Neurocognition and NMDAR co-agonists pathways in individuals with treatment resistant first-episode psychosis: a 3-year follow-up longitudinal study.

This study aims to determine whether 1) individuals with treatment-resistant schizophrenia display early cognitive impairment compared to treatment-responders and healthy controls and 2) N-methyl-D-aspartate-receptor hypofunction is an underlying mechanism of cognitive deficits in treatment-resistance. In this case‒control 3-year-follow-up longitudinal study, n = 697 patients with first-episode psychosis, aged 18 to 35, were screened for Treatment Response and Resistance in Psychosis criteria through an algorithm that assigns patients to responder, limited-response or treatment-resistant category (respectively resistant to 0, 1 or 2 antipsychotics). Assessments at baseline: MATRICS Consensus Cognitive Battery; N-methyl-D-aspartate-receptor co-agonists biomarkers in brain by MRS (prefrontal glutamate levels) and plasma (D-serine and glutamate pathways key markers). Patients were compared to age- and sex-matched healthy controls (n = 114). Results: patient mean age 23, 27% female. Treatment-resistant (n = 51) showed lower scores than responders (n = 183) in processing speed, attention/vigilance, working memory, verbal learning and visual learning. Limited responders (n = 59) displayed an intermediary phenotype. Treatment-resistant and limited responders were merged in one group for the subsequent D-serine and glutamate pathway analyses. This group showed D-serine pathway dysregulation, with lower levels of the enzymes serine racemase and serine-hydroxymethyltransferase 1, and higher levels of the glutamate-cysteine transporter 3 than in responders. Better cognition was associated with higher D-serine and lower glutamate-cysteine transporter 3 levels only in responders; this association was disrupted in the treatment resistant group. Treatment resistant patients and limited responders displayed early cognitive and persistent functioning impairment. The dysregulation of NMDAR co-agonist pathways provides underlying molecular mechanisms for cognitive deficits in treatment-resistant first-episode psychosis. If replicated, our findings would open ways to mechanistic biomarkers guiding response-based patient stratification and targeting cognitive improvement in clinical trials.

Improved reproducibility of γ-aminobutyric acid measurement from short-echo-time proton MR spectroscopy by linewidth-matched basis sets in LCModel.

γ-Aminobutyric acid (GABA), as the primary inhibitory neurotransmitter, is extremely important for maintaining healthy brain function, and deviations from GABA homeostasis are related to various brain diseases. Short-echo-time (short-TE) proton MR spectroscopy (1 H-MRS) has been employed to measure GABA concentration from various human brain regions at high magnetic fields. The aim of this study was to investigate the effect of spectral linewidth on GABA quantification and explore the application of an optimized basis-set preparation approach using a spectral-linewidth-matched (LM) basis set in LCModel to improve the reproducibility of GABA quantification from short-TE 1 H-MRS. In contrast to the fixed-linewidth basis-set approach, the LM basis-set preparation approach, where all metabolite basis spectra were simulated with a linewidth 4 Hz narrower than that of water, showed a smaller standard deviation of estimated GABA concentration from synthetic spectra with varying linewidths and lineshapes. The test-retest reproducibility was assessed by the mean within-subject coefficient of variation, which improved from 19.2% to 12.0% in the thalamus, from 27.9% to 14.9% in the motor cortex, and from 9.7% to 2.8% in the medial prefrontal cortex using LM basis sets at 7 T. We conclude that spectral linewidth has a large effect on GABA quantification from short-TE 1 H-MRS data and that using LM basis sets in LCModel can improve the reproducibility of GABA quantification.

MRI characterization of in vitro clots at 3T and 7T: A technical note.

In acute ischemic stroke, the composition of the occlusive clot can be associated with the underlying pathophysiology and the response to treatment. For these reasons, it is important to characterize the clot composition from clinical scans. We examine the ability of 3T and 7T MRI to distinguish the composition of in vitro clots, using quantitative T1 and T2*, alternatively R2*, mapping. When comparing the two field strengths, we found a tradeoff between sensitivity for clot composition and confidence in the clot depiction associated with spatial resolution. The loss of sensitivity at 7T can be mitigated by combining the T1 and T2* signals.

Dipolectric antenna for high-field MRI.

PURPOSE: To introduce the dipolectric antenna: a novel RF coil design for high-field MRI using a combination of a dipole antenna with a loop-coupled dielectric resonator antenna. METHODS: Simulations in human voxel model Duke involving 8-, 16-, and 38-channel dipolectric antenna arrays for brain MRI were conducted. An 8-channel dipolectric antenna for occipital lobe MRI at 7 T was designed and constructed. The array was built of four dielectric resonator antennas (dielectric constant = 1070) and four segmented dipole antennas. In vivo MRI experiments were conducted in one subject, and the SNR performance was benchmarked against a commercial 32-channel head coil. RESULTS: A 38-channel dipolectric antenna array provided the highest whole-brain SNR (up to a 2.3-fold SNR gain in the center of the Duke's head vs. an 8-channel dipolectric antenna array). Dipolectric antenna arrays driven in dipole-only mode (with dielectric resonators used as receive-only) yielded the highest transmit performance. The constructed 8-channel dipolectric antenna array provided up to threefold higher in vivo peripheral SNR when compared with a 32-channel commercial head coil. CONCLUSION: Dipolectric antenna can be considered a promising approach to enhance SNR in human brain MRI at 7 T. This strategy can be used to develop novel multi-channel arrays for different high-field MRI applications.

In vivo magnetic resonance 31 P-Spectral Analysis With Neural Networks: 31P-SPAWNN.

PURPOSE: We have introduced an artificial intelligence framework, 31P-SPAWNN, in order to fully analyze phosphorus-31 ( 31 $$ {}^{31} $$ P) magnetic resonance spectra. The flexibility and speed of the technique rival traditional least-square fitting methods, with the performance of the two approaches, are compared in this work. THEORY AND METHODS: Convolutional neural network architectures have been proposed for the analysis and quantification of 31 $$ {}^{31} $$ P-spectroscopy. The generation of training and test data using a fully parameterized model is presented herein. In vivo unlocalized free induction decay and three-dimensional 31 $$ {}^{31} $$ P-magnetic resonance spectroscopy imaging data were acquired from healthy volunteers before being quantified using either 31P-SPAWNN or traditional least-square fitting techniques. RESULTS: The presented experiment has demonstrated both the reliability and accuracy of 31P-SPAWNN for estimating metabolite concentrations and spectral parameters. Simulated test data showed improved quantification using 31P-SPAWNN compared with LCModel. In vivo data analysis revealed higher accuracy at low signal-to-noise ratio using 31P-SPAWNN, yet with equivalent precision. Processing time using 31P-SPAWNN can be further shortened up to two orders of magnitude. CONCLUSION: The accuracy, reliability, and computational speed of the method open new perspectives for integrating these applications in a clinical setting.

Fast in vivo assay of creatine kinase activity in the human brain by 31 P magnetic resonance fingerprinting.

A new and efficient magnetisation transfer 31 P magnetic resonance fingerprinting (MT-31 P-MRF) approach is introduced to measure the creatine kinase metabolic rate k CK between phosphocreatine (PCr) and adenosine triphosphate (ATP) in human brain. The MRF framework is extended to overcome challenges in conventional 31 P measurement methods in the human brain, enabling reduced acquisition time and specific absorption rate (SAR). To address the challenge of creating and matching large multiparametric dictionaries in an MRF scheme, a nested iteration interpolation method (NIIM) is introduced. As the number of parameters to estimate increases, the size of the dictionary grows exponentially. NIIM can reduce the computational load by breaking dictionary matching into subsolutions of linear computational order. MT-31 P-MRF combined with NIIM provides T 1 PCr , T 1 ATP and k CK estimates in good agreement with those obtained by the exchange kinetics by band inversion transfer (EBIT) method and literature values. Furthermore, the test-retest reproducibility results showed that MT-31 P-MRF achieves a similar or better coefficient of variation (<12%) for T 1 ATP and k CK measurements in 4 min 15 s, than EBIT with 17 min 4 s scan time, enabling a fourfold reduction in scan time. We conclude that MT-31 P-MRF in combination with NIIM is a fast, accurate, and reproducible approach for in vivo k CK assays in the human brain, which enables the potential to investigate energy metabolism in a clinical setting.

Redox and Immune Signaling in Schizophrenia: New Therapeutic Potential.

Redox biology and immune signaling play major roles in the body, including in brain function. A rapidly growing literature also suggests that redox and immune abnormalities are implicated in neuropsychiatric conditions such as schizophrenia (SZ), bipolar disorder, autism, and epilepsy. In this article we review this literature, its implications for the pathophysiology of SZ, and the potential for development of novel treatment interventions targeting redox and immune signaling. Redox biology and immune signaling in the brain are complex and not fully understood; in addition, there are discrepancies in the literature, especially in patient-oriented studies. Nevertheless, it is clear that abnormalities arise in SZ from an interaction between genetic and environmental factors during sensitive periods of brain development, and these abnormalities disrupt local circuits and long-range connectivity. Interventions that correct these abnormalities may be effective in normalizing brain function in psychotic disorders, especially in early phases of illness.

High field brain proton magnetic resonance spectroscopy and volumetry in children with chronic, compensated liver disease - A pilot study.

BACKGROUND: There is increasing evidence that children or young adults having acquired liver disease in childhood display neurocognitive impairment which may become more apparent as they grow older. The molecular, cellular and morphological underpinnings of this clinical problem are incompletely understood. AIM: Therefore, we used the advantages of highly-resolved proton magnetic resonance spectroscopy at ultra-high magnetic field to analyze the neurometabolic profile and brain morphometry of children with chronic, compensated liver disease, hypothesizing that with high field spectroscopy we would identify early evidence of rising brain glutamine and decreased myoinositol, such as has been described both in animals and humans with more significant liver disease. METHODS: Patients (n = 5) and age-matched controls (n = 19) underwent 7T MR scans and short echo time 1H MR spectra were acquired using the semi-adiabatic SPECIAL sequence in two voxels located in gray and white matter dominated prefrontal cortex, respectively. A 3D MP2RAGE sequence was also acquired for brain volumetry and T1 mapping. Liver disease had to have developed at least 6 months before entering the study. Subjects underwent routine blood analysis and neurocognitive testing using validated methods within 3 months of MRI and MRS. RESULTS: Five children aged 8-16 years with liver disease acquired in childhood were included. Baseline biological characteristics were similar among patients. There were no statistically significant differences between subjects and controls in brain metabolite levels or brain volumetry. Finally, there were minor neurocognitive fluctuations including attention deficit in one child, but none fell in the statistically significant range. CONCLUSION: Children with chronic, compensated liver disease did not display an abnormal neurometabolic profile, neurocognitive abnormalities, or signal intensity changes in the globus pallidus. Despite the absence of neurometabolic changes, it is an opportunity to emphasize that it is only by developing the use of 1H MRS at high field in the clinical arena that we will understand the significance and generalizability of these findings in children with CLD. Healthy children displayed neurometabolic regional differences as previously reported in adult subjects.

Apparent diffusion coefficients of 31P metabolites in the human calf muscle at 7 T.

PURPOSE: In this study, we aimed to measure the apparent diffusion coefficients (ADCs) of major phosphorous metabolites in the human calf muscle at 7 T with a diffusion-weighted (DW)-STEAM sequence. METHODS: A DW-STEAM sequence with bipolar gradients was implemented at 7 T, and DW MR spectra were acquired in three orthogonal directions in the human calf muscle of six healthy volunteers (TE/TM/TR = 15 ms/750 ms/5 s) at three b-values (0, 800, and 1200 s/mm2). Frequency and phase alignments were applied prior to spectral averaging. Averaged DW MR spectra were analyzed with LCModel, and ADCs of 31P metabolites were estimated. RESULTS: Four metabolites (phosphocreatine (PCr), adenosine triphosphate (ATP), inorganic phosphate (Pi) and glycerol phosphorylcholine (GPC)) were quantified at all b-values with mean CRLBs below 10%. The ADC values of PCr, ATP, Pi, and GPC were (0.24 ± 0.02, 0.15 ± 0.04, 0.43 ± 0.14, 0.40 ± 0.09) × 10-3 mm2/s, respectively. CONCLUSION: The ADCs of four 31P metabolites were successfully measured in the human calf muscle at 7 T, among which those of ATP, Pi and GPC were reported for the first time in humans. This study paves the way to investigate 31P metabolite diffusion properties in health and disease on the clinical MR scanner.

γ-aminobutyric acid measurement in the human brain at 7 T: Short echo-time or Mescher-Garwood editing.

The purposes of the current study were to introduce a Mescher-Garwood (MEGA) semi-adiabatic spin-echo full-intensity localization (MEGA-sSPECIAL) sequence with macromolecule (MM) subtraction and to compare the test-retest reproducibility of γ-aminobutyric acid (GABA) measurements at 7 T using the sSPECIAL and MEGA-sSPECIAL sequences. The MEGA-sSPECIAL editing scheme using asymmetric adiabatic and highly selective Gaussian pulses was used to compare its GABA measurement reproducibility with that of short echo-time (TE) sSPECIAL. Proton magnetic resonance spectra were acquired in the motor cortex (M1) and medial prefrontal cortex (mPFC) using the sSPECIAL (TR/TE = 4000/16 ms) and MEGA-sSPECIAL sequences (TR/TE = 4000/80 ms). The metabolites were quantified using LCModel with unsuppressed water spectra. The concentrations are reported in institutional units. The test-retest reproducibility was evaluated by scanning each subject twice. Between-session reproducibility was assessed using coefficients of variation (CVs), Pearson's r correlation coefficients, and intraclass correlation coefficients (ICCs). Intersequence agreement was evaluated using Pearson's r correlation coefficients and Bland-Altman plots. Regarding GABA measurements by sSPECIAL, the GABA concentrations were 0.92 ± 0.31 (IU) in the M1 and 1.56 ± 0.49 (IU) in the mPFC. This demonstrated strong between-session correlation across both regions (r = 0.81, p < 0.01; ICC = 0.82). The CVs between the two scans were 21.8% in the M1 and 10.2% in the mPFC. On the other hand, the GABA measurements by MEGA-sSPECIAL were 0.52 ± 0.04 (IU) in the M1 and 1.04 ± 0.24 (IU) in the mPFC. MEGA-sSPECIAL demonstrated strong between-session correlation across the two regions (r = 0.98, p < 0.001; ICC = 0.98) and lower CVs than sSPECIAL, providing 4.1% in the M1 and 5.8% in the mPFC. The MEGA-editing method showed better reproducibility of GABA measurements in both brain regions compared with the short-TE sSPECIAL method. Thus it is a more sensitive method with which to detect small changes in areas with low GABA concentrations. In GABA-rich brain regions, GABA measurements can be achieved reproducibly using both methods.

In vivo macromolecule signals in rat brain 1 H-MR spectra at 9.4T: Parametrization, spline baseline estimation, and T2 relaxation times.

PURPOSE: Reliable detection and fitting of macromolecules (MM) are crucial for accurate quantification of brain short-echo time (TE) 1 H-MR spectra. An experimentally acquired single MM spectrum is commonly used. Higher spectral resolution at ultra-high field (UHF) led to increased interest in using a parametrized MM spectrum together with flexible spline baselines to address unpredicted spectroscopic components. Herein, we aimed to: (1) implement an advanced methodological approach for post-processing, fitting, and parametrization of 9.4T rat brain MM spectra; (2) assess the concomitant impact of the LCModel baseline and MM model (ie, single vs parametrized); and (3) estimate the apparent T2 relaxation times for seven MM components. METHODS: A single inversion recovery sequence combined with advanced AMARES prior knowledge was used to eliminate the metabolite residuals, fit, and parametrize 10 MM components directly from 9.4T rat brain in vivo 1 H-MR spectra at different TEs. Monte Carlo simulations were also used to assess the concomitant influence of parametrized MM and DKNTMN parameter in LCModel. RESULTS: A very stiff baseline (DKNTMN ≥ 1 ppm) in combination with a single MM spectrum led to deviations in metabolite concentrations. For some metabolites the parametrized MM showed deviations from the ground truth for all DKNTMN values. Adding prior knowledge on parametrized MM improved MM and metabolite quantification. The apparent T2 ranged between 12 and 24 ms for seven MM peaks. CONCLUSION: Moderate flexibility in the spline baseline was required for reliable quantification of real/experimental spectra based on in vivo and Monte Carlo data. Prior knowledge on parametrized MM improved MM and metabolite quantification.

Contribution of macromolecules to brain 1 H MR spectra: Experts' consensus recommendations.

Proton MR spectra of the brain, especially those measured at short and intermediate echo times, contain signals from mobile macromolecules (MM). A description of the main MM is provided in this consensus paper. These broad peaks of MM underlie the narrower peaks of metabolites and often complicate their quantification but they also may have potential importance as biomarkers in specific diseases. Thus, separation of broad MM signals from low molecular weight metabolites enables accurate determination of metabolite concentrations and is of primary interest in many studies. Other studies attempt to understand the origin of the MM spectrum, to decompose it into individual spectral regions or peaks and to use the components of the MM spectrum as markers of various physiological or pathological conditions in biomedical research or clinical practice. The aim of this consensus paper is to provide an overview and some recommendations on how to handle the MM signals in different types of studies together with a list of open issues in the field, which are all summarized at the end of the paper.

Correction: MMP9/RAGE pathway overactivation mediates redox dysregulation and neuroinflammation, leading to inhibitory/excitatory imbalance: a reverse translation study in schizophrenia patients.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

MMP9/RAGE pathway overactivation mediates redox dysregulation and neuroinflammation, leading to inhibitory/excitatory imbalance: a reverse translation study in schizophrenia patients.

Various mechanisms involved in schizophrenia pathophysiology, such as dopamine dysregulation, glutamate/NMDA receptor dysfunction, neuroinflammation or redox imbalance, all appear to converge towards an oxidative stress "hub" affecting parvalbumine interneurones (PVI) and their perineuronal nets (PNN) (Lancet Psychiatry. 2015;2:258-70); (Nat Rev Neurosci. 2016;17:125-34). We aim to investigate underlying mechanisms linking oxidative stress with neuroinflammatory and their long-lasting harmful consequences. In a transgenic mouse of redox dysregulation carrying a permanent deficit of glutathione synthesis (gclm-/-), the anterior cingulate cortex presented early in the development increased oxidative stress which was prevented by the antioxidant N-acetylcysteine (Eur J Neurosci. 2000;12:3721-8). This oxidative stress induced microglia activation and redox-sensitive matrix metalloproteinase 9 (MMP9) stimulation, leading to the receptor for advanced glycation end-products (RAGE) shedding into soluble and nuclear forms, and subsequently to nuclear factor-kB (NF-kB) activation and secretion of various cytokines. Blocking MMP9 activation prevented this sequence of alterations and rescued the normal maturation of PVI/PNN, even if performed after an additional insult that exacerbated the long term PVI/PNN impairments. MMP9 inhibition thus appears to be able to interrupt the vicious circle that maintains the long-lasting deleterious effects of the reciprocal interaction between oxidative stress and neuroinflammation, impacting on PVI/PNN integrity. Translation of these experimental findings to first episode patients revealed an increase in plasma soluble RAGE relative to healthy controls. This increase was associated with low prefrontal GABA levels, potentially predicting a central inhibitory/excitatory imbalance linked to RAGE shedding. This study paves the way for mechanistically related biomarkers needed for early intervention and MMP9/RAGE pathway modulation may lead to promising drug targets.

Lactate measurement by neurochemical profiling in the dorsolateral prefrontal cortex at 7T: accuracy, precision, and relaxation times.

PURPOSE: This assesses the potential of measuring lactate in the human brain using three non-editing MRS methods at 7T and compares the accuracy and precision of the methods. METHODS: 1 H MRS data were measured in the right dorsolateral prefrontal cortex using a semi-adiabatic spin-echo full-intensity acquired localized sequence with three different protocols: (I) TE = 16 ms, (II) TE = 110 ms, and (III) TE = 16 ms, TI = 300 ms. T1 and T2 relaxation times of lactate were also measured. Simulated spectra were generated for three protocols with known concentrations, using a range of spectral linewidths and SNRs to assess the effect of data quality on the measurement precision and accuracy. RESULTS: Lactate was quantified in all three protocols with mean Cramér-Rao lower bound of 8% (I), 13% (II), and 7% (III). The T1 and T2 relaxation times of lactate were 1.9 ± 0.2 s and 94 ± 13 ms, respectively. Simulations predicted a spectral linewidth-associated underestimation of lactate measurement. Simulations, phantom and in vivo results showed that protocol II was most affected by this underestimation. In addition, the estimation error was insensitive to a broad range of spectral linewidth with protocol I. Within-session coefficient of variances of lactate were 6.1 ± 7.9% (I), 22.3 ± 12.3% (II), and 5.1 ± 5.4% (III), respectively. CONCLUSION: We conclude that protocols I and III have the potential to measure lactate at 7T with good reproducibility, whereas the measurement accuracy and precision depend on spectral linewidth and SNR, respectively. Moreover, simulation is valuable for the optimization of measurement protocols in future study design and the correction for measurement bias.

Advanced single voxel 1 H magnetic resonance spectroscopy techniques in humans: Experts' consensus recommendations.

Conventional proton MRS has been successfully utilized to noninvasively assess tissue biochemistry in conditions that result in large changes in metabolite levels. For more challenging applications, namely, in conditions which result in subtle metabolite changes, the limitations of vendor-provided MRS protocols are increasingly recognized, especially when used at high fields (≥3 T) where chemical shift displacement errors, B0 and B1 inhomogeneities and limitations in the transmit B1 field become prominent. To overcome the limitations of conventional MRS protocols at 3 and 7 T, the use of advanced MRS methodology, including pulse sequences and adjustment procedures, is recommended. Specifically, the semiadiabatic LASER sequence is recommended when TE values of 25-30 ms are acceptable, and the semiadiabatic SPECIAL sequence is suggested as an alternative when shorter TE values are critical. The magnetic field B0 homogeneity should be optimized and RF pulses should be calibrated for each voxel. Unsuppressed water signal should be acquired for eddy current correction and preferably also for metabolite quantification. Metabolite and water data should be saved in single shots to facilitate phase and frequency alignment and to exclude motion-corrupted shots. Final averaged spectra should be evaluated for SNR, linewidth, water suppression efficiency and the presence of unwanted coherences. Spectra that do not fit predefined quality criteria should be excluded from further analysis. Commercially available tools to acquire all data in consistent anatomical locations are recommended for voxel prescriptions, in particular in longitudinal studies. To enable the larger MRS community to take advantage of these advanced methods, a list of resources for these advanced protocols on the major clinical platforms is provided. Finally, a set of recommendations are provided for vendors to enable development of advanced MRS on standard platforms, including implementation of advanced localization sequences, tools for quality assurance on the scanner, and tools for prospective volume tracking and dynamic linear shim corrections.

Magnetic resonance spectroscopy in the rodent brain: Experts' consensus recommendations.

In vivo MRS is a non-invasive measurement technique used not only in humans, but also in animal models using high-field magnets. MRS enables the measurement of metabolite concentrations as well as metabolic rates and their modifications in healthy animals and disease models. Such data open the way to a deeper understanding of the underlying biochemistry, related disturbances and mechanisms taking place during or prior to symptoms and tissue changes. In this work, we focus on the main preclinical 1H, 31P and 13C MRS approaches to study brain metabolism in rodent models, with the aim of providing general experts' consensus recommendations (animal models, anesthesia, data acquisition protocols). An overview of the main practical differences in preclinical compared with clinical MRS studies is presented, as well as the additional biochemical information that can be obtained in animal models in terms of metabolite concentrations and metabolic flux measurements. The properties of high-field preclinical MRS and the technical limitations are also described.

Improved off-resonance phase behavior using a phase-inverted adiabatic half-passage pulse for 13 C MRS in humans at 7 T.

In vivo 13 C MRS at high field benefits from an improved SNR and spectral resolution especially when using surface coils in combination with adiabatic pulses, such as the adiabatic half-passage (AHP) pulse for 13 C excitation. However, the excitation profile of the AHP pulse is asymmetric relative to the carrier frequency, which could lead to asymmetric excitation of the spectral lines relative to the center of the spectrum. In this study, a pulse-acquire sequence was designed for adiabatic 13 C excitation with a symmetric bandwidth, utilizing a combination of two AHP pulses with inverted phases in alternate scans. Magnetization and phase behavior as a function of frequency offset and RF amplitude of the B1 field, as well as the steady-state transverse magnetization response to off-resonance, were simulated. Excitation properties of the combined pulse sequence were studied by 23 Na imaging and 13 C spectroscopy in vitro on a phantom and in vivo on the human calf at 7 T. Simulations demonstrated symmetric transverse magnetization and phase with respect to positive and negative frequency offsets when using two AHP pulses with inverted phases in alternate scans, thereby minimizing baseline distortion and achieving symmetric T1 weighting, as confirmed by in vitro measurements. The intensities of the lipid peaks at 15, 30, 62, 73, and 130 ppm were in agreement with those theoretically predicted using two AHP pulses with inverted phases in alternate scans. We conclude that using two phase-inverted AHP pulses improves the symmetry of the 13 C excitation profile and phase response to off-resonance effects at 7 T in comparison with using a single AHP pulse.

N-Acetyl-Cysteine Supplementation Improves Functional Connectivity Within the Cingulate Cortex in Early Psychosis: A Pilot Study.

BACKGROUND: There is increasing evidence that redox dysregulation, which can lead to oxidative stress and eventually to impairment of oligodendrocytes and parvalbumin interneurons, may underlie brain connectivity alterations in schizophrenia. Accordingly, we previously reported that levels of brain antioxidant glutathione in the medial prefrontal cortex were positively correlated with increased functional connectivity along the cingulum bundle in healthy controls but not in early psychosis patients. In a recent randomized controlled trial, we observed that 6-month supplementation with a glutathione precursor, N-acetyl-cysteine, increased brain glutathione levels and improved symptomatic expression and processing speed. METHODS: We investigated the effect of N-acetyl-cysteine supplementation on the functional connectivity between regions of the cingulate cortex, which have been linked to positive symptoms and processing speed decline. In this pilot study, we compared structural connectivity and resting-state functional connectivity between early psychosis patients treated with 6-month N-acetyl-cysteine (n = 9) or placebo (n = 11) supplementation with sex- and age-matched healthy control subjects (n = 74). RESULTS: We observed that 6-month N-acetyl-cysteine supplementation increases functional connectivity along the cingulum and more precisely between the caudal anterior part and the isthmus of the cingulate cortex. These functional changes can be partially explained by an increase of centrality of these regions in the functional brain network. CONCLUSIONS: N-acetyl-cysteine supplementation has a positive effect on functional connectivity within the cingulate cortex in early psychosis patients. To our knowledge, this is the first study suggesting that increased brain glutathione levels via N-acetyl-cysteine supplementation may improve brain functional connectivity.

Magnetic Resonance Spectroscopy in Schizophrenia: Evidence for Glutamatergic Dysfunction and Impaired Energy Metabolism.

In the past couple of decades, major efforts were made to increase reliability of metabolic assessments by magnetic resonance methods. Magnetic resonance spectroscopy (MRS) has been valuable for providing in vivo evidence and investigating biomarkers in neuropsychiatric disorders, namely schizophrenia. Alterations of glutamate and glutamine levels in brains of schizophrenia patients relative to healthy subjects are generally interpreted as markers of glutamatergic dysfunction. However, only a small fraction of MRS-detectable glutamate is involved in neurotransmission. Here we review and discuss brain metabolic processes that involve glutamate and that are likely to be implicated in neuropsychiatric disorders.