Letter to the Editor: Evaluation of the pathological cascade of post-subarachnoid hemorrhage anxiety and depression

Abstract

Anxiety and depression disorders following subarachnoid hemorrhage (SAH) are common neuropsychological complications, which will definitely affect the long-term functional recovery and quality of life of patients. So far, the pathophysiological mechanisms of such complications have not been fully elucidated, and effective treatment strategies are lacking. This letter to the editor is a comment on a preclinical study published in World Journal of Psychiatry by Qin et al. The research team established the SAH rat model, combined with multi-dimensional behavior detection, diffusion tensor imaging (DTI) scanning, inflammatory factor expression level detection and other methods to clarify the specific mechanism of emotional dysfunction after SAH. The study not only identified the temporal dynamic characteristics of emotional disorders, discovered a new pathological cascade of “cytotoxic edema - NOD-like receptor pyrin domain-containing 3 inflammasome activation - limbic-prefrontal circuit injury”, and verified the feasibility of diffusion tensor imaging parameters (fractional anisotropy/apparent diffusion coefficient values) and cerebrospinal fluid interleukin-1β as objective indicators for disease progression assessment. This article summarizes the core academic value of this study, and combined with the existing research progress in this field, further analyzes the reference value of this achievement for defining the intervention time window, the practical difficulties in the process of clinical transformation, and the possible breakthrough direction of follow-up research, in order to provide new ideas for the precise prevention and treatment of neuropsychiatric complications after SAH.

Key Words: Subarachnoid hemorrhage; Anxiety; Depression; NOD-like receptor pyrin domain-containing 3 inflammasome; Diffusion tensor imaging; Limbic-prefrontal circuit

Core Tip: This study identified a novel pathological cascade of “cytotoxic edema - NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation - limbic-prefrontal circuit injury”, which is a key driver of anxiety and depression after subarachnoid hemorrhage. The contributions of this study are mainly reflected in threefold: (1) Quantified the time-dependent changes of emotional behavior, brain structure, and inflammatory response, among which diffusion tensor imaging parameters and cerebrospinal fluid interleukin-1β emerged as robust, objective biomarkers; (2) Confirmed that the NLRP3-interleukin-1β axis is a central regulatory node; and (3) Demonstrated translational potential: diffusion tensor imaging can be used for risk stratification, and NLRP3 inhibitors can be used as intervention methods.

TO THE EDITOR

Subarachnoid hemorrhage (SAH) is a cerebrovascular emergency with a high risk of death. The incidence of SAH is approximately 9 cases per 100000 individuals, the probability of death and disability for patients after the onset of the disease is also at a relatively high level[1]. In recent years, with the continuous development and improvement of clinical diagnosis and treatment technologies, the treatment outcome of SAH in the acute stage has significantly improved, and the survival rate of patients has increased significantly compared with the past. However, the long-term neuropsychiatric sequelae, especially the symptoms of anxiety and depression, during the recovery of the disease will seriously affect the quality of daily life of patients. Current clinical evidence indicates that even for SAH patients with good functional recovery (modified Rankin Scale score 0-2), the proportion of those experiencing anxiety or depression still reaches 42.5%. Because there are no quantifiable objective evaluation criteria, such symptoms are often ignored in the process of diagnosis and treatment. The traditional function evaluation tool commonly used in clinic, represented by Barthel index, is difficult to screen out such problems that have mild symptoms but have a great impact on the prognosis of patients, eventually leading to missed diagnosis and delaying the best opportunity for intervention[2]. Such emotional abnormalities will not only slow down the recovery speed of patients, reduce the quality of life, but also hinder patients from returning to normal social life. A systematic review and meta-analysis that integrated 29 studies, involving a total of 4104 patients who survived SAH, showed that the weighted proportion of anxiety was 31.2%; these emotional issues were identified as independent predictors of decreased health-related quality of life[3]. Previous studies have confirmed that patients with SAH who also have emotional disorders will have abnormally elevated expression levels of inflammatory factors such as IL-6 and TNF-α in their bodies. However, the upstream regulatory mechanism of this phenomenon, as well as its association with specific brain circuit damage, still have no clear conclusions at present[4]. The frontier research recently published in World Journal of Psychiatry by Qin et al[5] filled the research gap in this field and systematically sorted out the dynamic changes of emotional disorders over time after the onset of SAH. This paper objectively analyzed and evaluated the academic value and shortcomings of this research.

CLINICAL DIAGNOSIS AND RESEARCH STATUS OF EMOTIONAL DISORDERS AFTER SAH

At present, the clinical diagnosis of emotional disorders secondary to subarachnoid hemorrhage (SAH) is still based on the doctor's clinical evaluation combined with standardized scale screening. The commonly used screening tools include hospital anxiety and Depression Scale (HADS), Hamilton Anxiety Scale (HAMA) and Hamilton Depression Scale (HAMD)[6]. This kind of assessment scheme is highly subjective, and the results are often affected by many factors such as the patient's own cognitive ability, education level and cultural environment. The existing commonly used neural function evaluation systems, such as Barthel Index and modified Rankin scale, mainly focus on the physical motor function and the ability of independent daily living. There are often deficiencies in the identification and evaluation of neuropsychiatric abnormalities such as emotional disorders. Focusing on these clinical problems, finding biological markers with objectivity and stability is an important breakthrough direction for early warning, accurate diagnosis and individualized intervention of emotional disorders after SAH.

Most of the existing achievements in the field of pathological mechanism research focus on classic pathological factors such as cerebral ischemia, vasospasm, intracranial pressure rise, etc., and analyze their mediating effects on neural function injury after subarachnoid hemorrhage (SAH). However, the exploration of specific regulatory pathways for emotional abnormalities is relatively less. In recent years, the research of neuroinflammation, brain connectomics and other cross fields has been developing continuously. More and more research data show that the neuroinflammatory cascade and the structural and functional reconstruction of brain network are the core regulatory links of the occurrence and development of neuropsychiatric complications after SAH. However, at present, the academic community has not yet clarified the complete path of how neuroinflammation triggers the impairment of specific brain network functions and ultimately induces emotional disorders. Combined with this research gap, the research results of Qin and other scholars[5] provide a new entry direction for the systematic analysis of the pathogenesis of emotional disorders after SAH.

Qin et al[5] have established a rigorous experimental framework in relevant research, systematically sorted out the characteristics of abnormal emotion over time after subarachnoid hemorrhage (SAH), and the possible neurobiological mechanism behind it. The core innovation of this study is to introduce the idea of multi-point dynamic observation, and simultaneously detect the behavioral changes, imaging characteristics and fluctuations of molecular biological indicators of experimental animals at six time points of 1, 6, 12, 24, 48 and 72 hours after SAH modeling. This dynamic monitoring method with high time resolution has accumulated sufficient empirical evidence for clarifying the development path of emotional disorder after SAH. From the research conclusion, it can be found that the occurrence and development of emotional disorders have clear time gradient characteristics: Cellular edema can be observed 1 hour after SAH, the peak of NLRP3 inflammasome activation and IL-1β release occurs at 6-24 hours after surgery, the injury degree of limbic system prefrontal cortex loop reaches the maximum at 24-48 hours, while the behavior performance of anxiety and depression mainly occurs in the range of 24-72 hours. The clarity of this time effect rule provides a key reference for the subsequent screening of the time window of clinical intervention.

This study achieved cross-dimensional integration and innovation at the method level, and integrated three kinds of technical systems of ethology, imaging and molecular biology. It carried out multi perspective verification around the pathological cascade hypothesis of "cytotoxic edema-nlrp3 inflammasome marginal prefrontal loop", and finally confirmed the existence of this pathway. At the behavioral assessment stage, three classical paradigms, namely, the elevated cross maze, the forced swimming experiment, and the sucrose preference test, were selected to systematically measure the anxiety and depression like behaviors of model animals. The changes obtained were completely consistent with the characteristics of "early emotional disorder entering the peak after subarachnoid hemorrhage (SAH)" observed clinically[7]. In terms of imaging detection, diffusion tensor imaging(DTI) technology was used to focus on the marginal prefrontal loop related to emotion regulation function, and the dynamic changes of the structural integrity of the loop were analyzed. At the molecular biological level, the activation levels of NLRP3 inflammasome and its downstream regulated inflammatory factors were detected. Two preclinical studies have shown that NLRP3-IL-1β axis plays a central role in the pathological process of SAH: Zou et al[8] have shown that G protein-coupled receptor 40 (GPR40) activation can inhibit NLRP3 inflammasome through cyclic adenosine monophosphate protein kinase A pathway, which can reduce the expression of IL-1β in cerebrospinal fluid (CSF) of SAH model mice by 45%, and also alleviate neurological deficits, directly proving that NLRP3 can be used as a key therapeutic target; Jiang et al[9] showed that G protein-coupled receptor 84 (GPR84) activation can expand the NLRP3 mediated cell death process, promote the expression of IL-1β by 2.5 times, and also be accompanied by blood-brain barrier injury. The two studies provided experimental basis for the functional role of NLRP3-IL-1β axis from the two reverse regulation directions of inhibition and activation. This multi-dimensional research design greatly improves the scientificity and persuasiveness of the conclusions.

This study for the first time confirmed that cytotoxic edema is the initial trigger factor of emotional disorder after subarachnoid hemorrhage (SAH), and used rigorous experimental demonstration to prove that NLRP3 inflammasome plays a central mediating role in this pathological process. The results showed that the cytotoxic edema first appeared after the onset of SAH could activate NLRP3 inflammasome, induce the production and release of pro-inflammatory factors such as IL-1β, and then further lead to white matter damage in the limbic system prefrontal loop, and finally let the patients show anxiety and depression behavior. Coincidentally, Chen et al[10] mentioned after the clinical study of 42 SAH patients that the functional connectivity level of the hippocampal Papez loop (including the anterior cingulate cortex and the medial superior frontal cortex) will be reduced. This conclusion and the anisotropy score (FA) data obtained by Qin et al, can complement each other, and together build a complete evidence chain of limbic system prefrontal injury at the "structural level (DTI-FA) + functional level (functional magnetic resonance imaging-functional connectivity)". In addition, Zhao et al[11] also found that there was abnormal β-wave synchronization in the medial prefrontal cortex and orbitofrontal gyrus of patients with neuropsychiatric diseases, which was highly consistent with the loop specific injury characteristics identified by the previous team. The analysis of this mechanism not only deepened the academic understanding of the pathogenesis of emotional disorders after SAH, but also provided potential targets for the development of new intervention programs.

CLINICAL SIGNIFICANCE AND TRANSLATIONAL VALUE OF THE RESEARCH FINDINGS

The research results of Qin et al[5] show significant clinical application and translational potential, mainly in the following areas: In the field of diagnosis and evaluation, the DTI parameters (FA value and apparent diffusion coefficient value) and CSF IL-1β level proposed in this study are expected to become objective biological markers for emotional disorders after SAH. Compared with traditional subjective assessment tools, these indicators have stronger quantification and comparability, which is conducive to the early identification and accurate judgment of emotional disorders after SAH. It is particularly pointed out that the study found that when the FA value of the hippocampal-prefrontal pathway is lower than 0.35 at 72 hours after SAH, it has high value in predicting subsequent emotional disorders (sensitivity 82%, specificity 78%). This result lays an important foundation for constructing a risk prediction model for emotional disorders after SAH.

In terms of treatment strategies, the pathological cascade of “cytotoxic edema - NLRP3 inflammasome - limbic-prefrontal circuit” revealed by the study provides a new target for the intervention of emotional disorders after SAH. According to the temporal characteristics of this cascade, the study identified two key intervention windows: Early stage (1-6 hours after SAH) targeting cytotoxic edema, and middle stage (6-24 hours after SAH) targeting the NLRP3 inflammasome. For cytotoxic edema, dehydrating agents such as mannitol can be considered; for the NLRP3 inflammasome, specific inhibitors such as MCC950 can be selected. Weimer et al[12] first reported that increased intracranial pressure after SAH causes cytotoxic edema, and Qin et al[5] positioned it as the starting point of the pathological cascade. Li et al[13] further found that inflammation caused by edema promotes CD8+ T cell infiltration through the C-X-C motif chemokine ligand 12-C-X-C motif chemokine receptor 4 pathway, damages the blood-brain barrier, and exacerbates white matter damage, filling the gap in the team’s “edema - circuit damage” mechanism. A study by Liu et al[14] supports this strategy - puerarin (a natural compound) can reduce CSF IL-1β by 42% and increase hippocampal FA value by 18% in SAH rats, providing preclinical drug evidence for the clinical translation of the team’s findings. These intervention methods open up new avenues for the development of targeted therapy for emotional disorders after SAH.

In the field of clinical management, research evidence supports the integration of neuroimaging and molecular biological indicators into the overall assessment system of SAH patients. Traditional management of SAH patients focuses on neurological function recovery and prevention of vasospasm, but pays insufficient attention to emotional disorders. Sousa et al[15] found that subjective cognitive complaints in patients with chronic diseases are associated with anxiety (r = -0.44) and depression (r = -0.33). The research results of Qin et al[5] suggest that the emotional abnormalities after the onset of SAH are supported by clear physiological and pathological mechanisms, which need to be included in the key intervention content of the whole course management of patients. We can try to build a multidisciplinary diagnosis and treatment mechanism, integrate the professional advantages of different personnel such as neurologists, psychiatrists, rehabilitation therapists, and ultimately achieve the goal of integrated diagnosis and treatment of physiological and mental health of SAH patients.

CHALLENGES AND LIMITATIONS IN CLINICAL TRANSLATION

Qin et al have made key progress in the relevant exploration, but the relevant achievements still face many practical problems when they are applied to clinical application: The animal models currently used in the experiment are not small deviations from the clinical actual disease characteristics. Most of the existing studies selected healthy young male Sprague Dawley rats[5], but clinically, patients with subarachnoid hemorrhage (SAH) are mainly middle-aged and elderly people with basic diseases such as hypertension and diabetes at the same time, and the gender difference of the incidence group is very obvious[16]. These differences may limit the promotion scope of research conclusions, especially that estrogen itself can regulate NLRP3 inflammasome, which may change the severity of neuroinflammation and affect the final prognosis of patients[17]. Therefore, it is necessary to reproduce and verify the existing research results in female animal groups.

There are obvious limitations in the observation duration of existing studies, which can not completely present the whole development process of clinical emotional disorder. The current experiment only tracks 72 hours after subarachnoid hemorrhage (SAH), but clinically, the emotional abnormalities of such patients usually last for several months, or even longer[18]. Relying only on the results of short-term observation, it is neither able to fully explain the long-term characteristics of pathological cascade reaction, nor can it accurately determine the actual role of compensatory neural plasticity in the course of disease. The follow-up study can further extend the observation time, and completely sort out the long-term evolution path and related influencing factors of emotional disorder after SAH.

The existing studies did not fully cover the impact of complications and drug intervention. Most patients with subarachnoid hemorrhage in clinical treatment have the combined symptoms of hydrocephalus, electrolyte disorder and infection at the same time. A variety of different drugs will be used in the treatment process, and these variables may affect the emotional state of patients[19]. However, at present, the relevant experiments are carried out under strictly controlled artificial conditions, and there is no way to restore the complex characteristics of the clinical scene. In subsequent related research, it is necessary to restore the real scene and make special analysis specifically for such interference variables.

There are still many problems to be solved for the completion of clinical transformation and landing of biomarkers. At present, although diffusion tensor imaging (DTI) parameters and inflammatory factors have shown good application prospects, in order to achieve large-scale clinical use, it is necessary to break through the unified and standardized measurement process one by one, sort out the application scenarios, and determine the reference values of different populations. As for the relationship between these markers and the current commonly used clinical evaluation system, it also needs to rely on a larger scale of clinical research to clarify whether they can form an alternative, complementary or deeply integrated collaboration mode, which still needs more actual data to prove.

FUTURE RESEARCH DIRECTIONS AND SUGGESTIONS

Combined with the research conclusions published by Qin et al[5] and the current practical problems in this field, the follow-up related research can be carried out from the following core directions: First, the clinical effectiveness verification of large samples and multiple scenarios should be carried out. To evaluate the predictive value of diffusion tensor imaging (DTI) and inflammatory biomarkers for emotional complications in patients with subarachnoid hemorrhage (SAH) with different basic characteristics in multiple medical centers, we can use the framework of prospective cohort study to collect images, biomarkers and other clinical data at multiple time points, and establish a high-precision early warning model. On this basis, we can further clarify the correlation between the above biomarkers and clinical manifestations, intervention response effect and long-term prognosis of patients, and accumulate sufficient supporting evidence for the application of such methods in clinical practice.

Second, expand the research dimensions related to mechanism details and individual heterogeneity. Future research can focus on exploring the upstream regulatory pathways and downstream pathways in the activation of NLRP3 inflammasome, identify the key intervention targets, and sort out the influencing factors of individual heterogeneity such as genetic background, age stratification, gender differences, and basic disease status, so as to provide theoretical support for the formulation of clinical individualized diagnosis and treatment programs. Epigenetic regulation, microbial brain gut axis and other cutting-edge research directions also need to be included in the scope of focus[20,21].

Third, we should promote the development and effect verification of targeted therapies, and develop targeted intervention methods for special targets, such as NLRP3 inflammasome antagonists, cytotoxic edema improvement agents, etc., in combination with the pathogenesis and development laws of diseases that have been proved in existing studies. The effectiveness and safety of these intervention schemes were verified in the preclinical research stage, so as to prepare for subsequent clinical trials. At the same time, the value of the combination of this new type of therapy and the current commonly used clinical treatment schemes (including antidepressants and psychological interventions) was further clarified.

Fourth, to build an interdisciplinary joint diagnosis and treatment system, the prevention and control of emotional disorders after subarachnoid hemorrhage (SAH) requires the cooperation of Neurology, psychiatry, rehabilitation and other departments[22]. It can promote the development of standardized diagnosis and treatment guidance documents covering biological, psychological and social factors, and integrate the early screening, accurate assessment and targeted intervention of emotional disorders into the routine clinical management path of SAH patients throughout the process. Special health education can also be conducted for patients and their families to improve their understanding of such emotional disorders and strengthen their attention.

Fifthly, the research focus should be on the long-term prognosis and quality of life improvement of patients. The follow-up related research should not only stay at the level of relieving symptoms, but also pay more attention to the long-term functional recovery of patients and the improvement effect of quality of life. It is necessary to build a multi-dimensional evaluation system, fully measure the comprehensive benefits of the treatment scheme, and analyze the related factors affecting the long-term prognosis, so as to provide an empirical basis for improving the overall prognosis of patients.

CONCLUSION

The study by Qin et al[5] revealed a novel pathological cascade of “cytotoxic edema - NLRP3 inflammasome activation - limbic-prefrontal circuit injury”, which provides a key contribution to understanding the pathogenesis of emotional disorders after SAH. This achievement not only broadens the understanding of the pathophysiological basis of neuropsychiatric complications after SAH, but also lays a solid theoretical foundation for the development of new diagnostic schemes and interventions. However, in order to translate such laboratory research results into clinical application, we still need to solve many practical problems, such as the differences between animal models and human pathology, the different individual conditions of patients, and the complex clinical scenes. The follow-up basic researchers and clinical medical staff need to further deepen cooperation, with the help of multi-dimensional and multi-level cross fusion research, to promote the establishment of accurate prevention and control system of emotional disorders after SAH, and ultimately improve the long-term prognosis and quality of life of patients.