Myelin Pathology in Post-traumatic Stress Disorder: Evolving Mechanistic Insights and Avenues for Future Investigation

Post-traumatic stress disorder (PTSD), a psychiatric condition associated with the abnormal consolidation of fear memories, continues to exhibit high global prevalence rates [1]. Current first-line treatments, such as selective serotonin reuptake inhibitors, show limited efficacy, often characterized by suboptimal response rates and significant residual symptoms [2]. This therapeutic bottleneck underscores our insufficient under- standing of the core pathological mechanisms underlying PTSD. In recent years, groundbreaking insight in neuroscience has revealed that myelination in the adult brain is a highly dynamic and experience-modulated plastic process. Newly formed myelin not only optimizes neural signal conduction but has also been shown to directly regulate neural circuit functions and participate in the modulation of learning and memory. This finding suggests that myelin abnormalities may constitute a novel neural basis for thepersistence of fear memories and emotional dysregulation in PTSD. Several clinical studies have observed structural alterations in myelin within the brains of patients with PTSD (e.g., in the hippocampus and prefrontal cortex), yet the causal role and specific mechanisms involved remain poorly understood.

1 Preliminary Evidence and Inconsistent Findings of Myelin Changes in PTSD

In 2015, Chao et al. [3] conducted the first study investigating the relationship between PTSD and hippocampal myelin content in individuals with PTSD. Using the T1-weighted/T2-weighted magnetic resonance imaging ratio to estimate myelin content, the study found that veterans with PTSD had significantly higher hippocampal myelin content compared with a trauma-exposed control group without PTSD. Additionally, myelin content was positively correlated with the severity of PTSD and depressive symptoms. This finding suggests that stress may influence hippocampal circuits, which are closely associated with memory and emotional regulation, by modulating myelination. However, subsequent larger-scale studies have revealed a more complex picture.

In 2021, a large multicenter study led by the PGC-ENIGMA PTSD Consortium, which included 28 cohorts and 3,047 adults, systematically assessed white matter microstructure in patients with PTSD using diffusion tensor imaging. The study found that, compared with controls, patients with PTSD exhibited reduced fractional anisotropy and increased radial diffusivity, primarily in the splenium of the corpus callosum, a region connecting the left and right hippocampi, suggesting impaired white matter integrity in this interhippocampal pathway. This finding shifted the focus of abnormality to the connective pathways between the hippocampi rather than the myelin content within the hippocampal gray matter itself [4].

Further narrowing the focus to a rigorously screened sample of veterans (excluding con- founding factors such as traumatic brain injury, major depression, and alcohol dependence), a 2022 study by Romaniuk et al.[5] reported partially divergent results. Their study did not identify significant differences in fractional anisotropy or mean diffusivity between PTSD and trauma-exposed control groups, either across the whole-brain white matter skeleton or in specific tracts such as the cingulum bundle. However, it is noteworthy that within the PTSD group, symptom severity was significantly negatively correlated with fractional anisotropy values in the left corticospinal tract and the left inferior cerebellar peduncle. Additionally, the study revealed reduced gray matter volume in brain regions associated with emotional regulation and cognitive control, such as the prefrontal cortex, bilateral middle frontal gyri, and left anterior insula, in patients with PTSD.

The inconsistencies in these research findings may stem from various factors: sample hetero- geneity (e.g., type of trauma, disease duration, age, sex composition), differences in neuroimaging methods (such as varying sensitivities of the T1-weighted/T2-weighted ratio and diffusion tensor imaging to myelin changes), whether key confounding variables were controlled (e.g., comorbid depression, substance abuse, medication use), and differences in statistical analysis strategies. These contradictions highlight both the potential of myelin changes as an innovative target for pathophysiological mechanism research and the considerable complexity involved, as well as the challenges in establishing them as reliable biomarkers for PTSD. They also suggest the need for mechanistic exploration in more controlled models.

2 The Scarcity of Animal Model Research and Preliminary Insights

In contrast to the relatively active clinical research, studies directly investigating the causal relationship between PTSD-like behaviors and dynamic changes in central myelin in animal models are extremely limited. This fact hinders our understanding of whether clinically observed myelin abnormalities are a cause (a susceptibility marker), a consequence (neurotoxic outcome), or a compensatory/maladaptive change in response to traumatic stress. A 2024 animal model study, for the first time, established a direct causal link between PTSD-like behaviors and specific myelin abnormalities [6]. The study employed chronic restraint stress to establish a PTSD model in mice and found that the model mice exhibited enhanced remote fear memory, anxiety, and depression-like behaviors. Concurrently, a distinct “hypermyelination” phenomenon was observed in their posterior parietal cortex and hippocampal CA3 region: the number of myelinated axons increased significantly, but the myelin sheath thickness decreased. Mechanistically, this hypermyelination resulted from excessive differentiation of oligodendrocyte precursor cells. Most importantly, the study revealed a unique therapeutic mechanism of the antidepressant fluoxetine (a selective serotonin reuptake inhibitor): it significantly reversed both the abnormal behaviors and hypermyelination in the model mice, whereas other drugs (risperidone, sertraline) showed limited efficacy. Unfortunately, this remains the only relevant report to date. Most related animal studies have focused on the effects of chronic stress on oligodendrocyte lineage cells and basic myelin structure in regions such as the prefrontal cortex and hippocampus, but research systematically linking these changes to specific PTSD-like behavioral phenotypes (e.g., hypervigilance, fear memory generalization, avoidance behavior) is still in its early stages. Therefore, there is an urgent need to establish animal models that can simulate the core symptoms of PTSD and, within this framework, to longitudinally and multimodally monitor the dynamic processes of myelin generation, maintenance, and remodeling, thereby enabling in-depth investigation into the mechanisms by which myelin influences the development and progression of PTSD.

3 Future Research Directions

Given the inconsistencies in current clinical findings and the insufficiency of fundamental research, future studies on “myelin and PTSD” may delve deeper into the following cutting-edge areas.

Intersection with established PTSD mechanisms: A promising avenue for future research involves integrating myelin-focused investigations with other well-established PTSD mechanisms. For instance, stress-induced neuroinflammation, particularly that involving pro-inflammatory cytokines such as interleukin-1β and tumor necrosis factor-α, has been shown to directly affect oligodendrocyte lineage cells, potentially disrupting myelination dynamics and contributing to the white matter abnormalities observed in PTSD [7, 8]. Conversely, myelin abnormalities may themselves perpetuate inflammatory cascades through impaired trophic support. Similarly, epigenetic mechanisms, especially those involving early-life stress, may program long-term alterations in myelin-related gene expression (e.g., through DNA methylation of oligodendrocyte-specific genes), thereby establishing enduring vulnerability to PTSD. Understanding how myelin pathology intersects with inflammation, epigenetic programming, and other PTSD mechanisms (such as hypothalamic–pituitary–adrenal axis dysfunction and neurotransmitter system alterations) will be essential for developing a comprehensive, multi- level understanding of PTSD pathophysiology.

Mechanism elucidation and causal validation: Using transgenic animals, cell-type-specific manipulations (e.g., oligodendrocyte precursor cells, mature oligodendrocytes), and live imaging techniques, future studies could aim to clarify how stress affects each stage of myelination (proliferation, differentiation, wrapping, maturation) in a PTSD animal model. Furthermore, through behavioral, electrophysiological, and optogenetic/ chemogenetic approaches, such studies could examine the necessity and sufficiency of myelin alterations in specific neural circuits for core PTSD symptoms, such as fear memory consolidation/ extinction and anxiety-like behaviors.

Clinical biomarker development: By integrating multimodal neuroimaging (e.g., more sensitive myelin imaging sequences, high-angular-resolution diffusion imaging), fluid-based biomarkers (e.g., myelin-related proteins, oligodendrocyte-derived

exosomes), and artificial intelligence-based analytics, research could aim to validate, within large-scale prospective clinical cohorts, whether features of myelin changes, such as the integrity of specific pathways or the rate of myelination, can serve as diagnostic aids for PTSD, symptom domain-specific markers (e.g., distinguishing pathways associated with hyperarousal vs. emotional numbness), or predictors of treatment response and prognosis. For instance, early myelin change patterns detected during acute stress disorder may predict the risk of subsequently developing chronic PTSD.

Research on critical periods and plasticity of myelination: This research direction focuses on how early-life stress or trauma affects the developmental timing of myelination in key brain regions (such as the prefrontal–limbic system), which may form the basis of “developmental programming” for susceptibility to PTSD in adulthood. Additionally, it explores whether interventions targeting myelin plasticity in adulthood (e.g., through environmental enrichment, specific behavioral training, or novel drugs that promote adaptive myelin remodeling) could offer new avenues for PTSD treatment.

Heterogeneity analysis and precision subtyping: Given the high heterogeneity in the clinical manifestations and etiology of PTSD, future research should focus on stratifying patients according to trauma type (single vs. complex, adult-onset vs. childhood-onset), genetic background, sex, and comorbidities. This approach will help explore whether different subtypes correspond to distinct myelin pathology patterns, thereby advancing the precision neurobiological subtyping of PTSD.

New therapeutic targets: on the basis of myelin- associated mechanisms (such as oligodendrocyte metabolism and axon–oligodendrocyte signaling), research could explore novel pharmacological or physical interventions (e.g., specific growth factors, metabolic modulators, transcranial magnetic stimulation) that target the promotion of myelin repair or protection and the regulation of myelin plasticity, and evaluate their ability to improve PTSD symptoms.

In summary, although preliminary evidence suggests that myelin abnormalities play a remarkable role in the pathophysiology of PTSD, current research remains in a “puzzle-solving” stage. By integrating rigorous clinical studies with in-depth mechanistic explorations in animal models, future efforts are expected to elucidate the precise role of myelin dynamics in the development and progression of PTSD, thereby opening a new pathway from understanding the disease’s essence to developing innovative therapies.