Deep Learning De-Noising Improves CT Perfusion Image Quality in the Setting of Lower Contrast Dosing: A Feasibility Study.

BACKGROUND AND PURPOSE: Considering recent iodinated contrast media (ICM) shortages, this study compared reduced ICM and standard dose CTP acquisitions, and the impact of deep learning (DL)-denoising on CTP image quality in preclinical and clinical studies. MATERIALS AND METHODS: Twelve swine underwent 9 CTP exams each, performed at combinations of 3 different X-ray (37, 67, and 127mAs) and ICM doses (10, 15, and 20mL). Clinical CTP acquisitions performed before and during the ICM shortage and protocol change (from 40 mL to 30 mL) were retrospectively included. Eleven patients with reduced ICM dose and 11 propensity-score-matched controls with standard ICM dose were included. A Residual Encoder-Decoder Convolutional-Neural-Network (RED-CNN) was trained for CTP denoising using K-space-Weighted Image Average (KWIA) filtered CTP images as the target. The standard, RED-CNN denoised, and KWIA noise-filtered images for animal and human studies were compared for quantitative SNR and qualitative image evaluation. RESULTS: The SNR of animal CTP images decreased with reductions in ICM and mAs doses. Contrast dose reduction had a greater effect on SNR than mAs reduction. Noise-filtering by KWIA and RED-CNN denoising progressively improved SNR of CTP maps, with RED-CNN resulting in the highest SNR. The SNR of clinical CTP images was generally lower with reduced ICM dose, which was improved by KWIA and RED-CNN denoising (p<0.05). Qualitative readings consistently rated RED-CNN denoised CTP as best quality, followed by KWIA and then standard CTP images. CONCLUSIONS: DL-denoising can improve image quality for low ICM CTP protocols, and could approximate standard ICM dose CTP, in addition to potentially improving image quality for low mAs acquisitions. ABBREVIATIONS: ICM=iodinated contrast media; DL=deep learning; KWIA=k-space weighted image average; LCD=low-contrast dose; SCD=standard contrast dose; RED-CNN=Residual Encoder-Decoder Convolutional Neural Network; PSNR=Peak Signal to Noise Ratio; RMSE=Root Mean Squared Error; SSIM=Structural Similarity Index.

Smoking, tobacco dependence, and neurometabolites in the dorsal anterior cingulate cortex.

Cigarette smoking has a major impact on global health and morbidity, and positron emission tomographic research has provided evidence for reduced inflammation in the human brain associated with cigarette smoking. Given the consequences of inflammatory dysfunction for health, the question of whether cigarette smoking affects neuroinflammation warrants further investigation. The goal of this project therefore was to validate and extend evidence of hypoinflammation related to smoking, and to examine the potential contribution of inflammation to clinical features of smoking. Using magnetic resonance spectroscopy, we measured levels of neurometabolites that are putative neuroinflammatory markers. N-acetyl compounds (N-acetylaspartate + N-acetylaspartylglutamate), glutamate, creatine, choline-compounds (phosphocholine + glycerophosphocholine), and myo-inositol, have all been linked to neuroinflammation, but they have not been examined as such with respect to smoking. We tested whether people who smoke cigarettes have brain levels of these metabolites consistent with decreased neuroinflammation, and whether clinical features of smoking are associated with levels of these metabolites. The dorsal anterior cingulate cortex was chosen as the region-of-interest because of previous evidence linking it to smoking and related states. Fifty-four adults who smoked daily maintained overnight smoking abstinence before testing and were compared with 37 nonsmoking participants. Among the smoking participants, we tested for associations of metabolite levels with tobacco dependence, smoking history, craving, and withdrawal. Levels of N-acetyl compounds and glutamate were higher, whereas levels of creatine and choline compounds were lower in the smoking group as compared with the nonsmoking group. In the smoking group, glutamate and creatine levels correlated negatively with tobacco dependence, and creatine correlated negatively with lifetime smoking, but none of the metabolite levels correlated with craving or withdrawal. The findings indicate a link between smoking and a hypoinflammatory state in the brain, specifically in the dorsal anterior cingulate cortex. Smoking may thereby increase vulnerability to infection and brain injury.

Alcohol Craving and Severity are Associated with Dorsal Anterior Cingulate Choline Levels in Individuals with an Alcohol Use Disorder.

AIMS: Magnetic resonance spectroscopy (MRS) has been used to probe inflammation in the brain. While altered MRS metabolite levels have previously been found in individuals with alcohol use disorder (AUD), the relationship between potential metabolite markers of inflammation and the clinical correlates of AUD remains understudied. Therefore, this exploratory study sought to elucidate the clinical significance of inflammation in AUD by examining relationships between metabolites, AUD severity, alcohol consumption, and craving in individuals with AUD. METHODS: Data for this secondary analysis are derived from a two-week clinical trial of ibudilast to treat AUD. Forty-three non-treatment-seeking individuals with an AUD (26M/17F) completed an MRS scan and alcohol-related questionnaires. MRS was performed using a multi-voxel array placed above the corpus callosum, extending from the pregnenual anterior cingulate to premotor cortex. The dorsal anterior cingulate was selected as the volume of interest. Metabolite levels of choline-compounds (Cho), myo-inositol (mI), and creatine+phosphocreatine (Cr) were quantified. Separate hierarchical regression models were used to evaluate the independent effects of metabolite levels on alcohol craving, alcohol problem severity, and alcohol consumption. RESULTS: Dorsal anterior cingulate Cho predicted alcohol craving and alcohol problem severity over and above demographics, medication, and alcohol consumption measures. mI and Cr did not predict alcohol craving or alcohol problem severity. Metabolite markers were not predictive of alcohol consumption. CONCLUSIONS: This preliminary study indicates that dACC Cho is sensitive to clinical characteristics of AUD. This is a further step in advancing neurometabolites, particularly Cho, as potential biomarkers and treatment targets for AUD.

Recent progress in analysis of intermediary metabolism by ex vivo 13 C NMR.

Advanced imaging technologies, large-scale metabolomics, and the measurement of gene transcripts or enzyme expression all enable investigations of intermediary metabolism in human patients. Complementary information about fluxes in individual metabolic pathways may be obtained by ex vivo 13 C NMR of blood or tissue biopsies. Simple molecules such as 13 C-labeled glucose are readily administered to patients prior to surgical biopsies, and 13 C-labeled glycerol is easily administered orally to outpatients. Here, we review recent progress in practical applications of 13 C NMR to study cancer biology, the response to oxidative stress, gluconeogenesis, triglyceride synthesis in patients, as well as new insights into compartmentation of metabolism in the cytosol. The technical aspects of obtaining the sample, preparing material for analysis, and acquiring the spectra are relatively simple. This approach enables convenient, valuable, and quantitative insights into intermediary metabolism in patients.

Preliminary evidence for a lower brain age in children with attention-deficit/hyperactivity disorder.

Attention-deficit hyperactivity disorder (ADHD) is a debilitating disorder with apparent roots in abnormal brain development. Here, we quantified the level of individual brain maturation in children with ADHD using structural neuroimaging and a recently developed machine learning algorithm. More specifically, we compared the BrainAGE index between three groups matched for chronological age (mean ± SD: 11.86 ± 3.25 years): 89 children diagnosed with ADHD, 34 asymptomatic siblings of those children with ADHD, and 21 unrelated healthy control children. Brains of children with ADHD were estimated significantly younger (-0.85 years) than brains of healthy controls (Cohen's d = -0.33; p = 0.028, one-tailed), while there were no significant differences between unaffected siblings and healthy controls. In addition, more severe ADHD symptoms were significantly associated with younger appearing brains. Altogether, these results are in line with the proposed delay of individual brain maturation in children with ADHD. However, given the relatively small sample size (N = 144), the findings should be considered preliminary and need to be confirmed in future studies.

Lactation alters the relationship between liver lipid synthesis and hepatic fat stores in the postpartum period.

In mothers who are nursing their infants, increased clearance of plasma metabolites into the mammary gland may reduce ectopic lipid in the liver. No study to date has investigated the role of lactation on liver lipid synthesis in humans, and we hypothesized that lactation would modify fatty acid and glucose handling to support liver metabolism in a manner synchronized with the demands of milk production. Lactating (n = 18) and formula-feeding women (n = 10) underwent metabolic testing at 6-week postpartum to determine whether lactation modified intrahepatic triacylglycerols (IHTGs), measured by proton magnetic resonance spectroscopy. Subjects ingested oral deuterated water to measure fractional de novo lipogenesis (DNL) in VLDL-TG during fasting and during an isotope-labeled clamp at an insulin infusion rate of 10 mU/m2/min. Compared with formula-feeding women, we found that lactating women exhibited lower plasma VLDL-TG concentrations, similar IHTG content and similar contribution of DNL to total VLDL-TG production. These findings suggest that lactation lowers plasma VLDL-TG concentrations for reasons that are unrelated to IHTG and DNL. Surprisingly, we determined that the rate of appearance of nonesterified fatty acids was not related to IHTG in either group, and the expected positive association between DNL and IHTG was only significant in formula-feeding women. Further, in lactating women only, the higher the prolactin concentration, the lower the IHTG, while greater DNL strongly associated with elevations in VLDL-TG. In conclusion, we suggest that future studies should investigate the role of lactation and prolactin in liver lipid secretion and metabolism.

Effects of ibudilast on central and peripheral markers of inflammation in alcohol use disorder: A randomized clinical trial.

Ibudilast, a neuroimmune modulator, shows promise as a pharmacotherapy for alcohol use disorder (AUD). In vivo administration of ibudilast reduces the expression of pro-inflammatory cytokines in animal models, but its effects on markers of inflammation in humans are unknown. This preliminary study examined the effect of ibudilast on peripheral and potential central markers of inflammation in individuals with AUD. This study also explored the predictive relationship of neurometabolite markers with subsequent drinking in the trial. Non-treatment-seeking individuals with an AUD (n = 52) were randomized to receive oral ibudilast (n = 24) or placebo (n = 28) for 2 weeks. Plasma levels of peripheral inflammatory markers were measured at baseline and after 1 and 2 weeks of medication. At study mid-point, proton magnetic resonance spectroscopy was performed to measure potential neurometabolite markers of inflammation: choline-compounds (Cho), myo-inositol (MI) and creatine + phosphocreatine (Cr) in frontal and cingulate cortices from 43 participants (ibudilast: n = 20; placebo: n = 23). The treatment groups were compared on peripheral and central markers. Ibudilast-treated participants had lower Cho in superior frontal white matter and nominally lower MI in pregenual anterior cingulate cortex. Ibudilast-treated participants had nominally lower C-reactive protein levels at visit 2 and nominally lower TNF-α/IL-10 ratios, relative to placebo. C-reactive protein and Cho levels were correlated, controlling for medication. Superior frontal white matter Cho predicted drinking in the following week. Micro-longitudinal ibudilast treatment may induce peripheral and putative central anti-inflammatory responses in patients with AUD. The neurometabolite responses may be associated with reduction in drinking, suggesting an anti-inflammatory component to the therapeutic action of ibudilast.

Magnetic resonance spectroscopy shows associations between neurometabolite levels and perivascular space volume in Parkinson's disease: a pilot and feasibility study.

OBJECTIVE: Higher volume fraction of perivascular space (PVS) has recently been reported in Parkinson's disease (PD) and related disorders. Both elevated PVS and altered levels of neurometabolites, assayed by proton magnetic resonance spectroscopy (MRS), are suspected indicators of neuroinflammation, but no published reports have concurrently examined PVS and MRS neurometabolites. METHODS: In an exploratory pilot study, we acquired multivoxel 3-T MRS using a semi-Localization by Adiabatic SElective Refocusing (sLASER) pulse-sequence (repetition time/echo time = 2810/60 ms, voxels 10 × 10 × 10 mm3) from a 2D slab sampling bilateral frontal white matter (FWM) and anterior middle cingulate cortex (aMCC). PVS maps obtained from high-resolution (0.8 × 0.8 × 0.8 mm3) T1-weighted MRI were co-registered with MRS. In each MRS voxel, PVS volume and neurometabolite levels were measured. RESULTS: Linear regression accounting for age, sex, and BMI found greater PVS volume for higher levels of choline-containing compounds (Cho; P = 0.047) in FWM and lower PVS volume for higher levels of N-acetyl compounds (NAA; P = 0.012) in aMCC. Since (putatively) higher Cho is associated with inflammation while NAA has anti-inflammatory properties, these observations add to evidence that higher PVS load is a sign of inflammation. Additionally, lower Montreal Cognitive Assessment scores were associated with lower NAA in aMCC (P = 0.002), suggesting that local neuronal dysfunction and inflammation contribute to cognitive impairment in PD. CONCLUSION: These exploratory findings indicate that co-analysis of PVS and MRS is feasible and may help elucidate the cellular and metabolic substrates of glymphatic and inflammatory processes in PD.

Combining neuroimaging and behavior to discriminate children with attention deficit-hyperactivity disorder with and without prenatal alcohol exposure.

In many patients, ostensible idiopathic attention deficit-hyperactivity disorder (ADHD) may actually stem from covert prenatal alcohol exposure (PAE), a treatment-relevant distinction. This study attempted a receiver-operator characteristic (ROC) classification of children with ADHD into those with PAE (ADHD+PAE) and those without (ADHD-PAE) using neurobehavioral instruments alongside magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) of supraventricular brain white matter. Neurobehavioral, MRS, and DTI endpoints had been suggested by prior findings. Participants included children aged 8-13 years, 23 with ADHD+PAE, 19 with familial ADHD-PAE, and 28 typically developing (TD) controls. With area-under-the-curve (AUC) >0.90, the Conners 3 Parent Rating Scale Inattention (CIn) and Hyperactivity/Impulsivity (CHp) scores and the Behavioral Regulation Index (BRI) of the Behavior Rating Inventory of Executive Function (BRIEF2) excellently distinguished the clinical groups from TD, but not from each other (AUC < 0.70). Combinations of MRS glutamate (Glu) and N-acetyl-compounds (NAA) and DTI mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), and fractional anisotropy (FA) yielded "good" (AUC > 0.80) discrimination. Neuroimaging combined with CIn and BRI achieved AUC 0.72 and AUC 0.84, respectively. But neuroimaging combined with CHp yielded 14 excellent combinations with AUC ≥ 0.90 (all p < 0.0005), the best being Glu·AD·RD·CHp/(NAA·FA) (AUC 0.92, sensitivity 1.00, specificity 0.82, p < 0.0005). Using Cho in lieu of Glu yielded AUC 0.83. White-matter microstructure and metabolism may assist efforts to discriminate ADHD etiologies and to detect PAE, beyond the ability of commonly used neurobehavioral measures alone.

Impact of prenatal alcohol exposure on intracortical myelination and deep white matter in children with attention deficit hyperactivity disorder.

White matter alterations have been reported in children with prenatal alcohol exposure (PAE) and in children with attention deficit hyperactivity disorder (ADHD); however, as children with PAE often present with ADHD, covert PAE may have contributed to previous ADHD findings. Additionally, data regarding intracortical myelination in ADHD are lacking. Therefore, we evaluated intracortical myelination (assessed as the T1w/T2w ratio at 4 cortical ribbon levels) and myelin-related deep white matter features in children (aged 8-13 years) with ADHD with PAE (ADHD + PAE), children with familial ADHD without PAE (ADHD-PAE), and typically developing (TD) children. In widespread tracts, ADHD + PAE children showed higher mean and radial diffusivity than TD and ADHD-PAE children and lower fractional anisotropy than ADHD-PAE children; ADHD-PAE and TD children did not differ significantly. Compared to TD children, ADHD + PAE children had lower intracortical myelination only at the deepest cortical level (mainly in right insula and cingulate cortices), while ADHD-PAE children had lower intracortical myelination at multiple cortical levels (mainly in right insula, sensorimotor, and cingulate cortices); ADHD + PAE and ADHD-PAE children did not differ significantly in intracortical myelination. Considering the two ADHD groups jointly (via non-parametric combination) revealed common reductions in intracortical myelination, but no common deep white matter abnormalities. These results suggest the importance of considering PAE in ADHD studies of white matter pathology. ADHD + PAE may be associated with deeper, white matter abnormalities, while familial ADHD without PAE may be associated with more superficial, cortical abnormalities. This may be relevant to the different treatment response observed in these two ADHD etiologies.

Cortical gyrification in children with attention deficit-hyperactivity disorder and prenatal alcohol exposure.

BACKGROUND: An improved understanding of the neurodevelopmental differences between attention deficit hyperactivity disorder with and without prenatal alcohol exposure (ADHD + PAE and ADHD-PAE, respectively) is needed. Herein, we evaluated gyrification (cortical folding) in children with ADHD + PAE compared to that in children with familial ADHD-PAE and typically developing (TD) children. METHODS: ADHD + PAE (n = 37), ADHD-PAE (n = 25), and TD children (n = 27), aged 8-13 years, were compared on facial morphological, neurobehavioral, and neuroimaging assessments. Local gyrification index (LGI) maps were compared between groups using general linear modelling. Relationships between LGI and clincobehavioral parameters in children with ADHD ± PAE were evaluated using multivariate partial least squares. RESULTS: ADHD + PAE and ADHD-PAE groups showed significantly lower LGI (relative to TD) in numerous regions, overlapping in medial prefrontal, parietal, and temporo-occipital cortices (p < 0.001). However, LGI in left mid-dorsolateral prefrontal cortex was uniquely lower in the ADHD + PAE group (p < 0.001). Partial least squares analysis identified one significant latent variable (accounting for 59.3 % of the crossblock correlation, p < 0.001), reflecting a significant relationship between a profile of lower LGI in prefrontal (including left mid-dorsolateral), insular, cingulate, temporal, and parietal cortices and a clinicobehavioral profile of PAE, including a flat philtrum and upper vermillion border, lower IQ, poorer behavioral regulation scores, and greater hyperactivity/impulsivity. CONCLUSIONS: Children with ADHD + PAE uniquely demonstrate lower mid-dorsolateral LGI, with widespread lower LGI related to more severe facial dysmorphia and neurobehavioral impairments. These findings add insight into the brain bases of PAE symptoms, potentially informing more targeted ADHD treatments based on an objective differential diagnosis of ADHD + PAE vs. ADHD-PAE.

Analysis of steady-state carbon tracer experiments using akaike information criteria.

INTRODUCTION: Carbon isotope tracers have been used to determine relative rates of tricarboxylic acid cycle (TCA) cycle pathways since the 1950s. Steady-state experimental data are typically fit to a single mathematical model of metabolism to determine metabolic fluxes. Whether the chosen model is appropriate for the biological system has generally not been evaluated systematically. An overly-simple model omits known pathways while an overly-complex model may produce incorrect results due to overfitting. OBJECTIVES: The objectives were to develop and study a method that systematically evaluates multiple TCA cycle mathematical models as part of the fitting process. METHODS: The problem of choosing overly-simple or overly-complex models was approached by developing software that automatically explores all possible combinations of flux through pyruvate dehydrogenase, pyruvate kinase, pyruvate carboxylase and anaplerosis at propionyl-CoA carboxylase, and equivalent pathways, all relative to TCA cycle flux. Typical TCA cycle metabolic tracer experiments that use 13C nuclear magnetic resonance for detection and quantification of 13C-enriched glutamate products were simulated and analyzed. By evaluating the multiple model fits with both the conventional sum-of-squares residual error (SSRE) and the Akaike Information Criterion (AIC), the software helps the investigator understand the interaction between model complexity and goodness of fit. RESULTS: When fitting alternative models of the TCA cycle metabolism, the SSRE may identify more than one model that fits the data well. Among those models, the AIC provides guidance as to which is the simplest of the candidate models is sufficient to describe the observed data. However under some conditions, AIC used alone inappropriately discriminates against necessary metabolic complexity. CONCLUSION: In combination, the SSRE and AIC help the investigator identify the model that best describes the metabolism of a biological system.

Neuroimaging of Supraventricular Frontal White Matter in Children with Familial Attention-Deficit Hyperactivity Disorder and Attention-Deficit Hyperactivity Disorder Due to Prenatal Alcohol Exposure.

Attention-deficit hyperactivity disorder (ADHD) is common in patients with (ADHD+PAE) and without (ADHD-PAE) prenatal alcohol exposure (PAE). Many patients diagnosed with idiopathic ADHD actually have covert PAE, a treatment-relevant distinction. To improve differential diagnosis, we sought to identify brain differences between ADHD+PAE and ADHD-PAE using neurobehavioral, magnetic resonance spectroscopy, and diffusion tensor imaging metrics that had shown promise in past research. Children 8-13 were recruited in three groups: 23 ADHD+PAE, 19 familial ADHD-PAE, and 28 typically developing controls (TD). Neurobehavioral instruments included the Conners 3 Parent Behavior Rating Scale and the Delis-Kaplan Executive Function System (D-KEFS). Two dimensional magnetic resonance spectroscopic imaging was acquired from supraventricular white matter to measure N-acetylaspartate compounds, glutamate, creatine + phosphocreatine (creatine), and choline-compounds (choline). Whole brain diffusion tensor imaging was acquired and used to to calculate fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity from the same superventricular white matter regions that produced magnetic resonance spectroscopy data. The Conners 3 Parent Hyperactivity/Impulsivity Score, glutamate, mean diffusivity, axial diffusivity, and radial diffusivity were all higher in ADHD+PAE than ADHD-PAE. Glutamate was lower in ADHD-PAE than TD. Within ADHD+PAE, inferior performance on the D-KEFS Tower Test correlated with higher neurometabolite levels. These findings suggest white matter differences between the PAE and familial etiologies of ADHD. Abnormalities detected by magnetic resonance spectroscopy and diffusion tensor imaging co-localize in supraventricular white matter and are relevant to executive function symptoms of ADHD.

Profiling Carbohydrate Metabolism in Liver and Hepatocellular Carcinoma with [13C]-Glycerate Probes.

The interplay between glycolysis and gluconeogenesis is central to carbohydrate metabolism. Here, we describe novel methods to assess carbohydrate metabolism using [13C]-probes derived from glycerate, a molecule whose metabolic fate in mammals remains underexplored. Isotope-based studies were conducted via NMR and mass spectrometry analyses of freeze-clamped liver tissue extracts after [2,3-13C2]glycerate infusion. The ex vivo investigations were correlated with in vivo measurements using hyperpolarized [1-13C]glycerate. Application of [13C]glycerate to N-nitrosodiethylamine (DEN)-treated rats provided further assessments of intermediary carbohydrate metabolism in hepatocellular carcinoma. This method afforded direct analyses of control versus DEN tissues, and altered ratios of 13C metabolic products as well as unique glycolysis intermediates were observed in the DEN liver/tumor. Isotopomer studies showed increased glycerate uptake and altered carbohydrate metabolism in the DEN rats.

The clinical utility of proton magnetic resonance spectroscopy in traumatic brain injury: recommendations from the ENIGMA MRS working group.

Proton (1H) 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 1H magnetic resonance spectroscopy and review 1H magnetic resonance spectroscopy findings in different injury populations. In addition, we propose a basic 1H 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 1H magnetic resonance spectroscopy in the study of traumatic brain injury, as well as recommendations to improve data harmonization across groups already using this technique.

Low Dose CT Perfusion With K-Space Weighted Image Average (KWIA).

CTP (Computed Tomography Perfusion) is widely used in clinical practice for the evaluation of cerebrovascular disorders. However, CTP involves high radiation dose (≥~200mGy) as the X-ray source remains continuously on during the passage of contrast media. The purpose of this study is to present a low dose CTP technique termed K-space Weighted Image Average (KWIA) using a novel projection view-shared averaging algorithm with reduced tube current. KWIA takes advantage of k-space signal property that the image contrast is primarily determined by the k-space center with low spatial frequencies and oversampled projections. KWIA divides each 2D Fourier transform (FT) or k-space CTP data into multiple rings. The outer rings are averaged with neighboring time frames to achieve adequate signal-to-noise ratio (SNR), while the center region of k-space remains unchanged to preserve high temporal resolution. Reduced dose sinogram data were simulated by adding Poisson distributed noise with zero mean on digital phantom and clinical CTP scans. A physical CTP phantom study was also performed with different X-ray tube currents. The sinogram data with simulated and real low doses were then reconstructed with KWIA, and compared with those reconstructed by standard filtered back projection (FBP) and simultaneous algebraic reconstruction with regularization of total variation (SART-TV). Evaluation of image quality and perfusion metrics using parameters including SNR, CNR (contrast-to-noise ratio), AUC (area-under-the-curve), and CBF (cerebral blood flow) demonstrated that KWIA is able to preserve the image quality, spatial and temporal resolution, as well as the accuracy of perfusion quantification of CTP scans with considerable (50-75%) dose-savings.

Dorsolateral prefrontal γ-aminobutyric acid in patients with treatment-resistant depression after transcranial magnetic stimulation measured with magnetic resonance spectroscopy

Background: The therapeutic mechanism of repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant depression (TRD) may involve modulation of γ-aminobutyric acid (GABA) levels. We used proton magnetic resonance spectroscopy (MRS) to assess changes in GABA levels at the site of rTMS in the left dorsolateral prefrontal cortex (DLPFC). Methods: In 26 adults with TRD, we used Mescher­Garwood point-resolved spectroscopy (MEGA-PRESS) spectral-editing MRS to measure GABA in the left DLPFC before and after standard clinical treatment with rTMS. All participants but 1 were medicated, including 12 patients on GABA agonist agents. Results: Mean GABA in the DLPFC increased 10.0% (p = 0.017) post-rTMS in the overall sample. As well, GABA increased significantly in rTMS responders (n = 12; 23.6%, p = 0.015) but not in nonresponders (n = 14; 4.1%, p = not significant). Changes in GABA were not significantly affected by GABAergic agonists, but clinical response was less frequent (p = 0.005) and weaker (p = 0.035) in the 12 participants who were receiving GABA agonists concomitant with rTMS treatment. Limitations: This study had an open-label design in a population receiving naturalistic treatment. Conclusion: Treatment using rTMS was associated with increases in GABA levels at the stimulation site in the left DLPFC, and the degree of GABA change was related to clinical improvement. Participants receiving concomitant treatment with a GABA agonist were less likely to respond to rTMS. These findings were consistent with earlier studies showing the effects of rTMS on GABA levels and support a GABAergic model of depression.

Progressive brain atrophy in chronically infected and treated HIV+ individuals.

Growing evidence points to persistent neurological injury in chronic HIV infection. It remains unclear whether chronically HIV-infected individuals on combined antiretroviral therapy (cART) develop progressive brain injury and impaired neurocognitive function despite successful viral suppression and immunological restoration. In a longitudinal neuroimaging study for the HIV Neuroimaging Consortium (HIVNC), we used tensor-based morphometry to map the annual rate of change of regional brain volumes (mean time interval 1.0 ± 0.5 yrs), in 155 chronically infected and treated HIV+ participants (mean age 48.0 ± 8.9 years; 83.9% male) . We tested for associations between rates of brain tissue loss and clinical measures of infection severity (nadir or baseline CD4+ cell count and baseline HIV plasma RNA concentration), HIV duration, cART CNS penetration-effectiveness scores, age, as well as change in AIDS Dementia Complex stage. We found significant brain tissue loss across HIV+ participants, including those neuro-asymptomatic with undetectable viral loads, largely localized to subcortical regions. Measures of disease severity, age, and neurocognitive decline were associated with greater atrophy. Chronically HIV-infected and treated individuals may undergo progressive brain tissue loss despite stable and effective cART, which may contribute to neurocognitive decline. Understanding neurological complications of chronic infection and identifying factors associated with atrophy may help inform strategies to maintain brain health in people living with HIV.

N-Acetyl and Glutamatergic Neurometabolites in Perisylvian Brain Regions of Methamphetamine Users.

Background: Methamphetamine induces neuronal N-acetyl-aspartate synthesis in preclinical studies. In a preliminary human proton magnetic resonance spectroscopic imaging investigation, we also observed that N-acetyl-aspartate+N-acetyl-aspartyl-glutamate in right inferior frontal cortex correlated with years of heavy methamphetamine abuse. In the same brain region, glutamate+glutamine is lower in methamphetamine users than in controls and is negatively correlated with depression. N-acetyl and glutamatergic neurochemistries therefore merit further investigation in methamphetamine abuse and the associated mood symptoms. Methods: Magnetic resonance spectroscopic imaging was used to measure N-acetyl-aspartate+N-acetyl-aspartyl-glutamate and glutamate+glutamine in bilateral inferior frontal cortex and insula, a neighboring perisylvian region affected by methamphetamine, of 45 abstinent methamphetamine-dependent and 45 healthy control participants. Regional neurometabolite levels were tested for group differences and associations with duration of heavy methamphetamine use, depressive symptoms, and state anxiety. Results: In right inferior frontal cortex, N-acetyl-aspartate+N-acetyl-aspartyl-glutamate correlated with years of heavy methamphetamine use (r = +0.45); glutamate+glutamine was lower in methamphetamine users than in controls (9.3%) and correlated negatively with depressive symptoms (r = -0.44). In left insula, N-acetyl-aspartate+N-acetyl-aspartyl-glutamate was 9.1% higher in methamphetamine users than controls. In right insula, glutamate+glutamine was 12.3% lower in methamphetamine users than controls and correlated negatively with depressive symptoms (r = -0.51) and state anxiety (r = -0.47). Conclusions: The inferior frontal cortex and insula show methamphetamine-related abnormalities, consistent with prior observations of increased cortical N-acetyl-aspartate in methamphetamine-exposed animal models and associations between cortical glutamate and mood in human methamphetamine users.

Magnetic resonance spectroscopy of fiber tracts in children with traumatic brain injury: A combined MRS - Diffusion MRI study.

Traumatic brain injury can cause extensive damage to the white matter (WM) of the brain. These disruptions can be especially damaging in children, whose brains are still maturing. Diffusion magnetic resonance imaging (dMRI) is the most commonly used method to assess WM organization, but it has limited resolution to differentiate causes of WM disruption. Magnetic resonance spectroscopy (MRS) yields spectra showing the levels of neurometabolites that can indicate neuronal/axonal health, inflammation, membrane proliferation/turnover, and other cellular processes that are on-going post-injury. Previous analyses on this dataset revealed a significant division within the msTBI patient group, based on interhemispheric transfer time (IHTT); one subgroup of patients (TBI-normal) showed evidence of recovery over time, while the other showed continuing degeneration (TBI-slow). We combined dMRI with MRS to better understand WM disruptions in children with moderate-severe traumatic brain injury (msTBI). Tracts with poorer WM organization, as shown by lower FA and higher MD and RD, also showed lower N-acetylaspartate (NAA), a marker of neuronal and axonal health and myelination. We did not find lower NAA in tracts with normal WM organization. Choline, a marker of inflammation, membrane turnover, or gliosis, did not show such associations. We further show that multi-modal imaging can improve outcome prediction over a single modality, as well as over earlier cognitive function measures. Our results suggest that demyelination plays an important role in WM disruption post-injury in a subgroup of msTBI children and indicate the utility of multi-modal imaging.