Retrospective frequency drift correction of rosette MRSI data using spectral registration.

PURPOSE: Frequency drift correction is an important postprocessing step in MRS that yields improvements in spectral quality and metabolite quantification. Although routinely applied in single-voxel MRS, drift correction is much more challenging in MRSI due to the presence of phase-encoding gradients. Thus, separately acquired navigator scans are normally required for drift estimation. In this work, we demonstrate the use of self-navigating rosette MRSI trajectories combined with time-domain spectral registration to enable retrospective frequency drift corrections without the need for separately acquired navigator echoes. METHODS: A rosette MRSI sequence was implemented to acquire data from the brains of 5 healthy volunteers. FIDs from the center of k-space ( k = 0 $$ k=0 $$ FIDs) were isolated from each shot of the rosette acquisition, and time-domain spectral registration was used to estimate the frequency offset of each k = 0 $$ k=0 $$ FID relative to a reference scan (the first k = 0 $$ k=0 $$ FID in the series). The estimated frequency offsets were then used to apply corrections throughout k $$ k $$ -space. Improvements in spectral quality were assessed before and after drift correction. RESULTS: Spectral registration resulted in significant improvements in signal-to-noise ratio (12.9%) and spectral linewidths (18.5%). Metabolite quantification was performed using LCModel, and the average Cramer-Rao lower bounds uncertainty estimates were reduced by 5.0% for all metabolites, following field drift correction. CONCLUSION: This study demonstrated the use of self-navigating rosette MRSI trajectories to retrospectively correct frequency drift errors in in vivo MRSI data. This correction yields meaningful improvements in spectral quality.

Exploring brain glutathione and peripheral blood markers in posttraumatic stress disorder: a combined [1H]MRS and peripheral blood study.

Introduction: Oxidative stress has been implicated in psychiatric disorders, including posttraumatic stress disorder (PTSD). Currently, the status of glutathione (GSH), the brain's most abundant antioxidant, in PTSD remains uncertain. Therefore, the current study investigated brain concentrations of GSH and peripheral concentrations of blood markers in individuals with PTSD vs. Healthy Controls (HC). Methods: GSH spectra was acquired in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) using MEGA-PRESS, a J-difference-editing acquisition method. Peripheral blood samples were analyzed for concentrations of metalloproteinase (MMP)-9, tissue inhibitors of MMP (TIMP)-1,2, and myeloperoxidase (MPO). Results: There was no difference in GSH between PTSD and HC in the ACC (n = 30 PTSD, n = 20 HC) or DLPFC (n = 14 PTSD, n = 18 HC). There were no group differences between peripheral blood markers (P > 0.3) except for (non-significantly) lower TIMP-2 in PTSD. Additionally, TIMP-2 and GSH in the ACC were positively related in those with PTSD. Finally, MPO and MMP-9 were negatively associated with duration of PTSD. Conclusions: We do not report altered GSH concentrations in the ACC or DLPFC in PTSD, however, systemic MMPs and MPO might be implicated in central processes and progression of PTSD. Future research should investigate these relationships in larger sample sizes.

Evaluating Back-to-Back and Day-to-Day Reproducibility of Cortical GABA+ Measurements Using Proton Magnetic Resonance Spectroscopy (1H MRS).

γ-aminobutyric acid (GABA) is a major inhibitory neurotransmitter implicated in neuropsychiatric disorders. The best method for quantifying GABA is proton magnetic resonance spectroscopy (1H MRS). Considering that accurate measurements of GABA are affected by slight methodological alterations, demonstrating GABA reproducibility in healthy volunteers is essential before implementing the changes in vivo. Thus, our study aimed to evaluate the back-to-back (B2B) and day-to-day (D2D) reproducibility of GABA+ macromolecules (GABA+) using a 3 Tesla MRI scanner, the new 32-channel head coil (CHC), and Mescher-Garwood Point Resolved Spectroscopy (MEGA-PRESS) technique with the scan time (approximately 10 min), adequate for psychiatric patients. The dorsomedial pre-frontal cortex/anterior cingulate cortex (dmPFC/ACC) was scanned in 29 and the dorsolateral pre-frontal cortex (dlPFC) in 28 healthy volunteers on two separate days. Gannet 3.1 was used to quantify GABA+. The reproducibility was evaluated by Pearson's r correlation, the interclass-correlation coefficient (ICC), and the coefficient of variation (CV%) (r/ICC/CV%). For Day 1, B2B reproducibility was 0.59/0.60/5.02% in the dmPFC/ACC and 0.74/0.73/5.15% for dlPFC. For Day 2, it was 0.60/0.59/6.26% for the dmPFC/ACC and 0.54/0.54/6.89 for dlPFC. D2D reproducibility of averaged GABA+ was 0.62/0.61/4.95% for the dmPFC/ACC and 0.58/0.58/5.85% for dlPFC. Our study found excellent GABA+ repeatability and reliability in the dmPFC/ACC and dlPFC.

Gamma-aminobutyric acid (GABA) levels in the midcingulate cortex and clozapine response in patients with treatment-resistant schizophrenia: A proton magnetic resonance spectroscopy (1 H-MRS) study.

BACKGROUND: Gamma-Aminobutyric Acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. GABAergic dysfunction has been implicated in the pathophysiology of schizophrenia. Clozapine, the only approved drug for treatment-resistant schizophrenia (TRS), involves the GABAergic system as one of its targets. However, no studies have investigated the relationship between brain GABA levels, as measured by proton magnetic resonance spectroscopy (1 H-MRS), and clozapine response in patients with TRS. METHODS: This study enrolled patients with TRS who did not respond to clozapine (ultra-resistant schizophrenia: URS) and who responded to clozapine (non-URS), patients with schizophrenia who responded to first-line antipsychotics (first-line responders: FLR), and healthy controls (HCs). We measured GABA levels in the midcingulate cortex (MCC) using 3T 1 H-MRS and compared these levels among the groups. The associations between GABA levels and symptom severity were also explored within the patient groups. RESULTS: A total of 98 participants (URS: n = 22; non-URS: n = 25; FLR: n = 16; HCs: n = 35) completed the study. We found overall group differences in MCC GABA levels (F(3,86) = 3.25, P = 0.04). Specifically, patients with URS showed higher GABA levels compared to those with non-URS (F(1,52) = 8.40, P = 0.03, Cohen's d = 0.84). MCC GABA levels showed no associations with any of the symptom severity scores within each group or the entire patient group. CONCLUSION: Our study is the first to report elevated GABA levels in the MCC in patients with schizophrenia resistant to clozapine treatment compared with those responsive to clozapine. Longitudinal studies are required to evaluate if GABA levels are a suitable biomarker to predict clozapine resistance.

NAA/Glu Ratio Associated with Suicidal Ideation in Pilot Sample of Autistic Youth and Young Adults.

Suicidality is increased in autism spectrum disorder (ASD), yet effective interventions are lacking. Developing biologically based approaches for preventing and treating suicidality in ASD hinges on the identification of biomarkers of suicidal ideation (SI). Here, we assessed magnetic resonance spectroscopy (MRS) markers of glutamatergic neurotransmission in ASD youth and young adults. Twenty-eight ASD participants (16-33 years) underwent 1H-MRS, and metabolites were quantified using LCModel. N-acetylaspartate (NAA), glutamate (Glu), and the NAA/Glu ratio from the left dorsolateral prefrontal cortex were compared between ASD SI+ (n = 13) and ASD SI- (n = 15) participants. We found that ASD SI+ participants had a higher NAA/Glu ratio compared ASD SI- participants. The NAA/Glu ratio also predicted SI and significantly discriminated between ASD SI+/SI- participants. All analyses including NAA and Glu alone were non-significant. Here, we provide preliminary evidence for the importance of NAA/Glu in ASD with SI, with implications for biomarker discovery. Further mechanistic research into risk and interventional approaches to address SI in ASD are needed.

Imaging oxidative stress in brains of chronic methamphetamine users: A combined 1H-magnetic resonance spectroscopy and peripheral blood biomarker study.

Introduction: Preclinical data suggest methamphetamine (MA), a widely used stimulant drug, can harm the brain by causing oxidative stress and inflammation, but only limited information is available in humans. We tested the hypothesis that levels of glutathione (GSH), a major antioxidant, would be lower in the brains of chronic human MA preferring polysubstance users. We also explored if concentrations of peripheral immunoinflammatory blood biomarkers were related with brain GSH concentrations. Methods: 20 healthy controls (HC) (33 years; 11 M) and 14 MA users (40 years; 9 M) completed a magnetic resonance spectroscopy (MRS) scan, with GSH spectra obtained by the interleaved J-difference editing MEGA-PRESS method in anterior cingulate cortex (ACC) and left dorsolateral prefrontal cortex (DLPFC). Peripheral blood samples were drawn for measurements of immunoinflammatory biomarkers. Independent samples t-tests evaluated MA vs. HC differences in GSH. Results: GSH levels did not differ between HC and MA users (ACC p = 0.30; DLPFC p = 0.85). A total of 17 of 25 immunoinflammatory biomarkers were significantly elevated in MA users and matrix metalloproteinase (MMP)-2 (r = 0.577, p = 0.039), myeloperoxidase (MPO) (r = -0.556, p = 0.049), and MMP-9 (r = 0.660, p = 0.038) were correlated with brain levels of GSH. Conclusion: Normal brain GSH in living brain of chronic MA users is consistent with our previous postmortem brain finding and suggests that any oxidative stress caused by MA, at the doses used by our participants, might not be sufficient to cause either a compensatory increase in, or substantial overutilization of, this antioxidant. Additionally, more research is required to understand how oxidative stress and inflammatory processes are related and potentially dysregulated in MA use.

MR Spectroscopy of the Insula: Within- and between-Session Reproducibility of MEGA-PRESS Measurements of GABA+ and Other Metabolites.

The insula plays a critical role in many neuropsychological disorders. Research investigating its neurochemistry with magnetic resonance spectroscopy (MRS) has been limited compared with cortical regions. Here, we investigate the within-session and between-session reproducibility of metabolite measurements in the insula on a 3T scanner. We measure N-acetylaspartate + N-acetylaspartylglutamate (tNAA), creatine + phosphocreatine (tCr), glycerophosphocholine + phosphocholine (tCho), myo-inositol (Ins), glutamate + glutamine (Glx), and γ-aminobutyric acid (GABA) in one cohort using a j-edited MEGA-PRESS sequence. We measure tNAA, tCr, tCho, Ins, and Glx in another cohort with a standard short-TE PRESS sequence as a reference for the reproducibility metrics. All participants were scanned 4 times identically: 2 back-to-back scans each day, on 2 days. Preprocessing was done using LCModel and Gannet. Reproducibility was determined using Pearson's r, intraclass-correlation coefficients (ICC), coefficients of variation (CV%), and Bland-Altman plots. A MEGA-PRESS protocol requiring averaged results over two 6:45-min scans yielded reproducible GABA measurements (CV% = 7.15%). This averaging also yielded reproducibility metrics comparable to those from PRESS for the other metabolites. Voxel placement inconsistencies did not affect reproducibility, and no sex differences were found. The data suggest that MEGA-PRESS can reliably measure standard metabolites and GABA in the insula.

Modulation of Dorsolateral Prefrontal Cortex Glutamate/Glutamine Levels Following Repetitive Transcranial Magnetic Stimulation in Young Adults With Autism.

Altered excitatory and inhibitory neurotransmission has been implicated in autism spectrum disorder (ASD). Interventions using repetitive transcranial magnetic stimulation (rTMS) to enhance or inhibit cortical excitability are under study for various targets, though the mechanistic effects of rTMS have yet to be examined in ASD. Here, we examined whether an excitatory rTMS treatment course modulates glutamatergic (Glx) or γ-aminobutyric acid (GABA) metabolite levels in emerging adults with ASD. Twenty-eight participants with ASD and executive function impairment [23.3 ± 4.69 years; seven-female] underwent two magnetic resonance spectroscopy (MRS) scans of the left dorsolateral prefrontal cortex (DLPFC). MRS scans were acquired before and after participants with ASD were randomized to receive a 20-session course of active or sham rTMS to the DLPFC. Baseline MRS data was available for 19 typically developing controls [23.8 ± 4.47 years; six-female]. Metabolite levels for Glx and GABA+ were compared between ASD and control groups, at baseline, and metabolite level change, pre-to-post-rTMS treatment, was compared in ASD participants that underwent active vs. sham rTMS. Absolute change in Glx was greater in the active vs. sham-rTMS group [F (1, 19) = 6.54, p = 0.02], though the absolute change in GABA+ did not differ between groups. We also examined how baseline metabolite levels related to pre/post-rTMS metabolite level change, in the active vs. sham groups. rTMS group moderated the relation between baseline Glx and pre-to-post-rTMS Glx change, such that baseline Glx predicted Glx change in the active-rTMS group only [b = 1.52, SE = 0.32, t (18) = 4.74, p < 0.001]; Glx levels increased when baseline levels were lower, and decreased when baseline levels were higher. Our results indicate that an interventional course of excitatory rTMS to the DLPFC may modulate local Glx levels in emerging adults with ASD, and align with prior reports of glutamatergic alterations following rTMS. Interventional studies that track glutamatergic markers may provide mechanistic insights into the therapeutic potential of rTMS in ASD. Clinical Trial Registration: Clinicaltrials.gov (ID: NCT02311751), https://clinicaltrials.gov/ct2/show/NCT02311751?term=ameis&rank=1; NCT02311751.

Disruption of a GATA2-TAL1-ERG regulatory circuit promotes erythroid transition in healthy and leukemic stem cells.

Changes in gene regulation and expression govern orderly transitions from hematopoietic stem cells to terminally differentiated blood cell types. These transitions are disrupted during leukemic transformation, but knowledge of the gene regulatory changes underpinning this process is elusive. We hypothesized that identifying core gene regulatory networks in healthy hematopoietic and leukemic cells could provide insights into network alterations that perturb cell state transitions. A heptad of transcription factors (LYL1, TAL1, LMO2, FLI1, ERG, GATA2, and RUNX1) bind key hematopoietic genes in human CD34+ hematopoietic stem and progenitor cells (HSPCs) and have prognostic significance in acute myeloid leukemia (AML). These factors also form a densely interconnected circuit by binding combinatorially at their own, and each other's, regulatory elements. However, their mutual regulation during normal hematopoiesis and in AML cells, and how perturbation of their expression levels influences cell fate decisions remains unclear. In this study, we integrated bulk and single-cell data and found that the fully connected heptad circuit identified in healthy HSPCs persists, with only minor alterations in AML, and that chromatin accessibility at key heptad regulatory elements was predictive of cell identity in both healthy progenitors and leukemic cells. The heptad factors GATA2, TAL1, and ERG formed an integrated subcircuit that regulates stem cell-to-erythroid transition in both healthy and leukemic cells. Components of this triad could be manipulated to facilitate erythroid transition providing a proof of concept that such regulatory circuits can be harnessed to promote specific cell-type transitions and overcome dysregulated hematopoiesis.

Glutathione Levels and Glutathione-Glutamate Correlation in Patients With Treatment-Resistant Schizophrenia.

Treatment-resistant schizophrenia (TRS) has been suggested to involve glutamatergic dysfunction. Glutathione (GSH), a dominant antioxidant, is known to be involved in glutamatergic neurotransmission. To date, no study has examined GSH levels in patients with TRS. The aim of this study was to examine GSH levels in the dorsal anterior cingulate cortex (dACC) of patients with TRS. Patients with schizophrenia were categorized into 3 groups with respect to their antipsychotic response: (1) clozapine (CLZ) nonresponders, (2) CLZ responders, and (3) first-line responders (FLR). GSH and glutamine + glutamate (Glx) levels were measured using 3T proton magnetic resonance spectroscopy. Firstly, dACC GSH levels were compared among the patient groups and healthy controls (HCs). Further, relationships between GSH and Glx levels were compared between the groups and GSH levels were explored stratifying the patient groups based on the glutamate-cysteine ligase catalytic (GCLC) subunit polymorphism. There was no difference in GSH levels between the groups. FLR showed a more negative relationship between GSH and Glx levels in the dACC compared to HCs. There were no effects of GCLC genotype on the GSH levels. However, CLZ responders had a higher ratio of high-risk GCLC genotype compared to CLZ nonresponders. This study demonstrated different relationships between GSH and Glx in the dACC between groups. In addition, the results suggest a potential link between CLZ response and GCLC genotype. However, it still remains unclear how these differences are related to the underlying pathophysiology of schizophrenia subtypes or the mechanisms of action of CLZ.

Glutathione, the Major Redox Regulator, in the Prefrontal Cortex of Individuals at Clinical High Risk for Psychosis.

Introduction: Oxidative stress and glutathione dysregulation have been implicated in the etiology of schizophrenia. To date, most in vivo studies have investigated alterations in cerebral glutathione levels in patients in which the disorder is already established; however, whether oxidative stress actually predates the onset of psychosis remains unknown. In the current study, we investigated cerebral glutathione levels of antipsychotic-naïve individuals at clinical high risk for psychosis. As exploratory analyses, we also investigated the associations between cerebral glutathione levels and peripheral glutathione peroxidase activity and clinical and neuropsychological measures. Methods: Glutathione levels were measured in the medial prefrontal cortex of 30 clinical high risk (n=26 antipsychotic naïve) and 26 healthy volunteers using 3T proton magnetic resonance spectroscopy. Each participant was assessed for glutathione peroxidase activity in plasma and genotyped for the glutamate cysteine ligase catalytic subunit polymorphism. Results: No significant differences were observed in glutathione levels between clinical high risk and healthy volunteers in the medial prefrontal cortex (F(1,54)=0.001, P =0.98). There were no significant correlations between cerebral glutathione levels and clinical and neuropsychological measures. Similarly, no significant differences were found in peripheral glutathione peroxidase activity between clinical high risk and healthy volunteers (F(1,37)=0.15, P =0.70). However, in clinical high risk, we observed a significant effect of lifetime history of cannabis use on glutathione peroxidase activity (F(1,23)=7.41, P =0.01). Discussion: The lack of significant differences between antipsychotic naïve clinical high risk and healthy volunteers suggests that alterations in glutathione levels in medial prefrontal cortex are not present in the clinical high risk state.

Effect of longitudinal flutes on miniscrew implant stability and 3-dimensional bone formation.

INTRODUCTION: The purpose of this study was to evaluate the effects of longitudinal flutes on miniscrew implant (MSI) stability and bone healing. METHODS: Using 11 skeletally mature New Zealand white rabbits, we placed 31 longitudinally fluted and 31 nonfluted, 3-mm-long MSIs in standardized positions in their calvaria and immediately loaded them with 100 g using nickel-titanium coil springs. Insertion torque values were obtained for each MSI placed; removal torque values were obtained for 28 MSIs that had been in place for 6 weeks and 20 MSIs that had been in place for 2 weeks. The bone volume fractions at 6 to 24, 24 to 42, and 42 to 60 µm from the MSI surfaces were evaluated using microcomputed tomography with an isotropic resolution of 6 µm. RESULTS: The success rate was 97% for both the fluted and nonfluted MSIs. The difference in insertion torque between the fluted and nonfluted MSIs was not statistically significant (P = 0.930). After 2 weeks, there was no statistically significant (P = 0.702) difference in removal torque between the fluted and nonfluted MSIs. After 6 weeks, removal torque values were significantly (P = 0.008) higher for the fluted (3.42 ± 0.26 N.cm) than the nonfluted (2.49 ± 0.20 N.cm) MSIs. Bone volume fractions of the 6-to-24-, 24-to-42-, and 42-to-60-µm layers were significantly (P <0.05) greater for the nonfluted than the fluted MSIs. CONCLUSIONS: Loaded 3-mm-long MSIs with and without flutes have high success rates. Longitudinal flutes placed in 3-mm MSIs increased their removal torque by 37% and decreased the amount of bone immediately surrounding them.

Mechanical stability assessment of novel orthodontic mini-implant designs: Part 2.

OBJECTIVE: To assess the mechanical stability of a newly revised orthodontic mini-implant design (N2) compared with a design introduced in Part 1 of the study (N1) and the most widely-used commercially-available design (CA). To evaluate the mean buccal bone thickness of maxillary and mandibular posterior teeth using cone-beam computed tomography (CBCT). MATERIALS AND METHODS: From the CBCT scans of 20 patients, six tomographic cross-sections were generated for each tooth. Buccal bone thickness was measured from the most convex point on the bone to the root surface. CA (1.5 mm in diameter and 6 mm in length), N1, and N2 (shorter and narrower than N1) were inserted in simulated bone with cortical and trabecular bone layers. Mechanical stability was compared in vitro through torque and lateral displacement tests. RESULTS: The bone thickness ranged from 2.26 to 3.88 mm. Maximum insertion torque was decreased significantly in N2 compared to N1. However, force levels for all displacement distances and torque ratio were the highest in N2, followed by N1 and CA (α = .05). CONCLUSIONS: Both torque and lateral displacement tests highlighted the enhanced stability of N2 compared with CA. Design revisions to N1 effectively mitigated N1's high insertion torque and thus potentially reduced microdamage to the surrounding bone. The N2 design is promising as evidenced by enhanced stability and high mechanical efficiency. Moreover, N2 is not limited to placement in interradicular spaces and has the capacity to be placed in the buccal bone superficial to the root surface with diminished risk of endangering nearby anatomic structures during placement and treatment.