Prefrontal Metabolite Alterations in Individuals with Posttraumatic Stress Disorder: A 7T Magnetic Resonance Spectroscopy Study

Watling S.E., Rhind S.G., Warsh J., Green D., McCluskey T., Tong J., Truong P., Chavez S., Richardson J.D., Kish S.J., Boileau I.

IntroductionOxidative 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).MethodsGSH 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).ResultsThere 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.ConclusionsWe 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.

Forkus S.R., Raudales A.M., Rafiuddin H.S., Weiss N.H., Messman B.A., Contractor A.A.

Ragnhildstveit A., Roscoe J., Bass L.C., Averill C.L., Abdallah C.G., Averill L.A.

Posttraumatic stress disorder (PTSD) is a devastating condition, for which there are few pharmacological agents, often with a delayed onset of action and poor efficacy. Trauma-focused psychotherapies are further limited by few trained providers and low patient engagement. This frequently results in disease chronicity as well as psychiatric and medical comorbidity, with considerable negative impact on quality of life. As such, off-label interventions are commonly used for PTSD, particularly in chronic refractory cases. Ketamine, an N-methyl-D-aspartate (NDMA) receptor antagonist, has recently been indicated for major depression, exhibiting rapid and robust antidepressant effects. It also shows transdiagnostic potential for an array of psychiatric disorders. Here, we synthesize clinical evidence on ketamine in PTSD, spanning case reports, chart reviews, open-label studies, and randomized trials. Overall, there is high heterogeneity in clinical presentation and pharmacological approach, yet encouraging signals of therapeutic safety, efficacy, and durability. Avenues for future research are discussed.

Ravanfar P., Syeda W.T., Jayaram M., Rushmore R.J., Moffat B., Lin A.P., Lyall A.E., Merritt A.H., Yaghmaie N., Laskaris L., Luza S., Opazo C.M., Liberg B., Chakravarty M.M., Devenyi G.A., et. al.

Brain iron is central to dopaminergic neurotransmission, a key component in schizophrenia pathology. Iron can also generate oxidative stress, which is one proposed mechanism for gray matter volume reduction in schizophrenia. The role of brain iron in schizophrenia and its potential link to oxidative stress has not been previously examined. In this study, we used 7-Tesla MRI quantitative susceptibility mapping (QSM), magnetic resonance spectroscopy (MRS), and structural T1 imaging in 12 individuals with chronic schizophrenia and 14 healthy age-matched controls. In schizophrenia, there were higher QSM values in bilateral putamen and higher concentrations of phosphocreatine and lactate in caudal anterior cingulate cortex (caCC). Network-based correlation analysis of QSM across corticostriatal pathways as well as the correlation between QSM, MRS, and volume, showed distinct patterns between groups. This study introduces increased iron in the putamen in schizophrenia in addition to network-wide disturbances of iron and metabolic status.

Kaul D., Schwab S.G., Mechawar N., Ooi L., Matosin N.

Dysregulation of excitatory and inhibitory signaling is commonly observed in major psychiatric disorders, including schizophrenia, depression, and bipolar disorder, and is often targeted by psychological and pharmacological treatment methods. The balance of excitation and inhibition is highly sensitive to severe psychological stress, one of the strongest risk factors for psychiatric disorders. The role of astrocytes in regulating excitatory and inhibitory signaling is now widely recognized; however, the specific involvement of astrocytes in the context of psychiatric disorders with a history of significant stress exposure remains unclear. In this review, we summarize how astrocytes regulate the balance of excitation and inhibition in the context of stress exposure and severe psychopathology, with a focus on the PFC, a brain area highly implicated in psychopathology. We first focus on preclinical models to demonstrate that the duration of stress (particularly acute vs chronic stress) is key to shaping astrocyte function and downstream behavior. We then provide a hypothesis for how astrocytes are involved in stress-associated cortical signaling imbalance, discuss how this directly contributes to phenotypes of psychopathologies, and provide suggestions for future research. We highlight that astrocytes are a key target to understand and treat the dysregulation of cortical signaling associated with stress-related psychiatric disorders.

Katrinli S., Oliveira N.C., Felger J.C., Michopoulos V., Smith A.K.

Posttraumatic stress disorder (PTSD) develops in a subset of individuals upon exposure to traumatic stress. In addition to well-defined psychological and behavioral symptoms, some individuals with PTSD also exhibit elevated concentrations of inflammatory markers, including C-reactive protein, interleukin-6, and tumor necrosis factor-α. Moreover, PTSD is often co-morbid with immune-related conditions, such as cardiometabolic and autoimmune disorders. Numerous factors, including lifetime trauma burden, biological sex, genetic background, metabolic conditions, and gut microbiota, may contribute to inflammation in PTSD. Importantly, inflammation can influence neural circuits and neurotransmitter signaling in regions of the brain relevant to fear, anxiety, and emotion regulation. Given the link between PTSD and the immune system, current studies are underway to evaluate the efficacy of anti-inflammatory treatments in those with PTSD. Understanding the complex interactions between PTSD and the immune system is essential for future discovery of diagnostic and therapeutic tools.

Kramer L.B., Whiteman S.E., Petri J.M., Spitzer E.G., Weathers F.W.

Posttraumatic stress disorder (PTSD) is commonly assessed with self-rated or clinician-rated measures. Although scores from these assessment modalities are strongly associated, they are often discrepant for individual symptoms, total symptom severity, and diagnostic status. To date, no known studies have empirically identified the sources of these discrepancies. In the present study, we had three aims: (a) replicate previously identified discrepancies; (b) examine contribution of possible objective predictors of discrepancies, including negative response bias, random responding, conscientiousness, neuroticism, and verbal IQ; and (c) identify subjective sources of discrepancies through analysis of participant feedback. Trauma-exposed undergraduates ( N = 60) were administered the PTSD Checklist for DSM-5 (PCL-5), the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), and other questionnaires. Interviewers identified discrepancies between corresponding PCL-5/CAPS-5 scores and asked participants to describe their attributions for discrepancies. Discrepancies, both dimensional and dichotomous, occurred at the item, cluster, and total score level. Objective predictors were weakly associated with discrepancies. The most commonly reported reasons for discrepancies were time-frame reminders, comprehension of symptoms, trauma-related attribution errors, increased awareness, and general errors. These findings help explain discordance between the PCL-5 and CAPS-5, and inform use and interpretation of these two widely used PTSD measures in clinical and research applications.

Vidor M.V., Panzenhagen A.C., Martins A.R., Cupertino R.B., Bandeira C.E., Picon F.A., da Silva B.S., Vitola E.S., Rohde L.A., Rovaris D.L., Bau C.H., Grevet E.H.

One of the main challenges in investigating the neurobiology of ADHD is our limited capacity to study its neurochemistry in vivo. Magnetic resonance spectroscopy (MRS) estimates metabolite concentrations within the brain, but approaches and findings have been heterogeneous. To assess differences in brain metabolites between patients with ADHD and healthy controls, we searched 12 databases screening for MRS studies. Studies were divided into ‘children and adolescents’ and ‘adults’ and meta-analyses were performed for each brain region with more than five studies. The quality of studies was assessed by the Newcastle–Ottawa Scale. Thirty-three studies met our eligibility criteria, including 874 patients with ADHD. Primary analyses revealed that the right medial frontal area of children with ADHD presented higher concentrations of a composite of glutamate and glutamine (p = 0.02, SMD = 0.53). Glutamate might be implicated in pruning and neurodegenerative processes as an excitotoxin, while glutamine excess might signal a glutamate depletion that could hinder neurotrophic activity. Both neuro metabolites could be implicated in the differential cortical thinning observed in patients with ADHD across all ages. Notably, more homogeneous designs and reporting guidelines are the key factors to determine how suitable MRS is for research and, perhaps, for clinical psychiatry. Results of this meta-analysis provided an overall map of the brain regions evaluated so far, addressed the role of glutamatergic metabolites in the pathophysiology of ADHD, and pointed to new perspectives for consistent use of the tool in the field.

Averill L.A., Jiang L., Purohit P., Coppoli A., Averill C.L., Roscoe J., Kelmendi B., De Feyter H.M., de Graaf R.A., Gueorguieva R., Sanacora G., Krystal J.H., Rothman D.L., Mason G.F., Abdallah C.G.

Background Trauma and chronic stress are believed to induce and exacerbate psychopathology by disrupting glutamate synaptic strength. However, in vivo in human methods to estimate synaptic strength are limited. In this study, we established a novel putative biomarker of glutamatergic synaptic strength, termed energy-per-cycle (EPC). Then, we used EPC to investigate the role of prefrontal neurotransmission in trauma-related psychopathology. Methods Healthy controls (n = 18) and patients with posttraumatic stress (PTSD; n = 16) completed 13C-acetate magnetic resonance spectroscopy (MRS) scans to estimate prefrontal EPC, which is the ratio of neuronal energetic needs per glutamate neurotransmission cycle (VTCA/VCycle). Results Patients with PTSD were found to have 28% reduction in prefrontal EPC ( t = 3.0; df = 32, P = .005). There was no effect of sex on EPC, but age was negatively associated with prefrontal EPC across groups ( r = –0.46, n = 34, P = .006). Controlling for age did not affect the study results. Conclusion The feasibility and utility of estimating prefrontal EPC using 13C-acetate MRS were established. Patients with PTSD were found to have reduced prefrontal glutamatergic synaptic strength. These findings suggest that reduced glutamatergic synaptic strength may contribute to the pathophysiology of PTSD and could be targeted by new treatments.

Swanberg K.M., Campos L., Abdallah C.G., Juchem C.

A stressor-related disorder wherein traumatic experience precipitates protracted disruptions to mood and cognition, post-traumatic stress disorder (PTSD) is associated with wide-ranging abnormalities across the body. While various methods have investigated these deviations, only proton magnetic resonance spectroscopy (1H MRS) enables noninvasive measurement of small-molecule metabolites in the living human. 1H MRS has correspondingly been employed to test hypotheses about the composition and function of multiple brain regions putatively involved in PTSD. Here we systematically review methodological considerations and reported findings, both positive and negative, of the current 1H-MRS literature in PTSD (N = 32 studies) to communicate the brain regional metabolite alterations heretofore observed, providing random-effects model meta-analyses for those most extensively studied. Our review suggests significant PTSD-associated decreases in N-acetyl aspartate in bilateral hippocampus and anterior cingulate cortex with less evident effect in other metabolites and regions. Model heterogeneities diverged widely by analysis (I2 < 0.01% to 90.1%) and suggested regional dependence on quantification reference (creatine or otherwise). While observed variabilities in methods and reported findings suggest that 1H-MRS explorations of PTSD could benefit from methodological standardization, informing this standardization by quantitative assessment of the existing literature is currently hampered by its small size and limited scope.

Smucny J., Carter C.S., Maddock R.J.

AbstractBackground Magnetic resonance spectroscopy studies measuring brain glutamate separately from glutamine are helping elucidate schizophrenia pathophysiology. An expanded literature and improved methodologies motivate an updated meta-analysis examining effects of measurement quality and other moderating factors in characterizing abnormal glutamate levels in schizophrenia. Methods Searching previous meta-analyses and the MEDLINE database identified 83 proton magnetic resonance spectroscopy datasets published through March 25, 2020. Three quality metrics were extracted—Cramér–Rao lower bound (CRLB), line width, and coefficient of variation. Pooled effect sizes (Hedges' g) were calculated with random-effects, inverse variance-weighted models. Moderator analyses were conducted using quality metrics, field strength, echo time, medication, age, and stage of illness. Results Across 36 datasets (2086 participants), medial prefrontal cortex glutamate was significantly reduced in patients (g = −0.19, confidence interval [CI] = −0.07 to −0.32). CRLB and coefficient of variation quality subgroups significantly moderated this effect. Glutamate was significantly more reduced in studies with lower CRLB or coefficient of variation (g = −0.44, CI = −0.29 to −0.60, and g = −0.43, CI = −0.29 to −0.57, respectively). Studies using echo time ≤20 ms also showed significantly greater reduction in glutamate (g = −0.41, CI = −0.26 to −0.55). Across 11 hippocampal datasets, group differences and moderator effects were nonsignificant. Group effects in thalamus and dorsolateral prefrontal cortex were also nonsignificant. Conclusions High-quality measurements reveal consistently reduced medial prefrontal cortex glutamate in schizophrenia. Stricter CRLB criteria and reduced nuisance variance may increase the sensitivity of future studies examining additional regions and the pathophysiological significance of abnormal glutamate levels in schizophrenia.

Rosso I.M., Silveri M.M., Olson E.A., Eric Jensen J., Ren B.

Gamma-aminobutyric acid (GABA) metabolism is implicated in posttraumatic stress disorder (PTSD) and may be altered in prefrontal-limbic brain regions involved in arousal regulation. This study used proton magnetic resonance spectroscopy (MRS) to test the hypothesis that PTSD and trauma-exposed non-PTSD comparison (TENC) adults have significantly different GABA than healthy comparison (HC) subjects in two brain areas implicated in arousal (medial prefrontal cortex, insula) but not in a control brain area (posterior temporal cortex). We also examined whether GABA alterations correlated with hyperarousal and dissociation symptoms. One hundred and fourteen participants (39 PTSD, 34 TENC, 41 HC) underwent 3T MRS of the medial prefrontal, right insular, and right posterior temporal cortices, and the GABA plus macromolecule signal (GABA+) was normalized to creatine (Cr). The Clinician Administered PTSD Scale measured hyperarousal symptoms, including sleep disruption. The Dissociative Experiences Scale assessed dissociation symptoms. PTSD and TENC participants had significantly lower mPFC GABA+/Cr than HC participants, and this deficit was significantly correlated with greater dissociation. Compared with HC, PTSD patients but not TENC had significantly lower insula GABA+/Cr. Total hyperarousal symptoms and sleep disruption were not significantly associated with GABA+/Cr alterations in either region. Our findings point to lower GABA in cortical areas implicated in arousal regulation in PTSD and suggest that GABA alterations are associated with symptoms of trauma-related psychopathology but not always a biomarker of diagnosis. These findings also add to evidence that dissociation has distinct neural correlates within PTSD, including high excitability of medial prefrontal cortex.

Reid M.A., Forloines M.R., Salibi N.

Establishing the reproducibility of brain MRS is important for clinical studies so that researchers can evaluate changes in metabolites due to treatment or the course of a disease and better understand the brain in healthy and disordered states. Prior 7-T MRS reproducibility studies using the stimulated echo acquisition mode (STEAM) sequence have focused on the anterior cingulate cortex or posterior cingulate cortex and precuneus. The purpose of this study was to evaluate the reproducibility of metabolite measurements in the dorsolateral prefrontal cortex (DLPFC) using an ultrashort echo time (TE) STEAM sequence and automated voxel repositioning. Spectra were acquired during two scan sessions from nine subjects using the AutoAlign method for voxel repositioning. Reproducibility was evaluated with coefficients of variation (CVs) and percentage differences. The mean intrasubject CVs were less than 6% for the major metabolites glutamate, N-acetylaspartate, total creatine, total choline, and myo-inositol. The mean CVs were less than 20% for the smaller signals of GABA, glutamine, glutathione, and taurine. These results indicate that 7-T MRS using a STEAM sequence with ultrashort TE and automated voxel repositioning provides excellent reproducibility of metabolites in the DLPFC.

Siegel C.E., Laska E.M., Lin Z., Xu M., Abu-Amara D., Jeffers M.K., Qian M., Milton N., Flory J.D., Hammamieh R., Daigle B.J., Gautam A., Dean K.R., Reus V.I., Wolkowitz O.M., et. al.

We sought to find clinical subtypes of posttraumatic stress disorder (PTSD) in veterans 6–10 years post-trauma exposure based on current symptom assessments and to examine whether blood biomarkers could differentiate them. Samples were males deployed to Iraq and Afghanistan studied by the PTSD Systems Biology Consortium: a discovery sample of 74 PTSD cases and 71 healthy controls (HC), and a validation sample of 26 PTSD cases and 36 HC. A machine learning method, random forests (RF), in conjunction with a clustering method, partitioning around medoids, were used to identify subtypes derived from 16 self-report and clinician assessment scales, including the clinician-administered PTSD scale for DSM-IV (CAPS). Two subtypes were identified, designated S1 and S2, differing on mean current CAPS total scores: S2 = 75.6 (sd 14.6) and S1 = 54.3 (sd 6.6). S2 had greater symptom severity scores than both S1 and HC on all scale items. The mean first principal component score derived from clinical summary scales was three times higher in S2 than in S1. Distinct RFs were grown to classify S1 and S2 vs. HCs and vs. each other on multi-omic blood markers feature classes of current medical comorbidities, neurocognitive functioning, demographics, pre-military trauma, and psychiatric history. Among these classes, in each RF intergroup comparison of S1, S2, and HC, multi-omic biomarkers yielded the highest AUC-ROCs (0.819–0.922); other classes added little to further discrimination of the subtypes. Among the top five biomarkers in each of these RFs were methylation, micro RNA, and lactate markers, suggesting their biological role in symptom severity.

Roalf D.R., Sydnor V.J., Woods M., Wolk D.A., Scott J.C., Reddy R., Moberg P.J.

Glutamate (Glu) is a key molecule in cellular metabolism, the most abundant excitatory neurotransmitter in the brain, and the principal neurotransmitter of cortical efferents. Glutamate dysfunction, on the other hand, is common in neurodegenerative disorders, and likely contributes to age-related declines in behavioral and cognitive functioning. Nonetheless, the extant literature measuring age-related changes in brain glutamate in vivo has yet to be comprehensively and quantitatively summarized. This meta-analysis examines proton spectroscopy (1HMRS) measures of Glu-related brain metabolites across 589 healthy young and older adults. Glu (Cohen's d = -0.82) and Glu+glutamine (Cohen's d = -0.51) concentrations were significantly lower in older compared with younger adults, whereas the concentration of glutamine (d = 0.43) was significantly higher in older individuals. Notably, 1HMRS methodological choices impacted effect sizes for age-related Glu differences. Glu metabolite change appears to be a robust marker of aging-related neurological change; however, additional studies are needed to elucidate age-related trajectories of glutamatergic alterations and their relationship to cognitive phenotypes.