicate that reactive oxygen speciesare associated with the pathogenesis of AD, as somecellular characteristics of this disease are either causesor effects of oxidative stress (Zhu et al, 2004; Sultana etal, 2006; Konrath et al, 2012). Generally, thephysiological role of antioxidant compounds is toattenuate the oxidation chain reactions by removingfree-radical intermediates (Liu and Nair, 2010). Since alarge amount of evidence demonstrates that oxidativestress is intimately involved in age-relatedneurodegenerative diseases, there have been a numberof studies which have examined the positive effects ofantioxidants in reducing or blocking neuronal deathoccurring in the pathophysiology of these disorders(Ramassamy, 2006). Consequently, the use ofantioxidants has been explored in an attempt to slowAD progression and neuronal degeneration (Howes andHoughton, 2003).Toxicity testing is an essential requirement for thedevelopment of modern pharmaceutical compounds.Medicinal plants are assumed to have low toxicity dueto their long-term consumption by humans and animals(Luseba et al, 2007; Verschaeve and van Staden, 2008;Aremu et al, 2011). However, several studies haveshown that many plants used as food or medicine, havepotential toxic effects (Du Plooy et al, 2001; Barlow andSchlatter, 2010). Almost all known AChE inhibitors haveseveral drawbacks, such as hepatotoxicity, shortduration of biological action, low bioavailability,adverse cholinergic side effects in the periphery andnarrow therapeutic windows (Lee et al, 2011). Somecommon synthetic antioxidants including butylatedhydroxyanisole (BHA) and butylated hydroxytoluene(BHT) have been reported to be toxic (Aremu et al,2011). Therefore, the search for new AChE inhibitorsand antioxidants, particularly from natural products,with low toxicity and higher efficacy continues.Many plants are reputed to have ‘anti-ageing’ or‘memory-enhancing’ effects and are used traditionallyto treat several neurodegenerative diseases (Howes andHoughton, 2003). One such plant, Boophane disticha(L.f.) Herb. belongs to the family Amaryllidaceae. It is anattractive, deciduous bulbous plant with a thickcovering of dry scales above the ground and is widelydistributed in Africa, ranging from Sudan in the north tothe Western Cape Province in the south (Wrinkle,1984). Decoctions of bulb scales are given to sedateviolent, psychotic patients while bulb infusions arereported to be used to treat mental illness (van Wykand Gericke, 2000; Sobiecki, 2002). Bulb decoctions arealso used in the treatment of headaches, abdominalpain, weakness, sharp chest pains and persistentbladder pains, as well as treatment of varicose ulcers,relief of urticaria, and cancer (Botha et al, 2005). Thisstudy was aimed at evaluating the AChE inhibitory andantioxidant activity of the bulbs and roots of B. distichato partially justify its traditional use in treatment ofneurodegenerative diseases. The safety of using thisplant in traditional medicine was also investigated byassessing its toxicity using the MTT and neutral redassays