Practical considerations of diffusion-weighted MRS with ultra-strong diffusion gradients.

Introduction: Diffusion-weighted magnetic resonance spectroscopy (DW-MRS) offers improved cellular specificity to microstructure-compared to water-based methods alone-but spatial resolution and SNR is severely reduced and slow-diffusing metabolites necessitate higher b-values to accurately characterize their diffusion properties. Ultra-strong gradients allow access to higher b-values per-unit time, higher SNR for a given b-value, and shorter diffusion times, but introduce additional challenges such as eddy-current artefacts, gradient non-uniformity, and mechanical vibrations. Methods: In this work, we present initial DW-MRS data acquired on a 3T Siemens Connectom scanner equipped with ultra-strong (300 mT/m) gradients. We explore the practical issues associated with this manner of acquisition, the steps that may be taken to mitigate their impact on the data, and the potential benefits of ultra-strong gradients for DW-MRS. An in-house DW-PRESS sequence and data processing pipeline were developed to mitigate the impact of these confounds. The interaction of TE, b-value, and maximum gradient amplitude was investigated using simulations and pilot data, whereby maximum gradient amplitude was restricted. Furthermore, two DW-MRS voxels in grey and white matter were acquired using ultra-strong gradients and high b-values. Results: Simulations suggest T2-based SNR gains that are experimentally confirmed. Ultra-strong gradient acquisitions exhibit similar artefact profiles to those of lower gradient amplitude, suggesting adequate performance of artefact mitigation strategies. Gradient field non-uniformity influenced ADC estimates by up to 4% when left uncorrected. ADC and Kurtosis estimates for tNAA, tCho, and tCr align with previously published literature. Discussion: In conclusion, we successfully implemented acquisition and data processing strategies for ultra-strong gradient DW-MRS and results indicate that confounding effects of the strong gradient system can be ameliorated, while achieving shorter diffusion times and improved metabolite SNR.

The impact of cumulative obstetric complications and childhood trauma on brain volume in young people with psychotic experiences.

Psychotic experiences (PEs) occur in 5-10% of the general population and are associated with exposure to childhood trauma and obstetric complications. However, the neurobiological mechanisms underlying these associations are unclear. Using the Avon Longitudinal Study of Parents and Children (ALSPAC), we studied 138 young people aged 20 with PEs (n = 49 suspected, n = 53 definite, n = 36 psychotic disorder) and 275 controls. Voxel-based morphometry assessed whether MRI measures of grey matter volume were associated with (i) PEs, (ii) cumulative childhood psychological trauma (weighted summary score of 6 trauma types), (iii) cumulative pre/peri-natal risk factors for psychosis (weighted summary score of 16 risk factors), and (iv) the interaction between PEs and cumulative trauma or pre/peri-natal risk. PEs were associated with smaller left posterior cingulate (pFWE < 0.001, Z = 4.19) and thalamus volumes (pFWE = 0.006, Z = 3.91). Cumulative pre/perinatal risk was associated with smaller left subgenual cingulate volume (pFWE < 0.001, Z = 4.54). A significant interaction between PEs and cumulative pre/perinatal risk found larger striatum (pFWE = 0.04, Z = 3.89) and smaller right insula volume extending into the supramarginal gyrus and superior temporal gyrus (pFWE = 0.002, Z = 4.79), specifically in those with definite PEs and psychotic disorder. Cumulative childhood trauma was associated with larger left dorsal striatum (pFWE = 0.002, Z = 3.65), right prefrontal cortex (pFWE < 0.001, Z = 4.63) and smaller left insula volume in all participants (pFWE = 0.03, Z = 3.60), and there was no interaction with PEs group. In summary, pre/peri-natal risk factors and childhood psychological trauma impact similar brain pathways, namely smaller insula and larger striatum volumes. The effect of pre/perinatal risk was greatest in those with more severe PEs, whereas effects of trauma were seen in all participants. In conclusion, environmental risk factors affect brain networks implicated in schizophrenia, which may increase an individual's propensity to develop later psychotic disorders.

Physiological effects of human body imaging with 300 mT/m gradients.

PURPOSE: The use of high-performance gradient systems (i.e., high gradient strength and/or high slew rate) for human MRI is limited by physiological effects (including the elicitation of magnetophosphenes and peripheral nerve stimulation (PNS)). These effects, in turn, depend on the interaction between time-varying magnetic fields and the body, and thus on the participant's position with respect to the scanner's isocenter. This study investigated the occurrence of magnetophosphenes and PNS when scanning participants on a high-gradient (300 mT/m) system, for different gradient amplitudes, ramp times, and participant positions. METHODS: Using a whole-body 300 mT/m gradient MRI system, a cohort of participants was scanned with the head, heart, and prostate at magnet isocenter and a train of trapezoidal bipolar gradient pulses, with ramp times from 0.88 to 4.20 ms and gradient amplitudes from 60 to 300 mT/m. Reports of magnetophosphenes and incidental reports of PNS were obtained. A questionnaire was used to record any additional subjective effects. RESULTS: Magnetophosphenes were strongly dependent on participant position in the scanner. 87% of participants reported the effect with the heart at isocenter, 33% with the head at isocenter, and only 7% with the prostate at isocenter. PNS was most widely reported by participants for the vertical gradient axis (67% of participants), and was the dominant physiological effect for ramp times below 2 ms. CONCLUSION: This study evaluates the probability of eliciting magnetophosphenes during whole-body imaging using an ultra-strong gradient MRI system. It provides empirical guidance on the use of high-performance gradient systems for whole-body human MRI.

Frequency drift in MR spectroscopy at 3T.

PURPOSE: Heating of gradient coils and passive shim components is a common cause of instability in the B0 field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites. METHOD: A standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson's and intraclass correlation coefficients (ICC). RESULTS: Of the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the first 5:20 min (64 transients), median (interquartile range) drift was 0.44 (1.29) Hz before fMRI and 0.83 (1.29) Hz after. This increased to 3.15 (4.02) Hz for the full 30 min (360 transients) run. Average drift rates were 0.29 Hz/min before fMRI and 0.43 Hz/min after. Paired t-tests indicated that drift increased after fMRI, as expected (p < 0.05). Simulated spectra convolved with the frequency drift showed that the intensity of the NAA singlet was reduced by up to 26%, 44 % and 18% for GE, Philips and Siemens scanners after fMRI, respectively. ICCs indicated good agreement between datasets acquired on separate days. The single site long acquisition showed drift rate was reduced to 0.03 Hz/min approximately three hours after fMRI. DISCUSSION: This study analyzed frequency drift data from 95 3T MRI scanners. Median levels of drift were relatively low (5-min average under 1 Hz), but the most extreme cases suffered from higher levels of drift. The extent of drift varied across scanners which both linear and nonlinear drifts were observed.

MICRA: Microstructural image compilation with repeated acquisitions.

We provide a rich multi-contrast microstructural MRI dataset acquired on an ultra-strong gradient 3T Connectom MRI scanner comprising 5 repeated sets of MRI microstructural contrasts in 6 healthy human participants. The availability of data sets that support comprehensive simultaneous assessment of test-retest reliability of multiple microstructural contrasts (i.e., those derived from advanced diffusion, multi-component relaxometry and quantitative magnetisation transfer MRI) in the same population is extremely limited. This unique dataset is offered to the imaging community as a test-bed resource for conducting specialised analyses that may assist and inform their current and future research. The Microstructural Image Compilation with Repeated Acquisitions (MICRA) dataset includes raw data and computed microstructure maps derived from multi-shell and multi-direction encoded diffusion, multi-component relaxometry and quantitative magnetisation transfer acquisition protocols. Our data demonstrate high reproducibility of several microstructural MRI measures across scan sessions as shown by intra-class correlation coefficients and coefficients of variation. To illustrate a potential use of the MICRA dataset, we computed sample sizes required to provide sufficient statistical power a priori across different white matter pathways and microstructure measures for different statistical comparisons. We also demonstrate whole brain white matter voxel-wise repeatability in several microstructural maps. The MICRA dataset will be of benefit to researchers wishing to conduct similar reliability tests, power estimations or to evaluate the robustness of their own analysis pipelines.

Population neuroimaging: generation of a comprehensive data resource within the ALSPAC pregnancy and birth cohort.

Neuroimaging offers a valuable insight into human brain development by allowing in vivo assessment of structure, connectivity and function. Multimodal neuroimaging data have been obtained as part of three sub-studies within the Avon Longitudinal Study of Parents and Children, a prospective multigenerational pregnancy and birth cohort based in the United Kingdom. Brain imaging data were acquired when offspring were between 18 and 24 years of age, and included acquisition of structural, functional and magnetization transfer magnetic resonance, diffusion tensor, and magnetoencephalography imaging. This resource provides a unique opportunity to combine neuroimaging data with extensive phenotypic and genotypic measures from participants, their mothers, and fathers.

Cortical and subcortical functional specificity associated with response inhibition.

Is motor response inhibition supported by a specialised neuronal inhibitory control mechanism, or by a more general system of action updating? This pre-registered study employed a context-cueing paradigm requiring both inhibitory and non-inhibitory action updating in combination with functional magnetic resonance imaging to test the specificity of responses under different updating conditions, including the cancellation of actions. Cortical regions of activity were found to be common to multiple forms of action updating. However, functional specificity during response inhibition was observed in the anterior right inferior frontal gyrus. In addition, fronto-subcortical activity was explored using a novel contrast method. These exploratory results indicate that the specificity for response inhibition observed in right prefrontal cortex continued downstream and was observed in right hemisphere subcortical activity, while left hemisphere activity was associated with right-hand response execution. Overall, our findings reveal both common and distinct correlates of response inhibition in prefrontal cortex, with exploratory analyses supporting putative models of subcortical pathways and extending them through the demonstration of lateralisation.

Estimating axon conduction velocity in vivo from microstructural MRI.

The conduction velocity (CV) of action potentials along axons is a key neurophysiological property central to neural communication. The ability to estimate CV in humans in vivo from non-invasive MRI methods would therefore represent a significant advance in neuroscience. However, there are two major challenges that this paper aims to address: (1) Much of the complexity of the neurophysiology of action potentials cannot be captured with currently available MRI techniques. Therefore, we seek to establish the variability in CV that can be captured when predicting CV purely from parameters that have been reported to be estimatable from MRI: inner axon diameter (AD) and g-ratio. (2) errors inherent in existing MRI-based biophysical models of tissue will propagate through to estimates of CV, the extent to which is currently unknown. Issue (1) is investigated by performing a sensitivity analysis on a comprehensive model of axon electrophysiology and determining the relative sensitivity to various morphological and electrical parameters. The investigations suggest that 85% of the variance in CV is accounted for by variation in AD and g-ratio. The observed dependency of CV on AD and g-ratio is well characterised by the previously reported model by Rushton. Issue (2) is investigated through simulation of diffusion and relaxometry MRI data for a range of axon morphologies, applying models of restricted diffusion and relaxation processes to derive estimates of axon volume fraction (AVF), AD and g-ratio and estimating CV from the derived parameters. The results show that errors in the AVF have the biggest detrimental impact on estimates of CV, particularly for sparse fibre populations (AVF<0.3). For our equipment set-up and acquisition protocol, CV estimates are most accurate (below 5% error) where AVF is above 0.3, g-ratio is between 0.6 and 0.85 and AD is high (above 4µm). CV estimates are robust to errors in g-ratio estimation but are highly sensitive to errors in AD estimation, particularly where ADs are small. We additionally show CV estimates in human corpus callosum in a small number of subjects. In conclusion, we demonstrate accurate CV estimates are possible in regions of the brain where AD is sufficiently large. Problems with estimating ADs for smaller axons presents a problem for estimating CV across the whole CNS and should be the focus of further study.

Neurochemical correlates of scene processing in the precuneus/posterior cingulate cortex: A multimodal fMRI and 1 H-MRS study.

Precuneus/posterior cingulate cortex (PCu/PCC) are key components of a midline network, activated during rest but also in tasks that involve construction of scene or situation models. Despite growing interest in PCu/PCC functional alterations in disease and disease risk, the underlying neurochemical modulators of PCu/PCC's task-evoked activity are largely unstudied. Here, a multimodal imaging approach was applied to investigate whether interindividual differences in PCu/PCC fMRI activity, elicited during perceptual discrimination of scene stimuli, were correlated with local brain metabolite levels, measured during resting-state 1 H-MRS. Forty healthy young adult participants completed an fMRI perceptual odd-one-out task for scenes, objects and faces. 1 H-MRS metabolites N-acetyl-aspartate (tNAA), glutamate (Glx) and γ-amino-butyric acid (GABA+) were quantified via PRESS and MEGA-PRESS scans in a PCu/PCC voxel and an occipital (OCC) control voxel. Whole brain fMRI revealed a cluster in right dorsal PCu/PCC that showed a greater BOLD response to scenes versus faces and objects. When extracted from an independently defined PCu/PCC region of interest, scene activity (vs. faces and objects and also vs. baseline) was positively correlated with PCu/PCC, but not OCC, tNAA. A voxel-wise regression analysis restricted to the PCu/PCC 1 H-MRS voxel area identified a significant PCu/PCC cluster, confirming the positive correlation between scene-related BOLD activity and PCu/PCC tNAA. There were no correlations between PCu/PCC activity and Glx or GABA+ levels. These results demonstrate, for the first time, that scene activity in PCu/PCC is linked to local tNAA levels, identifying a neurochemical influence on interindividual differences in the task-driven activity of a key brain hub.

Normalizing data from GABA-edited MEGA-PRESS implementations at 3 Tesla.

Standardization of results is an important milestone in the maturation of any truly quantitative methodology. For instance, a lack of measurement agreement across imaging platforms limits multisite studies, between-study comparisons based on the literature, and inferences based on and the generalizability of results. In GABA-edited MEGA-PRESS, two key sources of differences between implementations are: differences in editing efficiency of GABA and the degree of co-editing of macromolecules (MM). In this work, GABA editing efficiency κ and MM-co-editing µ constants are determined for three widely used MEGA-PRESS implementations (on the most common MRI platforms; GE, Philips, and Siemens) by phantom experiments. Implementation-specific κ,µ-corrections were then applied to two in vivo datasets, one consisted of 8 subject scanned on the three platforms and the other one subject scanned eight times on each platform. Manufacturer-specific κ and µ values were determined as: κGE=0.436, κSiemens=0.366 and κPhilips=0.394 and µGE=0.83, µSiemens=0.625 and µPhilips=0.75. Applying the κ,µ-correction on the Cr-referenced data decreased the coefficient of variation (CV) of the data for both in vivo data sets (multisubjects: uncorrected CV=13%, κ,µ-corrected CV=5%, single subject: uncorrected CV=23%, κ,µ-corrected CV=13%) but had no significant effect on mean GABA levels. For the water-referenced results, CV increased in the multisubject data (uncorrected CV=6.7%, κ,µ-corrected CV=14%) while it decreased in the single subject data (uncorrected CV=24%, κ,µ-corrected CV=21%) and manufacturer was a significant source of variance in the κ,µ-corrected data. Applying a correction for editing efficiency and macromolecule contamination decreases the variance between different manufacturers for creatine-referenced data, but other sources of variance remain.

Quantification of γ-aminobutyric acid (GABA) in 1 H MRS volumes composed heterogeneously of grey and white matter.

The quantification of γ-aminobutyric acid (GABA) concentration using localised MRS suffers from partial volume effects related to differences in the intrinsic concentration of GABA in grey (GM) and white (WM) matter. These differences can be represented as a ratio between intrinsic GABA in GM and WM: rM . Individual differences in GM tissue volume can therefore potentially drive apparent concentration differences. Here, a quantification method that corrects for these effects is formulated and empirically validated. Quantification using tissue water as an internal concentration reference has been described previously. Partial volume effects attributed to rM can be accounted for by incorporating into this established method an additional multiplicative correction factor based on measured or literature values of rM weighted by the proportion of GM and WM within tissue-segmented MRS volumes. Simulations were performed to test the sensitivity of this correction using different assumptions of rM taken from previous studies. The tissue correction method was then validated by applying it to an independent dataset of in vivo GABA measurements using an empirically measured value of rM . It was shown that incorrect assumptions of rM can lead to overcorrection and inflation of GABA concentration measurements quantified in volumes composed predominantly of WM. For the independent dataset, GABA concentration was linearly related to GM tissue volume when only the water signal was corrected for partial volume effects. Performing a full correction that additionally accounts for partial volume effects ascribed to rM successfully removed this dependence. With an appropriate assumption of the ratio of intrinsic GABA concentration in GM and WM, GABA measurements can be corrected for partial volume effects, potentially leading to a reduction in between-participant variance, increased power in statistical tests and better discriminability of true effects.

Volumetric, relaxometric and diffusometric correlates of psychotic experiences in a non-clinical sample of young adults.

BACKGROUND: Grey matter (GM) abnormalities are robust features of schizophrenia and of people at ultra high-risk for psychosis. However the extent to which neuroanatomical alterations are evident in non-clinical subjects with isolated psychotic experiences is less clear. METHODS: Individuals (mean age 20 years) with (n = 123) or without (n = 125) psychotic experiences (PEs) were identified from a population-based cohort. All underwent T1-weighted structural, diffusion and quantitative T1 relaxometry MRI, to characterise GM macrostructure, microstructure and myelination respectively. Differences in quantitative GM structure were assessed using voxel-based morphometry (VBM). Binary and ordinal models of PEs were tested. Correlations between socioeconomic and other risk factors for psychosis with cortical GM measures were also computed. RESULTS: GM volume in the left supra-marginal gyrus was reduced in individuals with PEs relative to those with no PEs. The greater the severity of PEs, the greater the reduction in T1 relaxation rate (R1) across left temporoparietal and right pre-frontal cortices. In these regions, R1 was positively correlated with maternal education and inversely correlated with general psychopathology. CONCLUSIONS: PEs in non-clinical subjects were associated with regional reductions in grey-matter volume reduction and T1 relaxation rate. The alterations in T1 relaxation rate were also linked to the level of general psychopathology. Follow up of these subjects should clarify whether these alterations predict the later development of an ultra high-risk state or a psychotic disorder.

Mediation of Developmental Risk Factors for Psychosis by White Matter Microstructure in Young Adults With Psychotic Experiences.

IMPORTANCE: White matter (WM) abnormalities have been identified in schizophrenia at the earliest stages of the disorder. Individuals in the general population with psychotic experiences (PEs) may show similar changes, suggesting dysfunction due to aberrant neurodevelopment. Studying such people is a powerful means of understanding the nature of neurodevelopmental problems without the confound of clinical management and allows other potential risk factors associated with the schizophrenia spectrum to be taken into account. OBJECTIVES: To compare WM microstructure and myelination in young adults with and without PEs identified from a population-based cohort using diffusion and relaxometry magnetic resonance imaging and to quantify potential mediating effects of WM on several known risk factors for psychosis. DESIGN, SETTING, AND PARTICIPANTS: In this case-control study, participants were drawn from the UK Avon Longitudinal Study of Parents and Children. Psychotic experiences were assessed using a semistructured interview. Magnetic resonance imaging was carried out at age 20 years in 123 participants who had PEs and 124 individuals serving as controls. Participants with PEs were subdivided into those with operationally defined suspected PEs, definite PEs, and psychotic disorder. MAIN OUTCOMES AND MEASURES: Diffusion tensor magnetic resonance imaging and relaxometry-derived myelin water fractions were used to measure WM microstructure and myelination, respectively. Differences in quantitative WM indices were assessed using tract-based spatial statistics. A binary model and a continuum-like ordinal model of PEs were tested. RESULTS: Among the 123 participants who had PEs (mean [SE] age, 20.01 [0.004] years), 37 were male and 86 were female. Among the 124 controls (mean [SE] age, 20.11 [0.004] years), 49 were male and 76 were female. Fractional anisotropy in left frontomedial WM was significantly reduced in individuals with PEs (Montreal Neurological Institute [MNI] coordinates, -18, 37, -2; P = .0046). The ordinal model identified a similar but more widespread effect, with a corresponding increase in radial diffusivity (MNI coordinates, -15, 29, 21; P = .0042). Low birth weight (ρ = -0.155; P = .015) and childhood IQ (ρ = -0.188; P = .003) were associated with the presence of PEs. Results of mediation analysis were consistent with the association between birth weight (21.1% mediation effect; P = 6.20 × 10-3) and childhood IQ (7.9% mediation effect; P = .041) and by PEs being mediated by fractional anisotropy changes in these regions. CONCLUSIONS AND RELEVANCE: The results of the study imply the presence of abnormal WM microstructure in young adults with PEs. The results are consistent with the hypothesis that neurodevelopmental factors cause alterations in the cellular composition of WM circuits critical to higher cognitive function. Such alterations may first manifest in childhood as reduced IQ and later contribute to PEs in early adulthood.

Pulmonary arterial response to hypoxia in survivors of chronic lung disease of prematurity.

BACKGROUND: It is unclear whether increased pulmonary arterial (PA) reactivity to hypoxia observed in preterm infants who develop chronic lung disease of prematurity (CLD) persists into childhood. AIM: We assessed and compared PA pulse wave velocity (PWV) in air and after 12% hypoxia using velocity-encoded MRI between children who had CLD in infancy and preterm-born and term-born controls. METHODS: From 67 recruited children, 59 (13 CLD, 21 preterm, 25 term), 9-12-year-old children successfully completed the study. Velocity-encoded phase-contrast MR PA images were acquired breathing air and during breathing 12% hypoxia. PA PWV was derived as the ratio of flow to area changes during early systole. RESULTS: There were no differences in mean (SD) PA PWV between the groups breathing air (CLD=1.3 (0.4) m/s, preterm control=1.3 (0.4) m/s, term control=1.3 (0.3) m/s)) but increased following hypoxia to 1.9 (0.7) m/s, 1.6 (0.6) m/s and 1.5 (0.5) m/s in CLD, preterm and term groups, respectively. The mean differences (95% CI) for PA PWV between CLD and the preterm and control groups were 0.37 (0.08 to 0.70) and 0.34 (0.05 to 0.70), respectively. There was no difference for change in PA PWV with hypoxia between the two control groups, mean difference 0.23 (-0.2 to 0.3). CONCLUSIONS: Children who had CLD in infancy had increased pulmonary arterial reactivity during hypoxia, thus long-term follow-up is warranted in this population.

Comparison of the repeatability of GABA-edited magnetic resonance spectroscopy with and without macromolecule suppression.

PURPOSE: The inhibitory neurotransmitter γ-aminobutyric acid (GABA) can be measured in vivo using edited magnetic resonance spectroscopy (MRS), but quantification suffers from contamination by macromolecules (MM). It is possible to suppress this contamination using symmetric editing, but this procedure potentially compromises reliability of the GABA measurement. The aim of this study was to compare the repeatability of GABA-edited MRS with and without MM suppression. METHODS: GABA' (non-MM contaminated) and GABA'+MM (MM-contaminated) concentration was measured in the occipital lobe (OCC) and anterior cingulate (AC) using symmetric and standard editing (n = 15). Each method was performed twice in each region. RESULTS: Within-participant coefficients of variation for each technique were 4.0% (GABA'+MM) and 8.6% (GABA') in the OCC and 14.8% (GABA'+MM) and 12.6% (GABA') in the AC. Intraclass correlation coefficients were better for the suppression method than standard editing in both the OCC (0.72 versus 0.67) and AC (0.41 versus 0.16). These findings were replicated in the OCC of a second cohort (n = 15). CONCLUSION: Symmetric suppression is shown to be comparable in repeatability to standard GABA-editing. Measuring a purer quantification of GABA becomes increasingly important as more research is conducted on links between GABA concentration, pathology and healthy behavior.

Early Cannabis Use, Polygenic Risk Score for Schizophrenia and Brain Maturation in Adolescence.

IMPORTANCE: Cannabis use during adolescence is known to increase the risk for schizophrenia in men. Sex differences in the dynamics of brain maturation during adolescence may be of particular importance with regard to vulnerability of the male brain to cannabis exposure. OBJECTIVE: To evaluate whether the association between cannabis use and cortical maturation in adolescents is moderated by a polygenic risk score for schizophrenia. DESIGN, SETTING, AND PARTICIPANTS: Observation of 3 population-based samples included initial analysis in 1024 adolescents of both sexes from the Canadian Saguenay Youth Study (SYS) and follow-up in 426 adolescents of both sexes from the IMAGEN Study from 8 European cities and 504 male youth from the Avon Longitudinal Study of Parents and Children (ALSPAC) based in England. A total of 1577 participants (aged 12-21 years; 899 [57.0%] male) had (1) information about cannabis use; (2) imaging studies of the brain; and (3) a polygenic risk score for schizophrenia across 108 genetic loci identified by the Psychiatric Genomics Consortium. Data analysis was performed from March 1 through December 31, 2014. MAIN OUTCOMES AND MEASURES: Cortical thickness derived from T1-weighted magnetic resonance images. Linear regression tests were used to assess the relationships between cannabis use, cortical thickness, and risk score. RESULTS: Across the 3 samples of 1574 participants, a negative association was observed between cannabis use in early adolescence and cortical thickness in male participants with a high polygenic risk score. This observation was not the case for low-risk male participants or for the low- or high-risk female participants. Thus, in SYS male participants, cannabis use interacted with risk score vis-à-vis cortical thickness (P = .009); higher scores were associated with lower thickness only in males who used cannabis. Similarly, in the IMAGEN male participants, cannabis use interacted with increased risk score vis-à-vis a change in decreasing cortical thickness from 14.5 to 18.5 years of age (t137 = -2.36; P = .02). Finally, in the ALSPAC high-risk group of male participants, those who used cannabis most frequently (≥61 occasions) had lower cortical thickness than those who never used cannabis (difference in cortical thickness, 0.07 [95% CI, 0.01-0.12]; P = .02) and those with light use (<5 occasions) (difference in cortical thickness, 0.11 [95% CI, 0.03-0.18]; P = .004). CONCLUSIONS AND RELEVANCE: Cannabis use in early adolescence moderates the association between the genetic risk for schizophrenia and cortical maturation among male individuals. This finding implicates processes underlying cortical maturation in mediating the link between cannabis use and liability to schizophrenia.

Effect of Early Adversity and Childhood Internalizing Symptoms on Brain Structure in Young Men.

IMPORTANCE: Early adversity is an important risk factor that relates to internalizing symptoms and altered brain structure. OBJECTIVE: To assess the direct effects of early adversity and child internalizing symptoms (ie, depression, anxiety) on cortical gray matter (GM) volume, as well as the extent to which early adversity associates with variation in cortical GM volume indirectly via increased levels of internalizing symptoms. DESIGN, SETTING, AND PARTICIPANTS: A prospective investigation of associations between adversity within the first 6 years of life, internalizing symptoms during childhood and early adolescence, and altered brain structure in late adolescence (age, 18-21 years) was conducted in a community-based birth cohort in England (Avon Longitudinal Study of Parents and Children). Participants from the cohort included 494 mother-son pairs monitored since the mothers were pregnant (estimated date of delivery between April 1, 1991, and December 31, 1992). Data collection for the present study was conducted between April 1, 1991, and November 30, 2010; the neuroimaging data were collected between September 1, 2010, and November 30, 2012, and data analyses for the present study occurred between January 25, 2013, and February 15, 2015. Risk factors were adversity within the first 6 years of the child's life (including prenatal exposure) and the child's internalizing symptoms between age 7 and 13 years. EXPOSURES: Early childhood adversity. MAIN OUTCOMES AND MEASURES: The main outcome was GM volume of cortical regions previously associated with major depression measured through T1-weighted magnetic resonance images collected in late adolescence. RESULTS: Among 494 young men included in this analysis, early adversity was directly associated with lower GM volumes in the anterior cingulate cortex (ß = -.18; P = .01) and higher GM volume in the precuneus (ß = .18; P = .009). Childhood internalizing symptoms were associated with lower GM volume in the right superior frontal gyrus (ß = -.20; P = .002). Early adversity was also associated with higher levels of internalizing symptoms (ß = .37; P < .001), which, in turn, were associated with lower superior frontal gyrus volume (ie, an indirect effect) (ß = -.08; 95% CI, -0.14 to -0.01; P = .02). CONCLUSIONS AND RELEVANCE: Adversity early in life was associated with higher levels of internalizing symptoms as well as with altered brain structure. Early adversity was related to variation in brain structure both directly and via increased levels of internalizing symptoms. These findings may suggest that some of the structural variation often attributed to depression might be associated with early adversity in addition to the effect of depression.

"Brain MR spectroscopy in autism spectrum disorder-the GABA excitatory/inhibitory imbalance theory revisited".

Magnetic resonance spectroscopy (MRS) from voxels placed in the left anterior cingulate cortex (ACC) was measured from 14 boys with Autism Spectrum Disorder (ASD) and 24 gender and age-matched typically developing (TD) control group. Our main aims were to compare the concentration of γ-aminobutyric acid (GABA) between the two groups, and to investigate the relationship between brain metabolites and autism symptom severity in the ASD group. We did find a significant negative correlation in the ASD group between Autism Spectrum Screening Questionnaire (ASSQ) and GABA+/Cr, which may imply that severity of symptoms in ASD is associated with differences in the level of GABA in the brain, supporting the excitatory/inhibitory (E/I) imbalance theory. However we did not find a significant difference between the two groups in GABA levels.

Schizophrenia-like topological changes in the structural connectome of individuals with subclinical psychotic experiences.

Schizophrenia is often regarded as a "dysconnectivity" disorder and recent work using graph theory has been used to better characterize dysconnectivity of the structural connectome in schizophrenia. However, there are still little data on the topology of connectomes in less severe forms of the condition. Such analysis will identify topological markers of less severe disease states and provide potential predictors of further disease development. Individuals with psychotic experiences (PEs) were identified from a population-based cohort without relying on participants presenting to clinical services. Such individuals have an increased risk of developing clinically significant psychosis. 123 individuals with PEs and 125 controls were scanned with diffusion-weighted MRI. Whole-brain structural connectomes were derived and a range of global and local GT-metrics were computed. Global efficiency and density were significantly reduced in individuals with PEs. Local efficiency was reduced in a number of regions, including critical network hubs. Further analysis of functional subnetworks showed differential impairment of the default mode network. An additional analysis of pair-wise connections showed no evidence of differences in individuals with PEs. These results are consistent with previous findings in schizophrenia. Reduced efficiency in critical core hubs suggests the brains of individuals with PEs may be particularly predisposed to dysfunction. The absence of any detectable effects in pair-wise connections illustrates that, at less severe stages of psychosis, white-matter alterations are subtle and only manifest when examining network topology. This study indicates that topology could be a sensitive biomarker for early stages of psychotic illness.

The relationship between fearfulness, GABA+, and fear-related BOLD responses in the insula.

The inhibitory neurotransmitter GABA plays a crucial role in anxiety and fear, but its relationship to brain activation during fear reactions is not clear. Previous studies suggest that GABA agonists lead to an attenuation of emotion-processing related BOLD signals in the insula. The aim of this study was to investigate the relationship between GABA concentration and fear-related BOLD responses in this region. In 44 female participants with different levels of fearfulness, GABA concentration in the left insula was measured using a GABA+ MRS acquisition during rest; additionally, BOLD signals were obtained during performance of a fear provocation paradigm. Fearfulness was not associated with GABA+ in the left insula, but could predict fear-related BOLD responses in a cluster in the left anterior insula. The BOLD signal change in this cluster did not correlate with GABA+ concentration. However, we found a significant positive correlation between GABA+ concentration and fear-related BOLD responses in a different cluster that included parts of the left insula, amygdala and putamen. Our findings indicate that low insular GABA concentration is not a predisposition for fearfulness, and that several factors influence whether a correlation between GABA and BOLD can be found.