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Neurological soft signs (NSS) are minor deviations in motor performance. During childhood and adolescence, NSS are examined for functional motor phenotyping to describe development, to screen for comorbidities, and to identify developmental vulnerabilities. Here, we investigate underlying brain structure alterations in association with NSS in physically trained adolescents. Male adolescent athletes (n = 136, 13–16 years) underwent a standardized neurological examination including 28 tests grouped into 6 functional clusters. Non-optimal performance in at least 1 cluster was rated as NSS (NSS+ group). Participants underwent T1- and diffusion-weighted magnetic resonance imaging. Cortical volume, thickness, and local gyrification were calculated using Freesurfer. Measures of white matter microstructure (Free-water (FW), FW-corrected fractional anisotropy (FAt), axial and radial diffusivity (ADt, RDt)) were calculated using tract-based spatial statistics. General linear models with age and handedness as covariates were applied to assess differences between NSS+ and NSS− group. We found higher gyrification in a large cluster spanning the left superior frontal and parietal areas, and widespread lower FAt and higher RDt compared with the NSS− group. This study shows that NSS in adolescents are associated with brain structure alterations. Underlying mechanisms may include alterations in synaptic pruning and axon myelination, which are hallmark processes of brain maturation.

Background: Repetitive head impacts (RHI) from contact sports have been associated with cognitive and neuropsychiatric disorders. However, not all individuals exposed to RHI develop such disorders. This may be explained by the reserve hypothesis. It remains unclear if the reserve hypothesis accounts for the heterogenous symptom presentation in RHI-exposed individuals. Moreover, optimal measurement of reserve in this population is unclear and likely unique from non-athlete populations. Objective: We examined the association between metrics of reserve and cognitive and neuropsychiatric functioning in 89 symptomatic former National Football League players. Methods: Individual-level proxies (e.g., education) defined reserve. We additionally quantified reserve as remaining residual variance in 1) episodic memory and 2) executive functioning performance, after accounting for demographics and brain pathology. Associations between reserve metrics and cognitive and neuropsychiatric functioning were examined. Results: Higher reading ability was associated with better attention/information processing (β=0.25; 95% CI, 0.05–0.46), episodic memory (β=0.27; 95% CI, 0.06–0.48), semantic and phonemic fluency (β=0.24; 95% CI, 0.02–0.46; β=0.38; 95% CI, 0.17–0.59), and behavioral regulation (β=–0.26; 95% CI, –0.48, –0.03) performance. There were no effects for other individual-level proxies. Residual episodic memory variance was associated with better attention/information processing (β=0.45; 95% CI, 0.25, 0.65), executive functioning (β=0.36; 95% CI, 0.15, 0.57), and semantic fluency (β=0.38; 95% CI, 0.17, 0.59) performance. Residual executive functioning variance was associated with better attention/information processing (β=0.44; 95% CI, 0.24, 0.64) and episodic memory (β=0.37; 95% CI, 0.16, 0.58) performance. Conclusion: Traditional reserve proxies (e.g., years of education, occupational attainment) have limitations and may be unsuitable for use in elite athlete samples. Alternative approaches of reserve quantification may prove more suitable for this population.

Context Nicotinamide adenine dinucleotide (NAD) levels decline with aging and age-related decline in NAD has been postulated to contribute to age-related diseases. Objective We evaluated the safety and physiologic effects of NAD augmentation by administering its precursor, β-nicotinamide mononucleotide (MIB-626, Metro International Biotech, Worcester, MA), in adults at risk for age-related conditions. Methods Thirty overweight or obese adults, ≥ 45 years, were randomized in a 2:1 ratio to 2 MIB-626 tablets each containing 500 mg of microcrystalline β-nicotinamide mononucleotide or placebo twice daily for 28 days. Study outcomes included safety; NAD and its metabolome; body weight; liver, muscle, and intra-abdominal fat; insulin sensitivity; blood pressure; lipids; physical performance, and muscle bioenergetics. Results Adverse events were similar between groups. MIB-626 treatment substantially increased circulating concentrations of NAD and its metabolites. Body weight (difference −1.9 [−3.3, −0.5] kg, P = .008); diastolic blood pressure (difference −7.01 [−13.44, −0.59] mmHg, P = .034); total cholesterol (difference −26.89 [−44.34, −9.44] mg/dL, P = .004), low-density lipoprotein (LDL) cholesterol (−18.73 [−31.85, −5.60] mg/dL, P = .007), and nonhigh-density lipoprotein cholesterol decreased significantly more in the MIB-626 group than placebo. Changes in muscle strength, muscle fatigability, aerobic capacity, and stair-climbing power did not differ significantly between groups. Insulin sensitivity and hepatic and intra-abdominal fat did not change in either group. Conclusions MIB-626 administration in overweight or obese, middle-aged and older adults safely increased circulating NAD levels, and significantly reduced total LDL and non-HDL cholesterol, body weight, and diastolic blood pressure. These data provide the rationale for larger trials to assess the efficacy of NAD augmentation in improving cardiometabolic outcomes in older adults.

The purpose was to explore the effects of transcutaneous trigeminal nerve stimulation (TNS) on neurochemical concentrations (brainstem, anterior cingulate cortex [ACC], dorsolateral prefrontal cortex [DLPFC], ventromedial prefrontal cortex [VMPFC], and the posterior cingulate cortex [PCC]) using ultrahigh-field magnetic resonance spectroscopy.This double-blinded study tested 32 healthy males (age: 25.4 ± 7.3 years) on two separate occasions where participants received either a 20-minute TNS or sham session. Participants were scanned at baseline and twice post-TNS/sham administration.There were no group differences in concentration changes of glutamate, gamma-aminobutyric acid, glutamine, myoinositol (mI), total N-acetylaspartate, total creatine (tCr), and total choline between the baseline scan and the first post-TNS/sham scan and between the first and second post-TNS/sham scan in the brainstem, ACC, DLPFC, VMPFC, and PCC. Between the baseline scan and the second post-TNS/sham scan, changes in tCr (mean difference = 0.280 mM [0.075 to 0.485], p = .026) and mI (mean difference = 0.662 mM [0.203 to 1.122], p = .026) in the DLPFC differed between groups. Post hoc analyses indicated that there was a decrease in tCr (mean change = -0.201 mM [-0.335 to -0.067], p = .003) and no change in mI (mean change = -0.327 mM [-0.737 to 0.083], p = .118) in the TNS group; conversely, there was no change in tCr (mean change = -0.100 mM [-0.074 to 0.274], p = .259) and an increase in mI (mean change = 0.347 mM [0.106 to 0.588], p = .005) in the sham group.These data demonstrate that a single session of unilateral TNS slightly decreased tCr concentrations in the DLPFC region.

Brain iron is central to dopaminergic neurotransmission, a key component in schizophrenia pathology. Iron can also generate oxidative stress, which is one proposed mechanism for gray matter volume reduction in schizophrenia. The role of brain iron in schizophrenia and its potential link to oxidative stress has not been previously examined. In this study, we used 7-Tesla MRI quantitative susceptibility mapping (QSM), magnetic resonance spectroscopy (MRS), and structural T1 imaging in 12 individuals with chronic schizophrenia and 14 healthy age-matched controls. In schizophrenia, there were higher QSM values in bilateral putamen and higher concentrations of phosphocreatine and lactate in caudal anterior cingulate cortex (caCC). Network-based correlation analysis of QSM across corticostriatal pathways as well as the correlation between QSM, MRS, and volume, showed distinct patterns between groups. This study introduces increased iron in the putamen in schizophrenia in addition to network-wide disturbances of iron and metabolic status.

Background Exposure to repetitive head impacts (RHI) is associated with an increased risk of later‐life neurobehavioral dysregulation and neurodegenerative disease. The underlying pathomechanisms are largely unknown. Purpose To investigate whether RHI exposure is associated with later‐life corpus callosum (CC) microstructure and whether CC microstructure is associated with plasma total tau and neuropsychological/neuropsychiatric functioning. Study Type Retrospective cohort study. Population Seventy‐five former professional American football players (age 55.2 ± 8.0 years) with cognitive, behavioral, and mood symptoms. Field Strength/Sequence Diffusion‐weighted echo‐planar MRI at 3 T. Assessment Subjects underwent diffusion MRI, venous puncture, neuropsychological testing, and completed self‐report measures of neurobehavioral dysregulation. RHI exposure was assessed using the Cumulative Head Impact Index (CHII). Diffusion MRI measures of CC microstructure (i.e., free‐water corrected fractional anisotropy (FA), trace, radial diffusivity (RD), and axial diffusivity (AD)) were extracted from seven segments of the CC (CC1‐7), using a tractography clustering algorithm. Neuropsychological tests were selected: Trail Making Test Part A (TMT‐A) and Part B (TMT‐B), Controlled Oral Word Association Test (COWAT), Stroop Interference Test, and the Behavioral Regulation Index (BRI) from the Behavior Rating Inventory of Executive Function, Adult version (BRIEF‐A). Statistical Tests Diffusion MRI metrics were tested for associations with RHI exposure, plasma total tau, neuropsychological performance, and neurobehavioral dysregulation using generalized linear models for repeated measures. Results RHI exposure was associated with increased AD of CC1 (correlation coefficient (r) = 0.32, P < 0.05) and with increased plasma total tau (r = 0.34, P < 0.05). AD of the anterior CC1 was associated with increased plasma total tau (CC1: r = 0.30, P < 0.05; CC2: r = 0.29, P < 0.05). Higher trace, AD, and RD of CC1 were associated with better performance (P < 0.05) in TMT‐A (trace, r = 0.33; AD, r = 0.31; and RD, r = 0.28) and TMT‐B (trace, r = 0.31; RD, r = 0.34). Higher FA and AD of CC2 were associated with better performance (P < 0.05) in TMT‐A (FA, r = 0.36; AD, r = 0.28), TMT‐B (FA, r = 0.36; AD, r = 0.27), COWAT (FA, r = 0.36; AD, r = 0.32), and BRI (AD, r = 0.29). Data Conclusion These results suggest an association among RHI exposure, CC microstructure, plasma total tau, and clinical functioning in former professional American football players. Level of Evidence: 3 Technical Efficacy Stage: 1, publishedVersion

The presentation, risk factors, and etiologies of white matter hyperintensities (WMH) in people exposed to repetitive head impacts are unknown. We examined the burden and distribution of WMH, and their association with years of play, age of first exposure, and clinical function in former American football players.A total of 149 former football players and 53 asymptomatic unexposed participants (all men, 45-74 years) completed fluid-attenuated inversion recovery magnetic resonance imaging, neuropsychological testing, and self-report neuropsychiatric measures. Lesion Segmentation Toolbox estimated WMH. Analyses were performed in the total sample and stratified by age 60.In older but not younger participants, former football players had greater total, frontal, temporal, and parietal log-WMH compared to asymptomatic unexposed men. In older but not younger former football players, greater log-WMH was associated with younger age of first exposure to football and worse executive function.In older former football players, WMH may have unique presentations, risk factors, and etiologies.Older but not younger former football players had greater total, frontal, temporal, and parietal lobe white matter hyperintensities (WMH) compared to same-age asymptomatic unexposed men. Younger age of first exposure to football was associated with greater WMH in older but not younger former American football players. In former football players, greater WMH was associated with worse executive function and verbal memory.

Traumatic brain injuries (TBIs) are common with an estimated 27.1 million cases per year. Approximately 80% of TBIs are categorized as mild TBI (mTBI) based on initial symptom presentation. While in most individuals, symptoms resolve within days to weeks, in some, symptoms become chronic. Advanced neuroimaging has the potential to characterize brain morphometric, microstructural, biochemical, and metabolic abnormalities following mTBI. However, translational studies are needed for the interpretation of neuroimaging findings in humans with respect to the underlying pathophysiological processes, and, ultimately, for developing novel and more targeted treatment options. In this review, we introduce the most commonly used animal models for the study of mTBI. We then summarize the neuroimaging findings in humans and animals after mTBI and, wherever applicable, the translational aspects of studies available today. Finally, we highlight the importance of translational approaches and outline future perspectives in the field of translational neuroimaging in mTBI.

Younger age at first exposure (AFE) to repetitive head impacts while playing American football increases the risk for later-life neuropsychological symptoms and brain alterations. However, it is not known whether AFE is associated with cortical thickness in American football players. Sixty-three former professional National Football League players (55.5 ± 7.7 years) with cognitive, behavioral, and mood symptoms underwent neuroimaging and neuropsychological testing. First, the association between cortical thickness and AFE was tested. Second, the relationship between clusters of decreased cortical thickness and verbal and visual memory, and composite measures of mood/behavior and attention/psychomotor speed was assessed. AFE was positively correlated with cortical thickness in the right superior frontal cortex (cluster-wise P value [CWP] = 0.0006), the left parietal cortex (CWP = 0.0003), and the occipital cortices (right: CWP = 0.0023; left: CWP = 0.0008). A positive correlation was found between cortical thickness of the right superior frontal cortex and verbal memory (R = 0.333, P = 0.019), and the right occipital cortex and visual memory (R = 0.360, P = 0.012). In conclusion, our results suggest an association between younger AFE and decreased cortical thickness, which in turn is associated with worse neuropsychological performance. Furthermore, an association between younger AFE and signs of neurodegeneration later in life in symptomatic former American football players seems likely.

OBJECTIVE: To evaluate the strength of associations between single-task and dual-task gait measures and Posterior Cingulate Gyrus (PCG) neurochemicals in acutely concussed collegiate athletes. SETTING: Participants were recruited from a NCAA Division 1 University. PARTICIPANTS: Nineteen collegiate athletes acutely (< 4 days) following sports-related concussion. DESIGN: We acquired Magnetic Resonance Spectroscopy (MRS) in the PCG and gait performance measurements in the participants, acutely following concussion. Linear mixed-effects models were constructed in order to measure the effect of gait performance, in the single and dual task settings, and sex on the six neurochemicals quantified with MRS in mmol. Correlation coefficients were also calculated to determine the direction and strength of the relationship between MRS neurochemicals and gait performance, post-concussion symptom score, and number of previous concussions. MAIN MEASURES: Average gait speed, average cadence, N-acetyl aspartate, choline, myo-inositol, glutathione, glutamate plus glutamine, creatine. RESULTS: Single-task gait speed (p=0.0056) and cadence (p=0.0065) had significant effects on myo-Inositol concentrations in the PCG, independent of sex, in concussed collegiate athletes. Single-task cadence (p=0.047) also had a significant effect on glutathione in the PCG. No significant effects were observed between dual-task gait performance and PCG neurochemistry. CONCLUSIONS: These findings indicate that increased concentrations of neuroinflammatory markers in the PCG are associated with slower single-task gait performance within four days of sport-related concussion.

Adult-onset noncirrhotic hyperammonemia (NCH) is poorly understood and has a high morbidity and mortality. To elucidate the etiology and management of NCH, we performed a retrospective analysis of 23 adults (median age 51) with NCH treated between 2014 and 2020 at two academic medical centers. Hyperammonemia was diagnosed in all cases during the evaluation of altered mental status, with 22% presenting with seizures. Peak ammonia levels were >200 μmol/L in 70% of cases. Defects in ammonia metabolism were assessed using urea cycle biochemical testing, germline genetic testing, and testing for urease-producing infectious agents. Ammonia metabolism defects in these cases appear attributable to four major sources: (a) infection with urease-producing organism (n = 5); (b) previously undiagnosed inborn errors of metabolism (IEMs) (n = 4); (c) clinical exposures causing acquired urea cycle dysfunction (n = 6); and (d) unexplained acquired urea cycle dysfunction (uaUCD) (n = 8), as evidenced by biochemical signatures of urea cycle dysfunction without a genetic or clinical exposure. Severe protein malnutrition appeared to be a reversible risk factor for uaUCD. Overall, 13% of our cohort died prior to resolution of hyperammonemia, 26% died after hyperammonemia resolution, 57% survived after having reversible neurological changes, and 4% survived with irreversible neurological changes. Renal replacement therapy for ammonia clearance was often utilized for patients with an ammonia level above 250 μmol/L and patients were frequently empirically treated with antibiotics targeting urea-splitting organisms. Our study demonstrates that acquired urea cycle dysfunction, IEMs and urease-producing infections are major sources of adult-onset NCH and highlights successful management strategies for adult-onset NCH.

Sport-related brain injury is very common, and the potential long-term effects include a wide range of neurological and psychiatric symptoms, and potentially neurodegeneration. Around the globe, researchers are conducting neuroimaging studies on primarily homogenous samples of athletes. However, neuroimaging studies are expensive and time consuming, and thus current findings from studies of sport-related brain injury are often limited by small sample sizes. Further, current studies apply a variety of neuroimaging techniques and analysis tools which limit comparability among studies. The ENIGMA Sports Injury working group aims to provide a platform for data sharing and collaborative data analysis thereby leveraging existing data and expertise. By harmonizing data from a large number of studies from around the globe, we will work towards reproducibility of previously published findings and towards addressing important research questions with regard to diagnosis, prognosis, and efficacy of treatment for sport-related brain injury. Moreover, the ENIGMA Sports Injury working group is committed to providing recommendations for future prospective data acquisition to enhance data quality and scientific rigor.

PURPOSE: Few studies have investigated recovery between sexes using objective outcome measures. Our purpose was to examine the independent association between biological sex and recovery of post-concussion gait among collegiate athletes. METHODS: We evaluated participants with a diagnosed concussion 0.56 and >0.50 gait velocity (m·s(−1))/height (m) under single and dual-task conditions, respectively. We used a multivariable Cox proportional hazard model to identify associations between sex and dual-task recovery, controlling for age, concussion history, symptom severity, and loss of consciousness at the time of injury. RESULTS: Ninety-four individuals participated in the study: 47 (50%) were female athletes (mean age=20.1, SD=1.3 years) and 47 (50%) were male athletes (mean age=20.3, SD=1.3 years). Sex was not independently associated with height-adjusted single-task gait velocity recovery after controlling for potential confounders (hazard ratio=1.62, 95% confidence interval=0.87, 3.01). However, male sex was independently associated with longer dual-task gait recovery time after controlling for potential confounders (hazard ratio=2.43, 95% confidence interval=1.11, 5.35). CONCLUSION: Male athletes required a longer duration of time after concussion to achieve dual-task gait recovery than female athletes. Thus, functional dual-task abilities after concussion may be affected differentially by sex, and should be accounted for within individualized concussion management strategies.

Stress exposures and dysregulated responses to stress are implicated in psychiatric disorders of mood, anxiety, and cognition. Perceived stress, an individual's appraisal of experienced stress and ability for coping, relates to dysregulated functioning in resting state brain networks. Alterations in GABAergic function may underlie perceived stress-related functional dysregulation in resting state networks but this has not yet been explored. Therefore, the current study examined the association of perceived stress, via the Perceived Stress Scale (PSS), with prefrontal GABA levels and corresponding resting state functional connectivity (RSFC) alterations. Twelve women and five men, ages 35–61, participated. MR spectroscopy was used to measure brain GABA levels in the anterior cingulate cortex (ACC), left dorsolateral prefrontal cortex (DLPFC), and ventromedial prefrontal cortex (VMPFC). Resting state functional scans acquired at 3 Tesla were used to measure RSFC within and between the default mode (DMN), salience (SN), and central executive networks (CEN), hippocampus and amygdala. We observed significant negative correlations between total PSS scores and left DLPFC GABA levels (r = −0.62, p = 0.023). However, PSS scores were not significantly correlated with RSFC measures (all p > 0.148). These preliminary results support a relationship between perceived stress and GABAergic functioning in DLPFC, a core node of the CEN, an intrinsic network thought to underlie goal-directed attentional processes. Our findings extend previous work suggesting that functioning in the CEN is related to perceived stress and may inform treatment strategies to improve outcomes in stress-related conditions.

Repetitive head impacts (RHI) are common in youth athletes participating in contact sports. RHI differ from concussions; they are considered hits to the head that usually do not result in acute symptoms and are therefore also referred to as "subconcussive" head impacts. RHI occur e.g., when heading the ball or during contact with another player. Evidence suggests that exposure to RHI may have cumulative effects on brain structure and function. However, little is known about brain alterations associated with RHI, or about the risk factors that may lead to clinical or behavioral sequelae. REPIMPACT is a prospective longitudinal study of competitive youth soccer players and non-contact sport controls aged 14 to 16 years. The study aims to characterize consequences of exposure to RHI with regard to behavior (i.e., cognition, and motor function), clinical sequelae (i.e., psychiatric and neurological symptoms), brain structure, function, diffusion and biochemistry, as well as blood- and saliva-derived measures of molecular processes associated with exposure to RHI (e.g., circulating microRNAs, neuroproteins and cytokines). Here we present the structure of the REPIMPACT Consortium which consists of six teams of clinicians and scientists in six countries. We further provide detailed information on the specific aims and the design of the REPIMPACT study. The manuscript also describes the progress made in the study thus far. Finally, we discuss important challenges and approaches taken to overcome these challenges. ispartof: Brain Imaging And Behavior vol:16 issue:1 ispartof: location:United States status: published

The biological mechanisms by which efavirenz (EFV) causes central nervous system (CNS) effects are unclear. The objective of this pilot study was to elucidate the mechanisms underlying these CNS effects by correlating well-described neuropsychological (NP) changes with neurometabolites and immunologic markers following switch off EFV.Two single-arm parallel switch studies among HIV-infected adults in Boston, USA, from 2015 to 2017.Twenty asymptomatic HIV-infected adults on EFV-containing regimens were switched to an integrase strand transfer inhibitor-based regimen for 8 weeks. NP assessments were conducted before and after switch and correlated with neurometabolite changes measured using magnetic resonance spectroscopy and immunological markers. All pre-EFV and post-EFV measures were evaluated using matched-paired analyses.NP testing demonstrated improvement in the domains of mood, cognition, and sleep off EFV. Magnetic resonance spectroscopy revealed decreases in the neurometabolite glutathione level (P = 0.03), a marker of oxidative stress after switch. Inhibitory neuronal activity as reflected by gamma-amino butyric acid levels increased (P = 0.03), whereas excitatory neurotransmitters glutamine + glutamate (Glx) and aspartate decreased (P = 0.04, 0.001). Switching off EFV was also associated with changes in inflammatory markers; plasma markers sCD14 (P = 0.008) decreased, whereas I-FABP and TNFRI levels increased (P = 0.05, 0.03). Cellular markers CD4 and CD8 HLA-DR-/CD38 subsets both increased (P = 0.05, 0.02).Even asymptomatic participants showed improvements in NP parameters when switched off EFV. These improvements were associated with decreased CNS oxidative stress and excitatory neuronal activity. Changes in immune activation biomarkers suggested overall decreased inflammation. EFV may exert CNS effects through oxidative and inflammatory pathways, providing insight into possible mechanisms of EFV neurotoxicity.

Proton Magnetic Resonance Spectroscopy ((1)H MRS) provides non-invasive, quantitative metabolite profiles of tissue and has been shown to aid the clinical management of several brain diseases. Whilst most modern clinical MR scanners support MRS capabilities, routine use is largely restricted to specialized centers with good access to MR research support. Widespread adoption has been slow for several reasons, and technical challenges towards obtaining reliable good-quality results have been identified as a contributing factor. Considerable progress has been made by the research community to address many of these challenges, and in this paper a consensus is presented on deficiencies in widely available MRS methodology and validated improvements that are currently in routine use at several clinical research institutions. In particular, the localization error for the popular point resolved spectroscopy (PRESS) localization sequence was found to be unacceptably high at 3T, and the use of the semi-adiabatic localization by adiabatic selective refocusing (semi-LASER) sequence is a recommended solution. The incorporation of simulated metabolite basis-sets into analysis routines is recommended for reliably capturing the full spectral detail available from short echo time acquisitions. In addition, the importance of achieving a highly homogenous static magnetic field (B(0)) in the acquisition region is emphasized, and the limitations of current methods and hardware are discussed. Most recommendations require only software improvements, greatly enhancing the capabilities of clinical MRS on existing hardware. We anticipate the implementation of these recommendations will strengthen current clinical applications and advance progress towards developing and validating new MRS biomarkers for clinical use.

Proton ((1)H) magnetic resonance spectroscopy provides a non-invasive and quantitative measure of brain metabolites. Traumatic brain injury impacts cerebral metabolism and a number of research groups have successfully used this technique as a biomarker of injury and/or outcome in both pediatric and adult TBI populations. However, this technique is underutilized, with studies being performed primarily at centers with access to MR research support. In this paper we present a technical introduction to the acquisition and analysis of in vivo (1)H magnetic resonance spectroscopy and review (1)H magnetic resonance spectroscopy findings in different injury populations. In addition, we propose a basic (1)H magnetic resonance spectroscopy data acquisition scheme (Supplemental Information) that can be added to any imaging protocol, regardless of clinical magnetic resonance platform. We outline a number of considerations for study design as a way of encouraging the use of (1)H magnetic resonance spectroscopy in the study of traumatic brain injury, as well as recommendations to improve data harmonization across groups already using this technique.

Adult-onset non-cirrhotic hyperammonemia (NCH) is a rare, but often fatal condition that can result in both reversible and irreversible neurological defects. Here we present five cases of adult-onset non-cirrhotic hyperammonemia wherein brain magnetic resonance spectroscopy (MRS) scans for cerebral glutamine (Gln) and myo-inositol (mI) levels helped guide clinical management. Specifically, we demonstrate that when combined with traditional brain magnetic resonance imaging (MRI) scans, cerebral Gln and mI MRS can help disentangle the reversible from irreversible neurological defects associated with hyperammonemic crisis. Specifically, we demonstrate that whereas an elevated brain MRS Gln level is associated with reversible neurological defects, markedly low mI levels are associated with a risk for irreversible neurological defects such as central pontine myelinolysis. Overall, our findings indicate the utility of brain MRS in guiding clinical care and prognosis in patients with adult-onset non-cirrhotic hyperammonemia.

Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disorder of γ-aminobutyric acid (GABA) degradation, resulting in elevations of brain GABA and γ-hydroxybutyric acid (GHB). Previous magnetic resonance (MR) spectroscopy studies have shown increased levels of Glx in SSADH deficiency patients. Here in this work, we measure brain GABA in a large cohort of SSADH deficiency patients using advanced MR spectroscopy techniques that allow separation of GABA from overlapping metabolite peaks. We observed significant increases in GABA concentrations in SSADH deficiency patients for all 3 brain regions that were evaluated. Although GABA levels were higher in all 3 regions, each region had different patterns in terms of GABA changes with respect to age. We also report results from structural magnetic resonance imaging (MRI) of the same cohort compared with age-matched controls. We consistently observed signal hyperintensities in globus pallidus and cerebellar dentate nucleus.

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. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.

The long-term neurologic consequences of exposure to repetitive head impacts (RHI) are not well understood. This study used magnetic resonance spectroscopy (MRS) to examine later-life neurochemistry and its association with RHI and clinical function in former National Football League (NFL) players. The sample included 77 symptomatic former NFL players and 23 asymptomatic individuals without a head trauma history. Participants completed cognitive, behavior, and mood measures. N-acetyl aspartate, glutamate/glutamine, choline, myo-inositol, creatine, and glutathione were measured in the posterior (PCG) and anterior (ACG) cingulate gyrus, and parietal white matter (PWM). A cumulative head impact index (CHII) estimated RHI. In former NFL players, a higher CHII correlated with lower PWM creatine (r = −0.23, p = 0.02). Multivariate mixed-effect models examined neurochemical differences between the former NFL players and asymptomatic individuals without a history of head trauma. PWM N-acetyl aspartate was lower among the former NFL players (mean diff. = 1.02, p = 0.03). Between-group analyses are preliminary as groups were recruited based on symptomatic status. The ACG was the only region associated with clinical function, including positive correlations between glutamate (r = 0.32, p = 0.004), glutathione (r = 0.29, p = 0.02), and myo-inositol (r = 0.26, p = 0.01) with behavioral/mood symptoms. Other positive correlations between ACG neurochemistry and clinical function emerged (i.e., behavioral/mood symptoms, cognition), but the positive directionality was unexpected. All analyses controlled for age, body mass index, and education (for analyses examining clinical function). In this sample of symptomatic former NFL players, there was a direct effect between RHI and reduced cellular energy metabolism (i.e., lower creatine). MRS neurochemicals associated with neuroinflammation also correlated with behavioral/mood symptoms.

Rationale: To assess the longitudinal changes and relationships of clinical measures and extent of CT lung abnormalities in COVID-19. Methods: 81 patients with COVID-19 were prospectively enrolled and followed until discharge. CT scores were quantified on a basis of a CT scoring system where each lung was divided into 3 zones: upper (above the carina), middle, and lower (below the inferior pulmonary vein) zones; each zone was evaluated for percentage of lung involvement on a scale of 0-4 (0, 0%; 1, 0-24%; 2, 25% - 49%; 3, 50% -74%; 4, >74%).Temporal trends of CT scores and the laboratory parameters characteristic of COVID-19 were analyzed. Correlations between the two were determined at three milestones (initial presentation, worst CT manifestation, and recovery finding before discharge). Their correlations with duration to worst CT manifestation and discharge from symptom onset were evaluated. Results: CT scores peaked during illness days 6-11 (median: 5), and stayed steady. C-reactive protein and lactate dehydrogenase increased, peaked on illness days 6-8 and 8-11 (mean: 23.5 mg/L, 259.9 U/L), and gradually declined. Continual decrease and increase were observed in hemoglobin and lymphocyte count, respectively. Albumin reduced and remained at low levels with a nadir on illness days 12-15 (36.6 g/L). Both initial (r = 0.58, 0.64, p < 0.05) and worst CT scores (r = 0.47, 0.65, p < 0.05) were correlated with C-reactive protein and lactate dehydrogenase; and CT scores before discharge, only with albumin (r = -0.41, p < 0.05). Duration to worst CT manifestation was associated with initial and worst CT scores (r = 0.33, 0.29, p < 0.05). No parameters were related to timespan to discharge. Conclusion: Our results illustrated the temporal changes of characteristic clinical measures and extent of CT lung abnormalities in COVID-19. CT scores correlated with some important laboratory parameters, and might serve as prognostic factors.

Traumatic brain injury (TBI) is a major cause of disability worldwide, but the heterogeneous nature of TBI with respect to injury severity and health comorbidities make patient outcome difficult to predict. Injury severity accounts for only some of this variance, and a wide range of preinjury, injury‐related, and postinjury factors may influence outcome, such as sex, socioeconomic status, injury mechanism, and social support. Neuroimaging research in this area has generally been limited by insufficient sample sizes. Additionally, development of reliable biomarkers of mild TBI or repeated subconcussive impacts has been slow, likely due, in part, to subtle effects of injury and the aforementioned variability. The ENIGMA Consortium has established a framework for global collaboration that has resulted in the largest‐ever neuroimaging studies of multiple psychiatric and neurological disorders. Here we describe the organization, recent progress, and future goals of the Brain Injury working group., Graphical Abstract

Magnetic Resonance Spectroscopy (MRS) is a non-invasive technique that quantitatively measures the metabolic composition of tissues in vivo using conventional magnetic resonance (MR) scanners. This technology is of special interest for clinical applications in psychiatry due to its non-invasive nature. In recent years, studies have demonstrated its diagnostic capability in psychiatric conditions such as schizophrenia, bipolar disorder, depression, as well as in neurodegenerative disorders and neuro-oncology among others. The most relevant brain chemicals that can be quantified include: N-acetylaspartate (NAA), a neuronal marker; creatine (Cr), involved in energy metabolism; choline (Cho), a key component of myelin; glutamate (Glu), an excitatory neurotransmitter; γ-aminobutyric acid (GABA), an inhibitory neurotransmitter, and glutathione (GSH), an anti-oxidant involved in neuroinflammation. In this chapter, the biological roles of the primary brain metabolites will be discussed. Moreover, the general principles of MRS and the specialized pulse sequences that enable the detection of each of these metabolites will be described. Furthermore, a comprehensive introduction of the most common techniques and examination protocols used in research and clinical applications will be presented.

Sports-related concussion is a serious health challenge, and females are at higher risk of sustaining a sports-related concussion compared to males. Although there are many studies that investigate outcomes following concussion, females remain an understudied population, despite representing a large proportion of the organized sports community. In this review, we provide a summary of studies that investigate sex-related differences in outcome following sports-related concussion. Moreover, we provide an introduction to the methods used to study sex-related differences after sports-related concussion, including common clinical and cognitive measures, neuroimaging techniques, as well as biomarkers. A literature search inclusive of articles published to March 2020 was performed using PubMed. The studies were reviewed and discussed with regard to the methods used. Findings from these studies remain mixed with regard to the effect of sex on clinical symptoms, concussion-related alterations in brain structure and function, and recovery trajectories. Nonetheless, there is initial evidence to suggest that sex-related differences following concussion are important to consider in efforts to develop objective biomarkers for the diagnosis and prognosis of concussion. Additional studies on this topic are, however, clearly needed to improve our understanding of sex-related differences following concussion, as well as to understand their neurobiological underpinnings. Such studies will help pave the way toward more personalized clinical management and treatment of sports-related concussion.