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Objectives: The aim of the present study was to examine N-acetylaspartate (NAA), a general marker of neuronal viability, and total NAA (tNAA), the combined signal of NAA and N-acetylaspartylglutamate, in bipolar depression before and after lamotrigine treatment. Given that NAA is synthesized through direct acetylation of aspartate by acetyl-coenzyme A-l-aspartate-N-acetyltransferase, we hypothesized that treatment with lamotrigine would be associated with an increase in NAA level. Methods: Patients with bipolar depression underwent two-dimensional proton magnetic resonance spectroscopy of the anterior cingulate at baseline (n = 15) and after 12 weeks of lamotrigine treatment (n = 10). A group of age-matched healthy controls (n = 9) underwent scanning at baseline for comparison. Results: At baseline, patients with bipolar depression had significantly lower NAA [mean standard deviation (SD) = 1.13 (0.21); p = 0.02] than controls [mean (SD) = 1.37 (0.27)]. Significant increases in NAA [mean (SD) = 1.39 (0.21); p = 0.01] and tNAA [mean (SD) = 1.61 (0.25); p = 0.02] levels were found after 12 weeks of lamotrigine treatment. Conclusions: These data suggest an NAA deficit in bipolar depression that is normalized after lamotrigine treatment. Future research is warranted to evaluate whether baseline NAA level is a potential biomarker for identifying lamotrigine response patterns and whether this functional brain change has an associated clinical response.

Purpose: To cross-validate skeletal muscle oxidative capacity measured by (31)P-MR spectroscopy with in vitro measurements of oxidative capacity in mitochondria isolated from muscle biopsies of the same muscle group in 18 healthy adults.Materials and Methods: Oxidative capacity in vivo was determined from PCr recovery kinetics following a 30-s maximal isometric knee extension. State 3 respiration was measured in isolated mitochondria using high-resolution respirometry. A second cohort of 10 individuals underwent two (31)P-MRS testing sessions to assess the test-retest reproducibility of the method.Results: Overall, the in vivo and in vitro methods were well-correlated (r = 0.66-0.72) and showed good agreement by Bland Altman plots. Excellent reproducibility was observed for the PCr recovery rate constant (CV = 4.6%; ICC = 0.85) and calculated oxidative capacity (CV = 3.4%; ICC = 0.83).Conclusion: These results indicate that (31)P-MRS corresponds well with gold-standard in vitro measurements and is highly reproducible. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the effect of intrathecal (IT) recombinant human arylsulfatase A (rhASA) on magnetic resonance imaging (MRI)-assessed brain tissue changes in children with metachromatic leukodystrophy (MLD). In total, 510 MRI scans were collected from 12 intravenous (IV) rhASA-treated children with MLD, 24 IT rhASA-treated children with MLD, 32 children with untreated MLD, and 156 normally developing children. Linear mixed models were fitted to analyze the time courses of gray matter (GM) volume and fractional anisotropy (FA) in the posterior limb of the internal capsule. Time courses for demyelination load and FA in the centrum semiovale were visualized using locally estimated scatterplot smoothing regression curves. All assessed imaging parameters demonstrated structural evidence of neurological deterioration in children with MLD. GM volume was significantly lower at follow-up (median duration, 104 weeks) in IV rhASA-treated versus IT rhASA-treated children. GM volume decline over time was steeper in children receiving low-dose (10 or 30 mg) versus high-dose (100 mg) IT rhASA. Similar effects were observed for demyelination. FA in the posterior limb of the internal capsule showed a higher trend over time in IT rhASA-treated versus children with untreated MLD, but FA parameters were not different between children receiving the low doses versus those receiving the high dose. GM volume in IT rhASA-treated children showed a strong positive correlation with 88-item Gross Motor Function Measure score over time. In some children with MLD, IT administration of high-dose rhASA may delay neurological deterioration (assessed using MRI), offering potential therapeutic benefit., (© 2024 Takeda. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Background: Catatonia is a challenging and heterogeneous neuropsychiatric syndrome of motor, affective and behavioral dysregulation which has been associated with multiple disorders such as structural brain lesions, systemic diseases, and psychiatric disorders. This systematic review summarized and compared functional neuroimaging abnormalities in catatonia associated with psychiatric and medical conditions., Methods: Using PRISMA methods, we completed a systematic review of 6 databases from inception to February 7th, 2024 of patients with catatonia that had functional neuroimaging performed., Results: A total of 309 studies were identified through the systematic search and 62 met the criteria for full-text review. A total of 15 studies reported patients with catatonia associated with a psychiatric disorder (n = 241) and one study reported catatonia associated with another medical condition, involving patients with N-methyl-d-aspartate receptor antibody encephalitis (n = 23). Findings varied across disorders, with hyperactivity observed in areas like the prefrontal cortex (PFC), the supplementary motor area (SMA) and the ventral pre-motor cortex in acute catatonia associated to a psychiatric disorder, hypoactivity in PFC, the parietal cortex, and the SMA in catatonia associated to a medical condition, and mixed metabolic activity in the study on catatonia linked to a medical condition., Conclusion: Findings support the theory of dysfunction in cortico-striatal-thalamic, cortico-cerebellar, anterior cingulate-medial orbitofrontal, and lateral orbitofrontal networks in catatonia. However, the majority of the literature focuses on schizophrenia spectrum disorders, leaving the pathophysiologic characteristics of catatonia in other disorders less understood. This review highlights the need for further research to elucidate the pathophysiology of catatonia across various disorders., Competing Interests: Declaration of competing interest Dr. Singh has received research grant support from Mayo Clinic, National Network of Depression Centers (NNDC), and BD2 (Breakthrough Discoveries for thriving with Bipolar Disorder). The remaining authors report no potential competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Food intake is regulated by homeostatic and hedonic systems that interact in a complex neuro-hormonal network. Dysregulation in energy intake can lead to obesity (OB) or anorexia nervosa (AN). However, little is known about the neurohormonal response patterns to food intake in normal weight (NW), OB, and AN., Material & Methods: During an ad libitum nutrient drink (Ensure®) test (NDT), participants underwent three pseudo-continuous arterial spin labeling (pCASL) MRI scans. The first scan was performed before starting the NDT after a > 12 h overnight fast (Hunger), the second after reaching maximal fullness (Satiation), and the third 30-min after satiation (postprandial fullness). We measured blood levels of ghrelin, cholecystokinin (CCK), glucagon-like peptide (GLP-1), and peptide YY (PYY) with every pCASL-MRI scan. Semiquantitative cerebral blood flow (CBF) maps in mL/100 gr brain/min were calculated and normalized (nCBF) with the CBF in the frontoparietal white matter. The hypothalamus (HT), nucleus accumbens [NAc] and dorsal striatum [DS] were selected as regions of interest (ROIs)., Results: A total of 53 participants, 7 with AN, 17 with NW (body-mass index [BMI] 18.5-24.9 kg/m 2 ), and 29 with OB (BMI ≥30 kg/m 2 ) completed the study. The NW group had a progressive decrease in all five ROIs during the three stages of food intake (hunger, satiation, and post-prandial fullness). In contrast, participants with OB showed a minimal change from hunger to postprandial fullness in all five ROIs. The AN group had a sustained nCBF in the HT and DS, from hunger to satiation, with a subsequent decrease in nCBF from satiation to postprandial fullness. All three groups had similar hormonal response patterns with a decrease in ghrelin, an increase in GLP-1 and PYY, and no change in CCK., Conclusion: Conditions of regulated (NW) and dysregulated (OB and AN) energy intake are associated with distinctive neurohormonal activity patterns in response to hunger, satiation, and postprandial fullness., (© 2023 John Wiley & Sons Ltd.)

This review describes targeted magnetic resonance imaging (tMRI) of small changes in the T 1 and the spatial properties of normal or near normal appearing white or gray matter in disease of the brain. It employs divided subtracted inversion recovery (dSIR) and divided reverse subtracted inversion recovery (drSIR) sequences to increase the contrast produced by small changes in T 1 by up to 15 times compared to conventional T 1 -weighted inversion recovery (IR) sequences such as magnetization prepared-rapid acquisition gradient echo (MP-RAGE). This increase in contrast can be used to reveal disease with only small changes in T 1 in normal appearing white or gray matter that is not apparent on conventional MP-RAGE, T 2 -weighted spin echo (T 2 -wSE) and/or fluid attenuated inversion recovery (T 2 -FLAIR) images. The small changes in T 1 or T 2 in disease are insufficient to produce useful contrast with conventional sequences. To produce high contrast dSIR and drSIR sequences typically need to be targeted for the nulling TI of normal white or gray matter, as well as for the sign and size of the change in T 1 in these tissues in disease. The dSIR sequence also shows high signal boundaries between white and gray matter. dSIR and drSIR are essentially T 1 maps. There is a nearly linear relationship between signal and T 1 in the middle domain (mD) of the two sequences which includes T 1 s between the nulling T 1 s of the two acquired IR sequences. The drSIR sequence is also very sensitive to reductions in T 1 produced by Gadolinium based contrast agents (GBCAs), and when used with rigid body registration to align three-dimensional (3D) isotropic pre and post GBCA images may be of considerable value in showing subtle GBCA enhancement. In serial MRI studies performed at different times, the high signal boundaries generated by dSIR and drSIR sequences can be used with rigid body registration of 3D isotropic images to demonstrate contrast arising from small changes in T 1 (without or with GBCA enhancement) as well as small changes in the spatial properties of normal tissues and lesions, such as their site, shape, size and surface. Applications of the sequences in cases of multiple sclerosis (MS) and methamphetamine dependency are illustrated. Using targeted narrow mD dSIR sequences, widespread abnormalities were seen in areas of normal appearing white matter shown with conventional T 2 -wSE and T 2 -FLAIR sequences. Understanding of the features of dSIR and drSIR images is facilitated by the use of their T 1 -bipolar filters; to explain their targeting, signal, contrast, boundaries, T 1 mapping and GBCA enhancement. Targeted MRI (tMRI) using dSIR and drSIR sequences may substantially improve clinical MRI of the brain by providing unequivocal demonstration of abnormalities that are not seen with conventional sequences., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-23-232/coif). JD serves as an unpaid editorial board member of Quantitative Imaging in Medicine and Surgery. MNJP is a scientific and technical adviser to Magnetica, Brisbane, Australia. GMB is a clinical consultant to Magnetica, Brisbane, Australia. The other authors have no conflicts of interest to declare., (2023 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

We investigated the extent, biologic characterization, phenotypic specificity, and possible regulation of a β1-adrenergic receptor-linked (β1-AR-linked) gene signaling network (β1-GSN) involved in left ventricular (LV) eccentric pathologic remodeling. A 430-member β1-GSN was identified by mRNA expression in transgenic mice overexpressing human β1-ARs or from literature curation, which exhibited opposite directional behavior in interventricular septum endomyocardial biopsies taken from patients with beta-blocker-treated, reverse remodeled dilated cardiomyopathies. With reverse remodeling, the major biologic categories and percentage of the dominant directional change were as follows: metabolic (19.3%, 81% upregulated); gene regulation (14.9%, 78% upregulated); extracellular matrix/fibrosis (9.1%, 92% downregulated); and cell homeostasis (13.3%, 60% upregulated). Regarding the comparison of β1-GSN categories with expression from 19,243 nonnetwork genes, phenotypic selection for major β1-GSN categories was exhibited for LV end systolic volume (contractility measure), ejection fraction (remodeling index), and pulmonary wedge pressure (wall tension surrogate), beginning at 3 months and persisting to study completion at 12 months. In addition, 121 lncRNAs were identified as possibly involved in cis-acting regulation of β1-GSN members. We conclude that an extensive 430-member gene network downstream from the β1-AR is involved in pathologic ventricular remodeling, with metabolic genes as the most prevalent category.

High-frequency repetitive transcranial magnetic stimulation (rTMS) to the left dorsolateral prefrontal cortex (L-DLPFC) shows promise as a treatment for treatment-resistant depression in adolescents. Conventional rTMS coil placement strategies include the 5 cm, the Beam F3, and the magnetic resonance imaging (MRI) neuronavigation methods. The purpose of this study was to use electric field (E-field) models to compare the three targeting approaches to a computational E-field optimization coil placement method in depressed adolescents. Ten depressed adolescents (4 females, age: 15.9±1.1) participated in an open-label rTMS treatment study and were offered MRI-guided rTMS five times per week over 6-8 weeks. Head models were generated based on individual MRI images, and E-fields were simulated for the four targeting approaches. Results showed a significant difference in the induced E-fields at the L-DLPFC between the four targeting methods (χ2=24.7, p<0.001). Post hoc pairwise comparisons showed that there was a significant difference between any two of the targeting methods (Holm adjusted p<0.05), with the 5 cm rule producing the weakest E-field (46.0±17.4V/m), followed by the F3 method (87.4±35.4V/m), followed by MRI-guided (112.1±14.6V/m), and followed by the computational approach (130.1±18.1V/m). Variance analysis showed that there was a significant difference in sample variance between the groups (K2=8.0, p<0.05), with F3 having the largest variance. Participants who completed the full course of treatment had median E-fields correlated with depression symptom improvement (r=-0.77, p<0.05). E-field models revealed limitations of scalp-based methods compared to MRI guidance, suggesting computational optimization could enhance dose delivery to the target.

Amyotrophic lateral sclerosis (ALS) is a disease leading to progressive motor degeneration and ultimately death. It is a complex disease that can take a significantly long time to be diagnosed, as other similar pathological conditions must be ruled out for a definite diagnosis of ALS. Noninvasive imaging of ALS has shed light on disease pathology and altered biochemistry in the ALS brain. Other than magnetic resonance imaging (MRI), two types of functional imaging, positron emission tomography (PET) and single photon emission computed tomography (SPECT), have provided valuable data about what happens in the brain of ALS patients compared to healthy controls. PET imaging has revealed a specific pattern of brain metabolism through [ 18 F]FDG, while other radiotracers have uncovered neuroinflammation, changes in neuronal density, and protein aggregation. SPECT imaging has shown a general decrease in regional cerebral blood flow (rCBF) in ALS patients. This educational review summarizes the current state of ALS imaging with various PET and SPECT radiopharmaceuticals to better understand the pathophysiology of ALS., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Ayaan M. Jamali et al.)

Objective: In this observational study on a cohort of biopsy-proven central nervous system demyelinating disease consistent with MS, we examined the relationship between early-active demyelinating lesion immunopattern (IP) with subsequent clinical course, radiographic progression, and cognitive function., Methods: Seventy-five patients had at least one early-active lesion on biopsy and were pathologically classified into three immunopatterns based on published criteria. The median time from biopsy at follow-up was 11 years, median age at biopsy - 41, EDSS - 4.0. At last follow-up, the median age was 50, EDSS - 3.0. Clinical examination, cognitive assessment (CogState battery), and 3-Tesla-MRI (MPRAGE/FLAIR/T2/DIR/PSIR/DTI) were obtained., Results: IP-I was identified in 14/75 (19%), IP-II was identified in 41/75 (56%), and IP-III was identified in 18/75 (25%) patients. Patients did not differ significantly by immunopattern in clinical measures at onset or last follow-up. The proportions of disease courses after a median of 11 years were similar across immunopatterns, relapsing-remitting being most common (63%), followed by monophasic (32%). No differences in volumetric or DTI measures were found. CogState performance was similar for most tasks. A slight yet statistically significant difference was identified for episodic memory scores, with IP-III patients recalling one word less on average., Interpretation: In this study, immunopathological heterogeneity of early-active MS lesions identified at biopsy does not correlate with different long-term clinical, neuroimaging or cognitive outcomes. This could be explained by the fact that while active white matter lesions are pathological substrates for relapses, MS progression is driven by mechanisms converging across immunopatterns, regardless of pathogenic mechanisms driving the acute demyelinated plaque., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Despite its morbidity and mortality, the neurobiology of treatment-resistant depression (TRD) in adolescents and the impact of treatment on this neurobiology is poorly understood., Methods: Using automatic segmentation in FreeSurfer, we examined brain magnetic resonance imaging baseline volumetric differences among healthy adolescents (n = 30), adolescents with major depressive disorder (MDD) (n = 19), and adolescents with TRD (n = 34) based on objective antidepressant treatment rating criteria. A pooled subsample of adolescents with TRD were treated with 6 weeks of active (n = 18) or sham (n = 7) 10-Hz transcranial magnetic stimulation (TMS) applied to the left dorsolateral prefrontal cortex. Ten of the adolescents treated with active TMS were part of an open-label trial. The other adolescents treated with active (n = 8) or sham (n = 7) were participants from a randomized controlled trial., Results: Adolescents with TRD and adolescents with MDD had decreased total amygdala (TRD and MDD: -5%, P = .032) and caudal anterior cingulate cortex volumes (TRD: -3%, P = .030; MDD: -.03%, P = .041) compared with healthy adolescents. Six weeks of active TMS increased total amygdala volumes (+4%, P < .001) and the volume of the stimulated left dorsolateral prefrontal cortex (+.4%, P = .026) in adolescents with TRD., Conclusions: Amygdala volumes were reduced in this sample of adolescents with MDD and TRD. TMS may normalize this volumetric finding, raising the possibility that TMS has neurostructural frontolimbic effects in adolescents with TRD. TMS also appears to have positive effects proximal to the site of stimulation., (© The Author(s) 2022. Published by Oxford University Press on behalf of CINP.)

In this pilot study (N = 9), we highlight new insights gained on ketamine's mechanism of action where we have mapped biochemical processes that are affected within 40 min of intravenous ketamine exposure. Targeting acylcarnitines, we demonstrated rapid utilization of short-chain acylcarnitines within 40 min of ketamine treatment followed by restoration within 24 h; this change in short chain acylcarnitine with rapid-acting antidepressant treatment is consistent with previous work identifying similar change but at 8-weeks with slower-acting SSRI treatment. Using a non-targeted metabolomics platform, we defined broader effects of ketamine on lipid metabolism and identified changes in triglyceride that correlate with ketamine response. This study provides novel insights into ketamine's action and highlighting a possible role for mitochondrial function and energy metabolism in ketamine's mechanism of action., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Preferential publication of studies with positive findings can lead to overestimation of diagnostic test accuracy (i.e. publication bias). Understanding the contribution of the editorial process to publication bias could inform interventions to optimize the evidence guiding clinical decisions., Purpose/hypothesis: To evaluate whether accuracy estimates, abstract conclusion positivity, and completeness of abstract reporting are associated with acceptance to radiology conferences and journals., Study Type: Meta-research., Population: Abstracts submitted to radiology conferences (European Society of Gastrointestinal and Abdominal Radiology (ESGAR) and International Society for Magnetic Resonance in Medicine (ISMRM)) from 2008 to 2018 and manuscripts submitted to radiology journals (Radiology, Journal of Magnetic Resonance Imaging [JMRI]) from 2017 to 2018. Primary clinical studies evaluating sensitivity and specificity of a diagnostic imaging test in humans with available editorial decisions were included., Assessment: Primary variables (Youden's index [YI > 0.8 vs. <0.8], abstract conclusion positivity [positive vs. neutral/negative], number of reported items on the Standards for Reporting of Diagnostic Accuracy Studies [STARD] for Abstract guideline) and confounding variables (prospective vs. retrospective/unreported, sample size, study duration, interobserver agreement assessment, subspecialty, modality) were extracted., Statistical Tests: Multivariable logistic regression to obtain adjusted odds ratio (OR) as a measure of the association between the primary variables and acceptance by radiology conferences and journals; 95% confidence intervals (CIs) and P-values were obtained; the threshold for statistical significance was P < 0.05., Results: A total of 1000 conference abstracts (500 ESGAR and 500 ISMRM) and 1000 journal manuscripts (505 Radiology and 495 JMRI) were included. Conference abstract acceptance was not significantly associated with YI (adjusted OR = 0.97 for YI > 0.8; CI = 0.70-1.35), conclusion positivity (OR = 1.21 for positive conclusions; CI = 0.75-1.90) or STARD for Abstracts adherence (OR = 0.96 per unit increase in reported items; CI = 0.82-1.18). Manuscripts with positive abstract conclusions were less likely to be accepted by radiology journals (OR = 0.45; CI = 0.24-0.86), while YI (OR = 0.85; CI = 0.56-1.29) and STARD for Abstracts adherence (OR = 1.06; CI = 0.87-1.30) showed no significant association. Positive conclusions were present in 86.7% of submitted conference abstracts and 90.2% of journal manuscripts., Data Conclusion: Diagnostic test accuracy studies with positive findings were not preferentially accepted by the evaluated radiology conferences or journals., Evidence Level: 3 TECHNICAL EFFICACY: Stage 2., (© 2022 International Society for Magnetic Resonance in Medicine.)

Cardiovascular disease (CVD) remains the largest cause of mortality worldwide. The development of new effective therapeutics is a major unmet need. The current review focuses broadly on the concept of nucleic acid (NA)-based therapies, considering the use of various forms of NAs, including mRNAs, miRNAs, siRNA, and guide RNAs, the latter specifically for the purpose of CRISPR-Cas directed gene editing. We describe the current state-of-the-art of RNA target discovery and development, the status of RNA therapeutics in the context of CVD, and some of the challenges and hurdles to be overcome., Competing Interests: Dr Robinson is funded by the American Heart Association grant #829504. Dr Port is partially funded by a supplement to the National Institutes of Health Training T32 Training Grant 3T32GM136444-02S1; and has a financial interest in Veridian Therapeutics, Inc., (© 2022 The Authors.)

Food intake regulation in humans is a complex process controlled by the dynamic interaction of homeostatic and hedonic systems. Homeostatic regulation is controlled by appetitive signals from the gut, adipose tissue, and the vagus nerve, while conscious and unconscious reward processes orchestrate hedonic regulation. On the one hand, sight, smell, taste, and texture perception deliver potent food-related feedback to the central nervous system (CNS) and influence brain areas related to food reward. On the other hand, macronutrient composition stimulates the release of appetite signals from the gut, which are translated in the CNS into unconscious reward processes. This multi-level regulation process of food intake shapes and regulates human ingestive behavior. Identifying the interface between hormones, neurotransmitters, and brain areas is critical to advance our understanding of conditions like obesity and develop better therapeutical interventions. Neuroimaging studies allow us to take a glance into the central nervous system (CNS) while these processes take place. This review focuses on the available neuroimaging evidence to describe this interaction between the homeostatic and hedonic components in human food intake regulation.

Background: Limited studies have described long-term outcomes in pathology confirmed multiple sclerosis (MS)., Objectives: To describe long-term clinical-radiographic-cognitive outcomes in a prospectively followed cohort of patients with pathologically confirmed CNS demyelinating disease, consistent with MS., Methods: Subjects underwent clinical assessment, standardized 3T-MRI brain, and cognitive battery., Results: Seventy-five patients were included. Biopsied lesion size was ⩾ 2 cm in 62/75. At follow-up, median duration since biopsy was 11 years. Median EDSS was 3 and lesion burden was large (median 10 cm 3 ). At follow-up, 57/75 met MS criteria, 17/75 had clinically isolated syndrome, and 1 radiographic changes only. Disability scores were comparable to a prevalence cohort in Olmsted County ( p < 0.001, n = 218). Cognitive outcomes below age-normed standards included psychomotor, attention, working memory, and executive function domains. Total lesion volume and index lesion-related severity correlated with EDSS and cognitive performance. Volumetric cortical/subcortical GM correlated less than lesion metrics to cognitive outcomes., Conclusion: Despite early aggressive course in pathologically confirmed MS, its long-term course was comparable to typical MS in our study. Cognitive impairment in this group seemed to correlate strongest to index lesion severity and total lesion volume. It remains to be established how the aggressive nature of the lesion, biopsy, and treatment affect clinical/cognitive outcomes.

Reductions in skeletal muscle mass and function are often reported in patients with cancer-associated weight loss and are associated with reduced quality of life, impaired treatment tolerance, and increased mortality. Although cellular changes, including altered mitochondrial function, have been reported in animals, such changes have been incompletely characterized in humans with cancer. Whole body and skeletal muscle physical function, skeletal muscle mitochondrial function, and whole body protein turnover were assessed in eight patients with cancer-associated weight loss (10.1 ± 4.2% body weight over 6-12 mo) and 19 age-, sex-, and body mass index (BMI)-matched healthy controls to characterize skeletal muscle changes at the whole body, muscle, and cellular level. Potential pathways involved in cancer-induced alterations in metabolism and mitochondrial function were explored by interrogating skeletal muscle and plasma metabolomes. Despite similar lean mass compared with control participants, patients with cancer exhibited reduced habitual physical activity (57% fewer daily steps), cardiorespiratory fitness [22% lower V̇o 2peak (mL/kg/min)] and leg strength (35% lower isokinetic knee extensor strength), and greater leg neuromuscular fatigue (36% greater decline in knee extensor torque). Concomitant with these functional declines, patients with cancer had lower mitochondrial oxidative capacity [25% lower State 3 O 2 flux (pmol/s/mg tissue)] and ATP production [23% lower State 3 ATP production (pmol/s/mg tissue)] and alterations in phospholipid metabolite profiles indicative of mitochondrial abnormalities. Whole body protein turnover was unchanged. These findings demonstrate mitochondrial abnormalities concomitant with whole body and skeletal muscle functional derangements associated with human cancer, supporting future work studying the role of mitochondria in the muscle deficits associated with cancer. NEW & NOTEWORTHY To our knowledge, this is the first study to suggest that skeletal muscle mitochondrial deficits are associated with cancer-associated weight loss in humans. Mitochondrial deficits were concurrent with reductions in whole body and skeletal muscle functional capacity. Whether mitochondrial deficits are causal or secondary to cancer-associated weight loss and functional deficits remains to be determined, but this study supports further exploration of mitochondria as a driver of cancer-associated losses in muscle mass and function.

Context: Familial partial lipodystrophy (FPL), Dunnigan variety is characterized by skeletal muscle hypertrophy and insulin resistance besides fat loss from the extremities. The cause for the muscle hypertrophy and its functional consequences is not known., Objective: To compare muscle strength and endurance, besides muscle protein synthesis rate between subjects with FPL and matched controls (n = 6 in each group). In addition, we studied skeletal muscle mitochondrial function and gene expression pattern to help understand the mechanisms for the observed differences., Methods: Body composition by dual-energy X-ray absorptiometry, insulin sensitivity by minimal modelling, assessment of peak muscle strength and fatigue, skeletal muscle biopsy and calculation of muscle protein synthesis rate, mitochondrial respirometry, skeletal muscle transcriptome, proteome, and gene set enrichment analysis., Results: Despite increased muscularity, FPL subjects did not demonstrate increased muscle strength but had earlier fatigue on chest press exercise. Decreased mitochondrial state 3 respiration in the presence of fatty acid substrate was noted, concurrent to elevated muscle lactate and decreased long-chain acylcarnitine. Based on gene transcriptome, there was significant downregulation of many critical metabolic pathways involved in mitochondrial biogenesis and function. Moreover, the overall pattern of gene expression was indicative of accelerated aging in FPL subjects. A lower muscle protein synthesis and downregulation of gene transcripts involved in muscle protein catabolism was observed., Conclusion: Increased muscularity in FPL is not due to increased muscle protein synthesis and is likely due to reduced muscle protein degradation. Impaired mitochondrial function and altered gene expression likely explain the metabolic abnormalities and skeletal muscle dysfunction in FPL subjects., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Childhood adversity is a global health problem affecting 25-50% of children worldwide. Few prior studies have examined the underlying neurochemistry of adversity in adolescents. This cross-sectional study examined spectroscopic markers of trauma in a cohort of adolescents with major depressive disorder (MDD) and healthy controls. We hypothesized that historical adversity would have a negative relationship with spectroscopic measures of glutamate metabolites in anterior cingulate cortex., Methods: Adolescent participants (aged 13-21) underwent a semi-structured diagnostic interview and clinical assessment, which included the self-report Childhood Trauma Questionnaire (CTQ), a 28-item assessment of childhood adversity. Proton magnetic resonance spectroscopy ( 1 H-MRS) scans at 3 Tesla of an anterior cingulate cortex (ACC) voxel (8 cm 3 ) encompassing both hemispheres were collected using a 2-dimensional J -averaged sequence to assess N -acetylaspartate (NAA), Glx (glutamate+glutamine) and [NAA]/[Glx] concentrations. Generalized linear models assessed the relationships between CTQ scores and metabolite levels in ACC., Results: Thirty-nine participants (17 healthy controls, 22 depressed participants) underwent 1 H-MRS and completed the CTQ measures. There were decrements in [NAA]/[Glx] ratio in the ACC of participants with childhood adversity while no significant relationship between CTQ total score and any of the ACC metabolites was found in the combined sample. Exploratory results revealed a positive association between Glx levels and CTQ scores in depressed participants. Conversely the [NAA]/[Glx] ratio had a negative association with total CTQ scores in the depressed participants. Emotional Abuse Scale showed a significant negative relationship with [NAA]/[Glx] ratio in the combined sample when adjusted for depression severity., Conclusions: Our findings suggest that childhood adversity may impact brain neurochemical profiles. Further longitudinal studies should examine neurochemical correlates of childhood adversity throughout development and in populations with other psychiatric disorders., Competing Interests: Statement of Interest Dr. Lewis. received grant support from the Brain & Behavior Research Foundation as the Alan G. Ross Memorial Investigator. He has been a site investigator for multicenter trials funded by Neuronetics, Inc. and NeoSync, Inc. Dr. Port has served as an imaging consultant for Takeda Pharmaceutical Company, Ltd., Biomedical Systems Corp., and Neuronetics, Inc. Dr. Choi is a scientific advisory board member for Peptron Inc. Dr Croarkin has received research grant support from Pfizer, Inc; equipment support from Neuronetics, Inc; equipment support from MagVenture, Inc; and supplies and genotyping services from Assurex Health, Inc for investigator-initiated studies. He was the primary investigator for a multicenter study funded by Neuronetics, Inc and a site primary investigator for a study funded by NeoSync, Inc. Dr Croarkin has served as a consultant for Engrail Therapeutics, Myriad Neuroscience, Procter & Gamble Companyand Sunovion. The other authors report no financial relationships with commercial interests.

Gamma-aminobutyric acid (GABA) and glutamate neurotransmission have been implicated in the pathophysiology of depression and mechanistically linked to ketamine's antidepressant response. Seven patients with treatment-resistant depression enrolled in an open-label, feasibility trial of a single IV 40-min ketamine infusion during a functional MR spectroscopy (fMRS) scan utilizing a novel frequency adjusting MEGA-PRESS sequence. Next-day treatment remission and reduction in the MADRS scores correlated with anterior cingulate cortex peak GABA levels. These novel findings provide further insights into the underlying neurobiological mechanisms of ketamine and, if confirmed in larger studies, would be encouraging for further development of GABAergic biomarker associated with ketamine response., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

BACKGROUNDType 1 diabetes (T1D) is a risk factor for dementia and structural brain changes. It remains to be determined whether transient insulin deprivation that frequently occurs in insulin-treated individuals with T1D alters brain function.METHODSWe therefore performed functional and structural magnetic resonance imaging, magnetic resonance spectroscopy, and neuropsychological testing at baseline and following 5.4 ± 0.6 hours of insulin deprivation in 14 individuals with T1D and compared results with those from 14 age-, sex-, and BMI-matched nondiabetic (ND) participants with no interventions.RESULTSInsulin deprivation in T1D increased blood glucose, and β-hydroxybutyrate, while reducing bicarbonate levels. Participants with T1D showed lower baseline brain N-acetyl aspartate and myo-inositol levels but higher cortical fractional anisotropy, suggesting unhealthy neurons and brain microstructure. Although cognitive functions did not differ between participants with T1D and ND participants at baseline, significant changes in fine motor speed as well as attention and short-term memory occurred following insulin deprivation in participants with T1D. Insulin deprivation also reduced brain adenosine triphosphate levels and altered the phosphocreatine/adenosine triphosphate ratio. Baseline differences in functional connectivity in brain regions between participants with T1D and ND participants were noted, and on insulin deprivation further alterations in functional connectivity between regions, especially cortical and hippocampus-caudate regions, were observed. These alterations in functional connectivity correlated to brain metabolites and to changes in cognition.CONCLUSIONTransient insulin deprivation therefore caused alterations in executive aspects of cognitive function concurrent with functional connectivity between memory regions and the sensory cortex. These findings have important clinical implications, as many patients with T1D inadvertently have periods of transient insulin deprivation.TRIAL REGISTRATIONClinicalTrials.gov NCT03392441.FUNDINGClinical and Translational Science Award (UL1 TR002377) from the National Center for Advancing Translational Science; NIH grants (R21 AG60139 and R01 AG62859); the Mayo Foundation.

Since the relatively recent regulatory approval for clinical use in both Europe and North America, 7-Tesla (T) MRI has been adopted for clinical practice at our institution. Based on this experience, this article reviews the unique features of 7-T MRI neuroimaging and addresses the challenges of establishing a 7-T MRI clinical practice. The underlying fundamental physics principals of high-field strength MRI are briefly reviewed. Scanner installation, safety considerations, and artifact mitigation techniques are discussed. Seven-tesla MRI case examples of neurologic diseases including epilepsy, vascular abnormalities, and tumor imaging are presented to illustrate specific applications of 7-T MRI. The advantages of 7-T MRI in conjunction with advanced neuroimaging techniques such as functional MRI are presented. Seven-tesla MRI produces more detailed information and, in some cases, results in specific diagnoses where previous 3-T studies were insufficient. Still, persistent technical issues for 7-T scanning present ongoing challenges for radiologists.

Background & Aims: Obese patients with nonalcoholic steatohepatitis (NASH) are at risk for cirrhosis if significant weight loss is not achieved. The single fluid-filled intragastric balloon (IGB) induces meaningful weight loss and might be used in NASH treatment. We performed an open-label prospective study to evaluate the effects of IGB placement on metabolic and histologic features of NASH., Methods: Twenty-one patients with early hepatic fibrosis (81% female; mean age, 54 years; average body mass index, 44 kg/m 2 ) underwent magnetic resonance elastography (MRE) and endoscopic ultrasound with core liver biopsy collection at time IGB placement and removal at a single center from October 2016 through March 2018. The primary outcome measure was the changes in liver histology parameters after IGB, including change in nonalcoholic fatty liver disease activity score (NAS) and fibrosis score. We also evaluated changes in weight, body mass index, waist to hip ratio, aminotransaminases, fasting levels of lipids, fasting glucose, glycosylated hemoglobin, and MRE-detected liver stiffness., Results: Six months after IGB, patients' mean total body weight loss was 11.7% ± 7.7%, with significant reductions in HbA1c (1.3% ± 0.5%) (P = .02). Waist circumference decreased by 14.4 ± 2.2 cm (P = .001). NAS improved in 18 of 20 patients (90%), with a median decrease of 3 points (range, 1-4 points); 16 of 20 patients (80%) had improvements of 2 points or more. Fibrosis improved by 1.17 stages in 15% of patients, and MRE-detected fibrosis improved by 1.5 stages in 10 of 20 patients (50%). Half of patients reached endpoints approved by the Food and Drug Administration of for NASH resolution and fibrosis improvement. Percent total body weight loss did not correlate with reductions in NAS or fibrosis. Other than post-procedural pain (in 5% of patients), no serious adverse events were reported., Conclusion: In a prospective study, IGB facilitated significant metabolic and histologic improvements in NASH. IGB appears to be safe and effective for NASH management when combined with a prescribed diet and exercise program. ClinicalTrials.gov no: NCT02880189., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: Prior studies demonstrate elevated cortical glutamate (Glu) in patients with bipolar disorder (BD). Studies assessing neurochemistry in early stages of bipolar illness before the emergence of manic symptoms are lacking. This study aimed to examine neurochemical correlates measured by proton magnetic resonance spectroscopy ( 1 H-MRS) and a dimensional measure of bipolarity in a sample of depressed adolescents. Methods: Adolescent participants (aged 13-21 years) underwent a semistructured diagnostic interview and clinical assessment, which included the General Behavior Inventory Parent Version (P-GBI), a 73-item, parent-rated assessment of symptoms and behaviors. 1 H-MRS scans of a left dorsolateral prefrontal cortex (L-DLPFC) voxel (8 cm 3 ) were collected using a two-dimensional J -averaged sequence to assess N -acetylaspartate (NAA), Glu, Glx (glutamate + glutamine), and NAA/Glx concentrations. We used generalized linear models to assess the relationships between P-GBI scores and metabolite levels in L-DLPFC. Results: Thirty-six participants (17 healthy controls, 19 depressed) underwent 1 H-MRS scans and clinical evaluation with the P-GBI. There was a significant negative relationship between P-GBI score and L-DLPFC NAA/Glx in the whole sample. However, the magnitude of the effect was small and statistical significance was lost after correcting for multiple comparisons. Conclusions: These preliminary results suggest that NAA/Glx may have utility as a marker of bipolar traits in healthy and depressed adolescents. If replicated, 1 H-MRS measures of glutamatergic metabolism anomalies might have a role in identifying depressed adolescents at risk for mixed symptom presentations or BD. Identifying bipolarity in the early stages of the disease would have a significant impact on treatment planning and prognosis. Further longitudinal studies should examine neurochemical correlates of mood state during the developmental emergence of BD.

Objective: To describe differences between lipomatosis of nerve (LN) and neuromuscular choristoma (NMC) evaluated with MR spectroscopy (MRS)., Materials and Methods: Eight patients were included in this prospective pilot study: three patients with LNs and five with NMCs. Single voxel PRESS MRS of the tumors were acquired with 3 T MRI. MRS data were processed with LCModel version 6.3-1J using the internal "lipid-8" basis set. From individual lipid peak and water content measurements, total fatty acid molecules (TFAM), unsaturated fatty acid molecules (UFAM), and glycerol molecules (GM) were computed and analyzed, as well as ratios of UFAM/TFAM, TFAM/GM, and a fatty-acid chain-length index (CLI)., Results: The LN group included two men and one woman (average age 58.3 years); the NMC group included two men and three women (average age 20.4 years). Lipid composition analysis showed that LN had considerably more fat than NMC: TFAM: LN = 15.29 vs NMC = 7.14; UFAM: LN = 4.48 vs NMC = 2.63; GM: LN = 5.20 vs NMC = 1.02. Both tumors had a similar fraction of unsaturated fatty acids: UFAM/TFAM: LN = 0.29 vs NMC = 0.37. LN had the usual number of FA molecules/glycerol molecule, while NMC had considerably more: TFAM/GM: LN = 2.94 vs NMC = 6.98. Finally, average FA chains were longer in NMC: CLI: LN = 17.39 vs NMC = 22.55., Conclusion: Our analysis suggests measurable differences in the amount and composition of lipid in LN and NMC. While a larger, statistically powered study is needed, these initial findings may be helpful to properly diagnose ambiguous cases and thereby avoid surgical intervention such as biopsy.

Purpose: Deep learning (DL) algorithms have shown promising results for brain tumor segmentation in MRI. However, validation is required prior to routine clinical use. We report the first randomized and blinded comparison of DL and trained technician segmentations. Approach: We compiled a multi-institutional database of 741 pretreatment MRI exams. Each contained a postcontrast T1-weighted exam, a T2-weighted fluid-attenuated inversion recovery exam, and at least one technician-derived tumor segmentation. The database included 729 unique patients (470 males and 259 females). Of these exams, 641 were used for training the DL system, and 100 were reserved for testing. We developed a platform to enable qualitative, blinded, controlled assessment of lesion segmentations made by technicians and the DL method. On this platform, 20 neuroradiologists performed 400 side-by-side comparisons of segmentations on 100 test cases. They scored each segmentation between 0 (poor) and 10 (perfect). Agreement between segmentations from technicians and the DL method was also evaluated quantitatively using the Dice coefficient, which produces values between 0 (no overlap) and 1 (perfect overlap). Results: The neuroradiologists gave technician and DL segmentations mean scores of 6.97 and 7.31, respectively ( p < 0.00007 ). The DL method achieved a mean Dice coefficient of 0.87 on the test cases. Conclusions: This was the first objective comparison of automated and human segmentation using a blinded controlled assessment study. Our DL system learned to outperform its "human teachers" and produced output that was better, on average, than its training data., (© The Authors. Published by SPIE under a Creative Commons Attribution 4.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.)

The anterior cingulate cortex (ACC) is involved in emotion regulation and salience processing. Prior research has implicated ACC dysfunction in suicidal ideation (SI) and suicidal behavior. This study aimed to quantify ACC glutamatergic concentrations and to examine relationships with SI in a sample of healthy and depressed adolescents. Forty adolescents underwent clinical evaluation and proton magnetic resonance spectroscopy ( 1 H-MRS) at 3 T, utilizing a 2-dimensional J-averaged PRESS sequence sampling a medial pregenual ACC voxel. Cerebrospinal fluid-corrected ACC metabolite concentrations were compared between healthy control (HC, n = 16), depressed without SI (Dep/SI-, n = 13), and depressed with SI (Dep/SI+, n = 11) youth using general linear models covarying for age, sex, and psychotropic medication use. Relationships between ACC metabolites and continuous measures of SI were examined using multiple linear regressions. ROC analysis was used to determine the ability of glutamate+glutamine (Glx) and the N-acetylaspartate (NAA)/Glx ratio to discriminate Dep/SI- and Dep/SI+ adolescents. Dep/SI+ adolescents had higher Glx than Dep/SI- participants (p adj  = 0.012) and had lower NAA/Glx than both Dep/SI- (p adj  = 0.002) and HC adolescents (p adj  = 0.039). There were significant relationships between SI intensity and Glx (p FDR  = 0.026), SI severity and NAA/Glx (p FDR  = 0.012), and SI intensity and NAA/Glx (p FDR  = 0.004). ACC Glx and NAA/Glx discriminated Dep/SI- from Dep/SI+ participants. Uncoupled NAA-glutamatergic metabolism in the ACC may play a role in suicidal ideation and behavior. Longitudinal studies are needed to establish whether aberrant glutamatergic metabolism corresponds to acute or chronic suicide risk. Glutamatergic biomarkers may be promising targets for novel risk assessment and interventional strategies for suicidal ideation and behavior.

Psychiatric disorders are common and can be severe. There is a need to identify biomarkers of psychiatric disorders to better diagnose and treat patients with psychiatric symptoms. Magnetic resonance spectroscopy (MRS) is a tool used to measure the levels of various metabolites in the human brain, and MRS studies of psychiatric disorders have identified potentially useful biomarkers of psychiatric illness. There have been significant advances in the way that psychiatric disorders are understood, classified, and researched as well as improvements in magnetic resonance imaging/MRS technology. MRS as a tool has not yet proved helpful to individual patients with psychiatric symptoms., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Glutamatergic dysregulation is implicated in the neurobiology of mood disorders. This study investigated the relationship between the anterior cingulate cortex (AC) glutamate, as measured by proton magnetic resonance spectroscopy ( 1 H-MRS), and single-nucleotide polymorphisms (SNPs) from four genes (GLUL, SLC1A3, SLC1A2, and SLC1A7) that regulate the extracellular glutamate in 26 depressed patients with major depressive disorder (MDD; n = 15) and bipolar disorder (BD; n = 11). Two SNPs (rs3812778 and rs3829280), in perfect linkage disequilibrium, in the 3' untranslated region of the EAAT2 gene SLC1A2, were associated with AC glutamate, with minor allele carriers having significantly higher glutamate levels (p < 0.001) in comparison with common allele homozygotes. In silico analysis revealed an association of minor allele carriers of rs3812778/rs382920 with an upregulation of the astrocytic marker CD44 localized downstream of SLC1A2 on chromosome 11. Finally, we tested the disease relevance of these SNPs in a large group of depressed patients [MDD (n = 458); BD (n = 1473)] and found that minor allele carriers had a significantly higher risk for rapid cycling (p = 0.006). Further work is encouraged to delineate the functional impact of excitatory amino acid transporter genetic variation on CD44 associated physiology and glutamatergic neurotransmission, specifically glutamate-glutamine cycling, and its contribution to subphenotypes of mood disorders.

We retrospectively identified autism spectrum disorder (ASD) incident cases among 31,220 individuals in a population-based birth cohort based on signs and symptoms uniformly abstracted from medical and educational records. Inclusive and narrow research definitions of ASD (ASD-R I and ASD-R N , respectively) were explored, along with clinical diagnoses of ASD (ASD-C) obtained from the records. The incidence of ASD-R I, ASD-R N , and ASD-C increased significantly from 1985 to 1998, then ASD-R I and ASD-R N plateaued while the rate of ASD-C continued to increase during 1998-2004. The rising incidence of research-defined ASD may reflect improved recognition and documentation of ASD signs and symptoms. Although the frequency of threshold ASD symptoms stabilized, the rate of ASD-C continued to increase, narrowing the gap between clinical ascertainment and symptom documentation.

Background: This exploratory study sought to examine the effect of an acute course of high-frequency repetitive TMS on suicidal ideation in adolescents., Methods: Data were pooled from 3 prior protocols providing a 30-session course of open-label TMS treatment for adolescents with treatment-resistant depression. All participants (n = 19) were outpatients taking antidepressant medication, with TMS provided as adjunctive treatment. Suicidality was assessed at baseline, after 10 treatments, after 20 treatments, and after 30 treatments. Outcome measures of suicidal ideation included the Columbia Suicide Severity Rating Scale (C-SSRS) "Intensity of Ideation" subscale and Item 13 "Suicidality" on the Children's Depression Rating Scale, Revised (CDRS-R)., Results: The predicted odds of suicidal ideation (CDRS-R Item 13 and C-SSRS Intensity of Ideation subscale) significantly decreased over 6 weeks of acute TMS treatment without adjustments for illness (depression) severity. However, the magnitude of the decrease in the predicted odds of suicidal ideation across 6 weeks of treatment was attenuated and rendered non-significant in subsequent analyses that adjusted for illness (depression) severity., Limitations: This was an exploratory study with a small sample size and no sham control. Regulatory and ethical barriers constrained enrollment of adolescents with severe suicidality., Conclusions: The present findings suggest that open-label TMS mitigated suicidal ideation in adolescents through the treatment and improvement of depressive symptom severity. Although caution is warranted in the interpretation of these results, the findings can inform the design and execution of future interventional trials targeting suicidal ideation in adolescents., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Connectivity features based on resting-state (RS) functional magnetic resonance imaging (fMRI) demonstrate great promise as biomarkers to guide diagnosis and treatment in major depressive disorder (MDD). However, there is a pressing need for valid, reliable biomarkers closer to the bedside for clinical research and practice. This study directly compared RS-fMRI connectivity features with transcranial magnetic stimulation (TMS) neurophysiological measures, long interval cortical inhibition (LICI) and cortical silent period (CSP), in female adolescents with MDD. LICI-200 showed the most significant associations with RS functional connectivity features, demonstrating its potential to evaluate the neurochemical underpinnings of network features in MDD., (Copyright © 2018. Published by Elsevier B.V.)

Although suicide is the second-leading cause of death in adolescents and young adults worldwide, little progress has been made in developing reliable biological markers of suicide risk and suicidal behavior. Converging evidence suggests that excitatory and inhibitory cortical processes mediated by the neurotransmitters glutamate and γ-aminobutyric acid (GABA) are dysregulated in suicidal individuals. This study utilized single- and paired-pulse transcranial magnetic stimulation (TMS) to assess excitatory and inhibitory cortical functioning in healthy control adolescents (n = 20), depressed adolescents without any history of suicidal behavior ("Depressed", n = 37), and depressed adolescents with lifetime history of suicidal behavior ("Depressed+SB", n = 17). In a fixed-effects general linear model analysis, with age, sex, and depression severity as covariates, no significant group main effects emerged for resting motor threshold, intracortical facilitation, short-interval intracortical inhibition, or cortical silent period. However, group main effects were significant for long-interval intracortical inhibition (LICI) at interstimulus intervals (ISIs) of 100 ms and 150 ms, but not 200 ms. Depressed+SB adolescents demonstrated impaired LICI compared to healthy control and Depressed adolescents, while healthy control and Depressed participants did not differ in LICI. Multiple linear robust regression revealed significant positive linear relationships between lifetime suicidal behavior severity and impairment in LICI at 100-ms and 150-ms ISIs. In a post hoc receiver operating characteristic analysis, LICI significantly discriminated Depressed from Depressed+SB youth in 100-ms and 150-ms paradigms. These findings suggest that GABA B receptor-mediated inhibition is distinctly dysregulated in depressed adolescents with histories of suicidal behavior. Further research is warranted to establish the utility of cortical inhibition in the assessment of suicide risk and as a target for treatment interventions.

Background and Purpose: The 2010 McDonald criteria are designed to sensitively detect MS; however, the low specificity of these criteria can occasionally lead to the misdiagnosis of MS. The purpose of this study was to determine whether a novel double inversion recovery MR imaging technique has the potential to increase the specificity of diagnostic criteria distinguishing MS from non-MS white matter lesions., Materials and Methods: This was a cross-sectional observational study. MR imaging data were acquired between 2011 and 2016. A novel double inversion recovery sequence that suppresses CSF and GM signal was used (GM-double inversion recovery). We compared WM lesions in a group of patients with multiple sclerosis and in a second group of positive controls with white matter lesions who did not have a diagnosis of MS. The presence of a rim on the GM-double inversion recovery MR imaging sequence was combined with the 2001 and 2010 McDonald disseminated-in-space criteria. Multiple MR imaging markers, including lesion location, size, and the presence of a rim, were compared between groups as well as a quantitative measure of lesion T1 hypointensity., Results: MR images from 107 patients with relapsing-remitting MS (median age, 32 years) and 36 positive control (median age, 39 years) subjects were analyzed. No significant differences were found in age and sex. In patients with MS, 1120/3211 lesions (35%) had a rim on GM-double inversion recovery; the positive control group had only 9/893 rim lesions (1%). Rims were associated with a decrease in the lesion T1 ratio. Using the 2010 MR imaging criteria plus the presence of rims on GM-double inversion recovery, we achieved 78% and 97% specificity in subjects with ≥1 and ≥2 rim lesions, respectively., Conclusions: The addition of a novel GM-double inversion recovery technique enhanced specificity for diagnosing MS compared with established MR imaging criteria., (© 2018 by American Journal of Neuroradiology.)

We consider the problem of model-based clustering in the presence of many correlated, mixed continuous, and discrete variables, some of which may have missing values. Discrete variables are treated with a latent continuous variable approach, and the Dirichlet process is used to construct a mixture model with an unknown number of components. Variable selection is also performed to identify the variables that are most influential for determining cluster membership. The work is motivated by the need to cluster patients thought to potentially have autism spectrum disorder on the basis of many cognitive and/or behavioral test scores. There are a modest number of patients (486) in the data set along with many (55) test score variables (many of which are discrete valued and/or missing). The goal of the work is to (1) cluster these patients into similar groups to help identify those with similar clinical presentation and (2) identify a sparse subset of tests that inform the clusters in order to eliminate unnecessary testing. The proposed approach compares very favorably with other methods via simulation of problems of this type. The results of the autism spectrum disorder analysis suggested 3 clusters to be most likely, while only 4 test scores had high (>0.5) posterior probability of being informative. This will result in much more efficient and informative testing. The need to cluster observations on the basis of many correlated, continuous/discrete variables with missing values is a common problem in the health sciences as well as in many other disciplines., (Copyright © 2018 John Wiley & Sons, Ltd.)