Prefrontal glutamate neurotransmission in PTSD: A novel approach to estimate synaptic strength in vivo in humans
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Abstract
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 psychopathology. Healthy control (n=18) and patients with posttraumatic stress (PTSD; n=16) completed 13 C-acetate magnetic resonance spectroscopy scans to estimate prefrontal EPC, which is the ratio of neuronal energetic needs per glutamate neurotransmission cycle (V TCA /V Cycle ). Patients with PTSD were found to have 28% reduction in prefrontal EPC ( t =3.0; df =32, p =0.005). There was no effect of sex on EPC, but age was negatively associated with prefrontal EPC across groups ( r =–0.46, n=34, p =0.006). Controlling for age did not affect the study results. The feasibility and utility of EPC 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.
Highlights
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Glutamatergic synaptic strength is critical for brain function in health and disease.
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In vivo in human methods to estimate glutamatergic synaptic strength are limited.
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We here propose a new approach to estimate glutamatergic synaptic strength.
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The new method employs carbon-13 magnetic resonance spectroscopy ( 13 C MRS).
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The utility of the new approach was demonstrated in posttraumatic stress disorder (PTSD).
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This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/6515611.
Disclosures: The reviewer declares no conflict of interest and has no personal or financial relationship with the study's authors. The reviewers did not analyze the validity of the statistical analysis as these were beyond the scope of their expertise. This review represents a general consensus. I thank the authors for sharing their manuscript as a preprint.
Summary.
The goal of this paper was to investigate a novel technique to determine the glutamatergic strength level in the prefrontal cortex (PFC) by measuring the energy-per-cycle (EPC) in post-traumatic stress disorder (PTSD) patients. Healthy participants and participants suffering from severe PTSD underwent 13C-acetate magnetic …
This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/6515611.
Disclosures: The reviewer declares no conflict of interest and has no personal or financial relationship with the study's authors. The reviewers did not analyze the validity of the statistical analysis as these were beyond the scope of their expertise. This review represents a general consensus. I thank the authors for sharing their manuscript as a preprint.
Summary.
The goal of this paper was to investigate a novel technique to determine the glutamatergic strength level in the prefrontal cortex (PFC) by measuring the energy-per-cycle (EPC) in post-traumatic stress disorder (PTSD) patients. Healthy participants and participants suffering from severe PTSD underwent 13C-acetate magnetic resonance spectroscopy (MRS) scans that would estimate the upstream input and downstream output of glutamate synaptic strength. This was used to detect a radio-labeled glutamate/glutamine ratio and measured changes in glutamate signaling in the PFC. The authors are trying to use this glutamate/glutamine ratio as a proxy for glutamate transmission in the PFC. Major findings from the paper include that patients with PTSD had a 28% reduction of prefrontal EPC. The relevance of this work is important in studying debilitating neurological diseases including PTSD, which results from maladaptive learning and wiring of the brain from traumatic memory. It is important to study glutamate because it is the most abundant excitatory input in the brain, and much of the PFC neurons are glutamatergic. The rationale and research question behind the study is justified, as this work has the potential to have a large impact on how scientists can study and measure stress in the brain. I believe that this paper merits publication after all major concerns are addressed.
Major strengths.
-The authors are investigating a novel technique that could have large benefits to understanding how glutamate plays a role in measuring stress levels.
-Table 1, Figure 1, and Figure 2 are clearly presented and the statistics are well-interpretable to ensure the similarity between the groups and the appropriate tests were done to determine significance.
-Major limitations of the study were discussed, such as that this study should be treated as a first-level trial to compare EPC levels for PTSD in humans.
-The study includes well-reasoned conclusions about the importance of this work and how its preliminary conclusions can be used for future studies. The paper does a good job at showing how this work has the potential to impact our understanding of stress-related neurological conditions.
-The 13C MRS processing was conducted while blinded. This is a strength that ensures less bias when recording the results.
-The study looked at individual variables (such as age, race, etc) as shown in Table 1 to investigate potential moderator effects on EPC levels.
-The graphs are done in blue and red, which is accessible to colorblind individuals.
-Because rats and humans have similar glutamatergic systems, this novel approach could be tested in animal models for future studies.
Major weaknesses.
-The study is very preliminary, and there is weak significance between variables with overlap between the experimental and control groups.
-The background section should include more relevance on the importance of studying glutamate as a measurement of stress, and why the study is testing glutamate on people with PTSD diagnoses (as opposed to other neurological disorders).
-It is difficult to interpret the findings because the method of obtaining the EPC does not specifically measure the synaptic glutamate transmission but rather upstream and downstream effects of the neurotransmitter on receptors and vesicles.
Major critiques.
-More should be added to the future directions section of the paper to ensure better interpretation of the results. The authors should consider writing about the following experimental design in the manuscript: 1) adding a third experimental group that includes individuals with chronic stress but no PTSD diagnosis, and 2) conducting a CAPS-5 assessment with all groups to determine the severity of PTSD symptoms that can be measured to statistically analyze the difference in PTSD severity with EPC level.
-It is not clear if the authors are using this novel approach to measure glutamate as a way of detecting the severity of PTSD or if they are using 13C-MRS scanning to look at glutamate as a way of measuring stress. Please clarify this in the manuscript.
-The authors should emphasize why 13C-glutamate measurement is superior to previous scanning methods such as 13C-glucose, and why the ratio of glutamate/glutamine is an important biomarker of synaptic glutamatergic strength.
-The sample size is very small. If the experiment is repeated, there should be approximately 50 participants that demographically reflect the general population in each group.
-The authors should expand more into the pharmacokinetics of PTSD and why they chose glutamate as a way of measuring symptoms. For example, including that there are regional brain differences and functional connectivity deficits in the brains of people with PTSD. The amygdala is overactive, and the PFC is under active, so people can't quiet their amygdala responses as effectively. This will help clear up any confusion around why glutamate in the PFC is being studied.
Minor critiques.
-Because of the difficulty in interpreting the findings, I suggest changing the language of this paper so that readers do not think that the EPC is measuring synaptic strength or transmission. For example, the title should be changed so as not to include the words "neurotransmission" and "synaptic strength".
-I believe the criteria for choosing participants with PTSD could be improved. For example, having patients treated with SSRIs for 4 weeks is an insufficient time frame because it takes SSRIs up to 6 weeks to start feeling the effects (Chu et al, 2022). If the experiment is repeated, consider recruiting people who have been on SSRIs for 8 weeks or longer.
-Participants were chosen if they have had no prior diagnosis of bipolar or psychotic disorders, depression, or suicide ideation. Suicide ideation is a major symptom of PTSD, and there is a lot of overlap in diagnosing PTSD with bipolar disorder. Is the reason for excluding individuals with these symptoms? Is it due to safety concerns or liability? Please explain this briefly.
-During 13C processing, why was the steady state spectra averaged after 70 minutes from the time of the acquisitions? Why this particular time was chosen should be explained.
-In Table 1, "White" percentage was listed as a category. What about other races/ethnicities? This should be fully broken down.
Results
The major conclusion of the paper is that EPC levels are significantly reduced among PTSD individuals, showing reduced glutamatergic strength in the PFC. They also found that age is a moderating variable that affects EPC levels. An additional finding is that as age increases the level of EPC decreases, making age a moderating variable. This paper is preliminary data showing that the novel approach of 13C-MRS processing can be used as a biomarker for measuring glutamatergic levels in the PFC as a way to study stress and trauma in neurological disorders.
Resources Cited.
Chu A, Wadhwa R. Selective Serotonin Reuptake Inhibitors. [Updated 2022 Jan 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554406/
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