Reproducibility and Repeatability of Intravoxel Incoherent Motion MRI Acquisition Methods in Liver.

BACKGROUND: Intravoxel incoherent motion (IVIM) diffusion weighted MRI (DWI) has potential for evaluating hepatic fibrosis but image acquisition technique influence on diffusion parameter estimation bears investigation. PURPOSE: To minimize variability and maximize repeatably in abdominal DWI in terms of IVIM parameter estimates. STUDY TYPE: Prospective test-retest and image quality comparison. SUBJECTS: Healthy volunteers (3F/7M, 29.9 ± 12.9 years) and Family Study subjects (18F/12M, 51.7 ± 16.7 years), without and with liver steatosis. FIELD STRENGTH/SEQUENCE: Abdominal single-shot echo-planar imaging (EPI) and simultaneous multi-slice (SMS) DWI sequences with respiratory triggering (RT), breath-holding (BH), and navigator echo (NE) at 3 Tesla. ASSESSMENT: SMS-BH, EPI-NE, and SMS-RT data from twice-scanned healthy volunteers were analyzed using 6 × b-values (0-800 s⋅mm-2 ) and lower (LO) and higher (HI) b-value ranges. Family Study subjects were scanned using SMS and standard EPI sequences. The biexponential IVIM model was used to estimate fast-diffusion coefficient (Df ), fraction of fast diffusion (f), and slow-diffusion coefficient (Ds ). Scan time, estimated signal-to-noise ratio (eSNR), eSNR per acquisition, and distortion ratio were compared. STATISTICAL TESTS: Coefficients of variation (CoV) and Bland Altman analyses were performed for test-retest repeatability. Interclass correlation coefficient (ICC) assessed interobserver agreement with P < 0.05 deemed significant. RESULTS: Within-subject CoVs among volunteers (N = 10) for f and Ds were lowest in EPI-NE-LO (11.6%) and SMS-RT-HI (11.1%). Inter-observer ICCs for f and Ds were highest for EPI-NE-LO (0.63) and SMS-RT-LO (0.76). Df could not be estimated for most subjects. Estimated eSNR (EPI = 21.9, SMS = 4.7) and eSNR time (EPI = 6.7, SMS = 16.6) were greater for SMS, with less distortion in the liver region (DR-PE: EPI = 23.6, SMS = 13.1). DATA CONCLUSION: Simultaneous multislice acquisitions had significantly less variability and higher ICCs of Ds , higher eSNR, less distortion, and reduced scan time compared to EPI. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

Long-Term Neurocognitive Outcomes in Pediatric Nonfatal Drowning: Results of a Family Caregiver Survey.

BACKGROUND: Drowning is a leading cause of brain injury in children. Long-term outcome data for drowning survivors are sparse. This study reports neurocognitive outcomes for 154 children hospitalized following drowning. METHODS: A survey for parent caregivers was distributed online. Likert scale items assessed 10 outcome variables in four domains: motor (three), perception (three), language (three), and social/emotional (one). Cluster analysis, outcome relative risk, and descriptive statistics were applied. RESULTS: Of 208 surveys received, 154 met inclusion criteria. Coma was the most common admission status (n = 137). Cluster analysis identified three outcome groups: Mild (n = 39), Moderate (n = 75), and Severe (n = 40). Motor impairment with cognitive and perceptual sparing (deefferentation) was present in Moderate (P < 1 × 10-26) and Severe (P < 1 × 10-12) but absent in Mild. Locked-in state was endorsed in both Moderate (83%) and Severe (70%). The strongest predictor of good outcome (Mild) was hospitalization with no medical intervention (relative risk [RR] = 6.7). Responsivity on admission (RR = 4.2) or discharge (RR = 12.22) also predicted good outcome. In-hospital prognostication and counseling predicted outcome weakly (RR = 1.3) or not at all. CONCLUSIONS: Long-term outcomes in pediatric drowning ranged widely. Overall, motor impairments exceeded perceptual or cognitive (P < 1 × 10-18), with "locked-in state" endorsed in most (93 of 154). The strongest predictors of good outcome were the lack of necessity for interventions and responsivity on admission or discharge. The eponym "Conrad syndrome" is proposed for locked-in state following nonfatal drowning in children.

Cocktail-party listening and cognitive abilities show strong pleiotropy.

Introduction: The cocktail-party problem refers to the difficulty listeners face when trying to attend to relevant sounds that are mixed with irrelevant ones. Previous studies have shown that solving these problems relies on perceptual as well as cognitive processes. Previously, we showed that speech-reception thresholds (SRTs) on a cocktail-party listening task were influenced by genetic factors. Here, we estimated the degree to which these genetic factors overlapped with those influencing cognitive abilities. Methods: We measured SRTs and hearing thresholds (HTs) in 493 listeners, who ranged in age from 18 to 91 years old. The same individuals completed a cognitive test battery comprising 18 measures of various cognitive domains. Individuals belonged to large extended pedigrees, which allowed us to use variance component models to estimate the narrow-sense heritability of each trait, followed by phenotypic and genetic correlations between pairs of traits. Results: All traits were heritable. The phenotypic and genetic correlations between SRTs and HTs were modest, and only the phenotypic correlation was significant. By contrast, all genetic SRT-cognition correlations were strong and significantly different from 0. For some of these genetic correlations, the hypothesis of complete pleiotropy could not be rejected. Discussion: Overall, the results suggest that there was substantial genetic overlap between SRTs and a wide range of cognitive abilities, including abilities without a major auditory or verbal component. The findings highlight the important, yet sometimes overlooked, contribution of higher-order processes to solving the cocktail-party problem, raising an important caveat for future studies aiming to identify specific genetic factors that influence cocktail-party listening.

Metabolic syndrome predictors of brain gray matter volume in an age-stratified community sample of 776 Mexican- American adults: Results from the genetics of brain structure image archive.

Introduction: This project aimed to investigate the association between biometric components of metabolic syndrome (MetS) with gray matter volume (GMV) obtained with magnetic resonance imaging (MRI) from a large cohort of community-based adults (n = 776) subdivided by age and sex and employing brain regions of interest defined previously as the "Neural Signature of MetS" (NS-MetS). Methods: Lipid profiles, biometrics, and regional brain GMV were obtained from the Genetics of Brain Structure (GOBS) image archive. Participants underwent T1-weighted MR imaging. MetS components (waist circumference, fasting plasma glucose, triglycerides, HDL cholesterol, and blood pressure) were defined using the National Cholesterol Education Program Adult Treatment Panel III. Subjects were grouped by age: early adult (18-25 years), young adult (26-45 years), and middle-aged adult (46-65 years). Linear regression modeling was used to investigate associations between MetS components and GMV in five brain regions comprising the NS-MetS: cerebellum, brainstem, orbitofrontal cortex, right insular/limbic cluster and caudate. Results: In both men and women of each age group, waist circumference was the single component most strongly correlated with decreased GMV across all NS-MetS regions. The brain region most strongly correlated to all MetS components was the posterior cerebellum. Conclusion: The posterior cerebellum emerged as the region most significantly associated with MetS individual components, as the only region to show decreased GMV in young adults, and the region with the greatest variance between men and women. We propose that future studies investigating neurological effects of MetS and its comorbidities-namely diabetes and obesity-should consider the NS-MetS and the differential effects of age and sex.

The Genetic contribution to solving the cocktail-party problem.

Communicating in everyday situations requires solving the cocktail-party problem, or segregating the acoustic mixture into its constituent sounds and attending to those of most interest. Humans show dramatic variation in this ability, leading some to experience real-world problems irrespective of whether they meet criteria for clinical hearing loss. Here, we estimated the genetic contribution to cocktail-party listening by measuring speech-reception thresholds (SRTs) in 425 people from large families and ranging in age from 18 to 91 years. Roughly half the variance of SRTs was explained by genes (h 2 = 0.567). The genetic correlation between SRTs and hearing thresholds (HTs) was medium (ρ G = 0.392), suggesting that the genetic factors influencing cocktail-party listening were partially distinct from those influencing sound sensitivity. Aging and socioeconomic status also strongly influenced SRTs. These findings may represent a first step toward identifying genes for "hidden hearing loss," or hearing problems in people with normal HTs.

Using the Schmahmann Syndrome Scale to Assess Cognitive Impairment in Young Adults with Metabolic Syndrome: a Hypothesis-Generating Report.

The posterior cerebellum is the most significantly compromised brain structure in individuals with metabolic syndrome (MetS) (Hum Brain Mapp 40(12):3575-3588, 2019). In light of this, we hypothesized that cognitive decline reported in patients with MetS is likely related to posterior cerebellar atrophy. In this study, we performed a post hoc analyses using T1-weighted magnetic resonance imaging (MRI), diffusion tensor imaging (DTI) in the form of voxel-wise tract-based spatial statistics (TBSS), biometric, and psychometric data from young participants with (n = 52, aged 18-35 years) and without MetS (n = 52, aged 18-35 years). To test the predictive value of components of the Schmahmann syndrome scale (SSS), also known as the cerebellar cognitive affective syndrome scale, we used structural equation modeling to adapt available psychometric scores in our participant sample to the SSS and compare them to the composite score of all psychometric data available. Our key findings point to a statistically significant correlation between TBSS fractional anisotropy (FA) values from DTI and adapted SSS psychometric scores in individuals with MetS (r2 = .139, 95% CI = 0.009, .345). This suggests that the SSS could be applied to assess cognitive and likely neuroanatomical effects associated with MetS. We strongly suggest that future work aimed at investigating the neurocognitive effects of MetS and related comorbidities (i.e., dyslipidemia, diabetes, obesity) would benefit from implementing and further exploring the validity of the SSS in this patient population.

A neural signature of metabolic syndrome.

That metabolic syndrome (MetS) is associated with age-related cognitive decline is well established. The neurobiological changes underlying these cognitive deficits, however, are not well understood. The goal of this study was to determine whether MetS is associated with regional differences in gray-matter volume (GMV) using a cross-sectional, between-group contrast design in a large, ethnically homogenous sample. T1-weighted MRIs were sampled from the genetics of brain structure (GOBS) data archive for 208 Mexican-American participants: 104 participants met or exceeded standard criteria for MetS and 104 participants were age- and sex-matched metabolically healthy controls. Participants ranged in age from 18 to 74 years (37.3 ± 13.2 years, 56.7% female). Images were analyzed in a whole-brain, voxel-wise manner using voxel-based morphometry (VBM). Three contrast analyses were performed, a whole sample analysis of all 208 participants, and two post hoc half-sample analyses split by age along the median (35.5 years). Significant associations between MetS and decreased GMV were observed in multiple, spatially discrete brain regions including the posterior cerebellum, brainstem, orbitofrontal cortex, bilateral caudate nuclei, right parahippocampus, right amygdala, right insula, lingual gyrus, and right superior temporal gyrus. Age, as shown in the post hoc analyses, was demonstrated to be a significant covariate. A further functional interpretation of the structures exhibiting lower GMV in MetS reflected a significant involvement in reward perception, emotional valence, and reasoning. Additional studies are needed to characterize the influence of MetS's individual clinical components on brain structure and to explore the bidirectional association between GMV and MetS.

Functional integrity in children with anoxic brain injury from drowning.

Drowning is a leading cause of accidental injury and death in young children. Anoxic brain injury (ABI) is a common consequence of drowning and can cause severe neurological morbidity in survivors. Assessment of functional status and prognostication in drowning victims can be extremely challenging, both acutely and chronically. Structural neuroimaging modalities (CT and MRI) have been of limited clinical value. Here, we tested the utility of resting-state functional MRI (rs-fMRI) for assessing brain functional integrity in this population. Eleven children with chronic, spastic quadriplegia due to drowning-induced ABI were investigated. All were comatose immediately after the injury and gradually regained consciousness, but with varying ability to communicate their cognitive state. Eleven neurotypical children matched for age and gender formed the control group. Resting-state fMRI and co-registered T1-weighted anatomical MRI were acquired at night during drug-aided sleep. Network integrity was quantified by independent components analysis (ICA), at both group- and per-subject levels. Functional-status assessments based on in-home observations were provided by families and caregivers. Motor ICNs were grossly compromised in ABI patients both group-wise and individually, concordant with their prominent motor deficits. Striking preservations of perceptual and cognitive ICNs were observed, and the degree of network preservation correlated (ρ = 0.74) with the per-subject functional status assessments. Collectively, our findings indicate that rs-fMRI has promise for assessing brain functional integrity in ABI and, potentially, in other disorders. Furthermore, our observations suggest that the severe motor deficits observed in this population can mask relatively intact perceptual and cognitive capabilities. Hum Brain Mapp 38:4813-4831, 2017. © 2017 Wiley Periodicals, Inc.

The genetic basis of the comorbidity between cannabis use and major depression.

BACKGROUND AND AIMS: While the prevalence of major depression is elevated among cannabis users, the role of genetics in this pattern of comorbidity is not clear. This study aimed to estimate the heritability of cannabis use and major depression, quantify the genetic overlap between these two traits and localize regions of the genome that segregate in families with cannabis use and major depression. DESIGN: Family-based univariate and bivariate genetic analysis. SETTING: San Antonio, Texas, USA. PARTICIPANTS: Genetics of Brain Structure and Function study (GOBS) participants: 1284 Mexican Americans from 75 large multi-generation families and an additional 57 genetically unrelated spouses. MEASUREMENTS: Phenotypes of life-time history of cannabis use and major depression, measured using the semistructured MINI-Plus interview. Genotypes measured using ~1 M single nucleotide polymorphisms (SNPs) on Illumina BeadChips. A subselection of these SNPs were used to build multi-point identity-by-descent matrices for linkage analysis. FINDINGS: Both cannabis use [h2  = 0.614, P = 1.00 × 10-6 , standard error (SE) = 0.151] and major depression (h2  = 0.349, P = 1.06 × 10-5 , SE = 0.100) are heritable traits, and there is significant genetic correlation between the two (ρg  = 0.424, P = 0.0364, SE = 0.195). Genome-wide linkage scans identify a significant univariate linkage peak for major depression on chromosome 22 [logarithm of the odds (LOD) = 3.144 at 2 centimorgans (cM)], with a suggestive peak for cannabis use on chromosome 21 (LOD = 2.123 at 37 cM). A significant pleiotropic linkage peak influencing both cannabis use and major depression was identified on chromosome 11 using a bivariate model (LOD = 3.229 at 112 cM). Follow-up of this pleiotropic signal identified a SNP 20 kb upstream of NCAM1 (rs7932341) that shows significant bivariate association (P = 3.10 × 10-5 ). However, this SNP is rare (seven minor allele carriers) and does not drive the linkage signal observed. CONCLUSIONS: There appears to be a significant genetic overlap between cannabis use and major depression among Mexican Americans, a pleiotropy that appears to be localized to a region on chromosome 11q23 that has been linked previously to these phenotypes.

Lenticulostriate arterial distribution pathology may underlie pediatric anoxic brain injury in drowning.

Drowning is a leading cause of neurological morbidity and mortality in young children. Anoxic brain injury (ABI) can result from nonfatal drowning and typically entails substantial neurological impairment. The neuropathology of drowning-induced pediatric ABI is not well established. Specifically, quantitative characterization of the spatial extent and tissue distribution of anoxic damage in pediatric nonfatal drowning has not previously been reported but could clarify the underlying pathophysiological processes and inform clinical management. To this end, we used voxel-based morphometric (VBM) analyses to quantify the extent and spatial distribution of consistent, between-subject alterations in gray and white matter volume. Whole-brain, high-resolution T1-weighted MRI datasets were acquired in 11 children with chronic ABI and 11 age- and gender-matched neurotypical controls (4-12 years). Group-wise VBM analyses demonstrated predominantly central subcortical pathology in the ABI group in both gray matter (bilateral basal ganglia nuclei) and white matter (bilateral external and posterior internal capsules) (P < 0.001); minimal damage was found outside of these deep subcortical regions. These highly spatially convergent gray and white matter findings reflect the vascular distribution of perforating lenticulostriate arteries, an end-arterial watershed zone, and suggest that vascular distribution may be a more important determinant of tissue loss than oxygen metabolic rate in pediatric ABI. Further, these results inform future directions for diagnostic and therapeutic modalities.

Regional cerebral glucose metabolism differentiates danger- and non-danger-based traumas in post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is presumably the result of life threats and conditioned fear. However, the neurobiology of fear fails to explain the impact of traumas that do not entail threats. Neuronal function, assessed as glucose metabolism with (18)fluoro-deoxyglucose positron emission tomography, was contrasted in active duty, treatment-seeking US Army Soldiers with PTSD endorsing either danger- (n = 19) or non-danger-based (n = 26) traumas, and was compared with soldiers without PTSD (Combat Controls, n = 26) and Civilian Controls (n = 24). Prior meta-analyses of regions associated with fear or trauma script imagery in PTSD were used to compare glucose metabolism across groups. Danger-based traumas were associated with higher metabolism in the right amygdala than the control groups, while non-danger-based traumas associated with heightened precuneus metabolism relative to the danger group. In the danger group, PTSD severity was associated with higher metabolism in precuneus and dorsal anterior cingulate and lower metabolism in left amygdala (R(2 )= 0.61). In the non-danger group, PTSD symptom severity was associated with higher precuneus metabolism and lower right amygdala metabolism (R(2 )= 0.64). These findings suggest a biological basis to consider subtyping PTSD according to the nature of the traumatic context.

Discovering schizophrenia endophenotypes in randomly ascertained pedigrees.

BACKGROUND: Although case-control approaches are beginning to disentangle schizophrenia's complex polygenic burden, other methods will likely be necessary to fully identify and characterize risk genes. Endophenotypes, traits genetically correlated with an illness, can help characterize the impact of risk genes by providing genetically relevant traits that are more tractable than the behavioral symptoms that classify mental illness. Here, we present an analytic approach for discovering and empirically validating endophenotypes in extended pedigrees with very few affected individuals. Our approach indexes each family member's risk as a function of shared genetic kinship with an affected individual, often referred to as the coefficient of relatedness. To demonstrate the utility of this approach, we search for neurocognitive and neuroanatomic endophenotypes for schizophrenia in large unselected multigenerational pedigrees. METHODS: A fixed-effects test within the variance component framework was performed on neurocognitive and cortical surface area traits in 1606 Mexican-American individuals from large, randomly ascertained extended pedigrees who participated in the Genetics of Brain Structure and Function study. As affecteds were excluded from analyses, results were not influenced by disease state or medication usage. RESULTS: Despite having sampled just 6 individuals with schizophrenia, our sample provided 233 individuals at various levels of genetic risk for the disorder. We identified three neurocognitive measures (digit-symbol substitution, facial memory, and emotion recognition) and six medial temporal and prefrontal cortical surfaces associated with liability for schizophrenia. CONCLUSIONS: With our novel analytic approach, one can discover and rank endophenotypes for schizophrenia, or any heritable disease, in randomly ascertained pedigrees.

Association of clinical symptoms and neurocognitive performance in bipolar disorder: a longitudinal study.

OBJECTIVE: Despite evidence that individuals with bipolar disorder have neurocognitive impairment that persists during euthymia, the impact of changes in affective symptoms on cognitive function has not been well established. Here, we sought to determine whether specific neurocognitive functions are sensitive to mood changes in individuals with bipolar disorder assessed three months apart without changes in treatment regimen. METHODS: A total of 29 individuals with DSM-IV bipolar disorder and 30 healthy controls participated in the study. All participants received a comprehensive neuropsychological assessment and ratings of depressive [Hamilton Depression Rating Scale (HAMD)] and manic [Young Mania Rating Scale (YMRS)] symptoms at baseline and follow-up. Changes in symptoms over time were calculated and were examined in relation to changes in neurocognitive performance. RESULTS: At baseline, clinically stable but symptomatic patients were impaired on measures of speed of processing and attention. Over the three-month follow-up period, HAMD scores changed by 6 points on average [range: -10 to +18] and YMRS scores changed by 5.31 points on average [range -11 to +15]. Changes in depressive symptoms were correlated with poorer verbal fluency, while no relationship between manic symptoms and neuropsychological performance was detected. CONCLUSIONS: Individuals with bipolar disorder showed consistent impairment on speed of processing and attention over time, despite significant changes in mood.

Deconstructing processing speed deficits in schizophrenia: application of a parametric digit symbol coding test.

Cognitive processing inefficiency, often measured using digit symbol coding tasks, is a putative vulnerability marker for schizophrenia and a reliable indicator of illness severity and functional outcome. Indeed, performance on the digit symbol coding task may be the most severe neuropsychological deficit patients with schizophrenia display at the group level. Yet, little is known about the contributions of simpler cognitive processes to coding performance in schizophrenia (e.g. decision making, visual scanning, relational memory, motor ability). We developed an experimental behavioral task, based on a computerized digit symbol coding task, which allows the manipulation of demands placed on visual scanning efficiency and relational memory while holding decisional and motor requirements constant. Although patients (n=85) were impaired on all aspects of the task when compared to demographically matched healthy comparison subjects (n=30), they showed a particularly striking failure to benefit from the presence of predictable target information. These findings are consistent with predicted impairments in cognitive processing speed due to schizophrenia patients' well-known memory impairment, suggesting that this mnemonic deficit may have consequences for critical aspects of information processing that are traditionally considered quite separate from the memory domain. Future investigation into the mechanisms underlying the wide-ranging consequences of mnemonic deficits in schizophrenia should provide additional insight.