Purpose The purpose of this study was to determine the reproducibility of a very short echo time (TE) phase rotation stimulated echo acquisition mode (STEAM) sequence at 3T with a focus on the detection of glutathione. Methods Ten healthy subjects were scanned on two separate visits. Spectra were acquired from voxels placed in the anterior and posterior cingulates. Reproducibility was assessed using mean coefficients of variation (CVs) and mean absolute differences (ADs), and reliability was assessed using standard error of measurement (SEM) and intraclass correlations (ICCs). Phantoms containing glutathione and metabolites with overlapping resonances were scanned to test the validity of glutathione quantification. Results Excellent reproducibility as illustrated by CVs ≤8.3% and ADs ≤11.6% for both regions was obtained for glutathione and other commonly reported metabolites. Reproducibility measures for γ-aminobutyric acid and glutamine were good overall with CVs ranging from 6.4%–10.5% and ADs ranging from 8.6%–15.5% for both regions. Glutathione absolute and relative reliability were very good (SEMs ≤9.9%) and fair (ICCs 0.42–0.51), respectively. Phantom studies demonstrated the ability to accurately detect glutathione from other metabolites with overlapping resonances with great precision (R2 = 0.09). Conclusion A very short TE phase rotation STEAM sequence proved reproducible for metabolites difficult to quantify but important for the study of psychiatric and neurological illness.

Individuals with a family history of substance use disorders (FH+) are at a greater risk of developing substance use disorders than their peers with no such family histories (FH−) and this vulnerability is proportional to the number of affected relatives (FH density). The risk for developing substance use disorders peaks during adolescence to early adulthood in the general population, and that is thought to be related to delayed maturation of frontocortical and frontostriatal functional circuits. We hypothesized that FH+ youth and young adults have impaired myelination of frontocortical and frontostriatal white matter tracts. We examined fractional anisotropy (FA) data in 80 FH+ and 34 FH− youths (12.9±1.0 years) and in 25 FH+ and 30 FH− young adults (24.3±3.4 years). FH+ youths had lower FA values in both frontocortical and frontostriatal tracts as well as parietocortical tracts including the anterior, superior and posterior corona radiata and the superior frontal-occipital fasciculus. Moreover, FA values in these tracts were negatively correlated with FH density. FH+ adults had lower FA values in two frontocortical tracts: the genu of the corpus callosum and anterior corona radiata and also significant negative correlations between FA and FH density in these same tracts. In both groups, lower FA values corresponded to higher radial diffusivity suggesting reduced axonal myelination. We interpreted our findings as evidence for impaired myelination of frontal white matter that was proportional to FH density. Our data suggest that deficits may partially resolve with age, paralleling an age-related decline in risk for developing substance use disorders.

2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018.

Memory is robustly impaired in schizophrenia (SZ) and related to functional outcome. Memory dysfunction has been shown to be related to altered brain glucose metabolism and brain insulin resistance in animal models and human studies of Alzheimer's disease. In this study, differences in brain glucose using magnetic resonance spectroscopy (MRS) and blood Extracellular Vesicle (EV) biomarkers of neuronal insulin resistance (i.e. Akt and signaling effectors) between SZ and controls were investigated, as well as whether these measures were related to memory impairments. Neuronal insulin resistance biomarkers showed a trend for being lower in SZ compared to controls, and memory measures were lower in SZ compared to controls. Occipital cortex glucose was higher in SZ compared to controls indicating lower brain glucose utilization. Linear regression analyses revealed significant relationships between neuronal insulin resistance biomarkers, memory measures, and brain glucose. More specifically, p70S6K, an insulin signaling effector, was related to verbal learning and brain MRS glucose in the SZ group. For the first time, we show that memory impairments in SZ may be related to brain glucose and brain insulin resistance. These data suggest that brain insulin resistance may play a role in the pathophysiology of learning and memory dysfunction in SZ.

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Long-term potentiation (LTP) is a basic cellular mechanism underlying learning and memory. LTP-like plasticity in the visual cortex can be induced by high frequency visual stimulation in rodents and humans. Since glutamate plays a fundamental role in LTP, this study investigated if visual cortical glutamate and glutamine levels, measured by proton magnetic resonance spectroscopy (MRS), relate to visual plasticity in humans. Since plasticity requires a delicate excitation and inhibition balance, GABA was also explored. Eighteen healthy participants completed MRS and a visual fMRI paradigm. Results revealed enhanced fMRI activations after high frequency visual stimulation, suggesting visual plasticity occurred. Higher activations were associated with higher resting glutamine levels after family wise error-correction. Exploratory analyses revealed that higher resting glutamate and GABA levels were associated with visual plasticity, suggesting there may be a critical excitation-inhibition balance necessary for experience dependent plasticity. This is the first empirical evidence that resting glutamine levels and potentially glutamate and GABA levels are associated with visual plasticity in humans.

The neurobiology of schizophrenia (SZ) may be altered in older versus younger adults with SZ, as less frequent episodes of symptom exacerbation and increased sensitivity to medications are observed in older age. The goal of this study was to examine the effect of age and diagnosis on glutamate and cerebral blood flow (rCBF) in adults with SZ and healthy controls. Young and older adults with SZ and healthy controls were recruited to participate in this study. Participants completed a neuropsychological battery and neuroimaging that included optimized magnetic resonance spectroscopy to measure anterior cingulate (AC) glutamate (Glu) and glutamine (Gln) and arterial spin labeling evaluation for rCBF. Regression analyses revealed significant effects of age with Glu, Gln, Gln/Glu, and AC white matter (WM) rCBF. Glu and WM rCBF decreased linearly with age while Gln and Gln/Glu increased linearly with age. Glu was lower in adults with SZ compared with healthy controls and in older adults versus younger adults but there was no interaction. Glu and WM rCBF were correlated with the UCSD Performance-Based Skills Assessment (UPSA) and processing speed, and the correlations were stronger in the SZ group. In the largest sample to date, lower Glu and elevated Gln/Glu levels were observed in adults with SZ and in older subjects. Contrary to expectation, these results do not show evidence of accelerated Glu aging in the anterior cingulate region in SZ compared with healthy controls.

Individuals with a family history of substance use disorder (FH+) show impaired frontal white matter as indicated by diffusion tensor imaging (DTI). This impairment may be due to impaired or delayed development of myelin in frontal regions, potentially contributing to this population’s increased risk for developing substance use disorders. In this study, we examined high angular resolution DTI and proton magnetic resonance spectroscopy data from the anterior corona radiata were collected in 80 FH+ and 34 FH− youths (12.9 ±1.0 years old). White matter integrity indices included fractional anisotropy (FA), N-acetylaspartate (NAA), and total choline (tCho). Lower FA suggests decreased myelination. Decreased NAA coupled with higher tCho suggests impaired build-up and maintenance of cerebral myelin and consequently greater breakdown of cellular membranes. We found FH+ youths had lower FA (P <0.0001) and NAA (P =0.017) and higher tCho (P =0.04). FH density (number of parents and grandparents with substance use disorders) was negatively correlated with FA (P <0.0001) and NAA (P =0.011) and positively correlated with tCho (P =0.001). FA was independently predicted by both FH density (P =0.006) and NAA (P= 0.002), and NAA and tCho were both independent predictors of FH density (P <0.001). Our finding of lower frontal FA in FH+ youths corresponding to lower NAA and increased tCho is consistent with delayed or impaired development of frontal white matter in FH+ youths. Longitudinal studies are needed to determine how these differences relate to substance use outcomes.