Aneurysmal subarachnoid hemorrhage (aSAH) is typically characterized by extravasation of blood into the subarachnoid space and is induced by the spontaneous rupture of intracranial aneurysms. aSAH accounts for approximately 85% of atraumatic subarachnoid hemorrhages and is a crucial cause of morbidity and mortality worldwide (1). At the very minimum, a quarter (25%) of aSAH patients die, while around half (50%) of the survivors will experience prolonged psychological and neurological deficits (2).

In addition to causing severe impairment to the central nervous system, aSAH also has deleterious effects on various organs, including the gastrointestinal and cardiovascular systems. These effects can pose challenges to the provision of patient care and treatment (3). Stress-related mucosal disease accompanies a state of severe stress, such as critical illnesses and severe trauma. It results in injury to the superficial or deep local mucosal layers in the form of stress-related mucosal injury or stress ulcers, respectively. About 5–33% of stress-related gastrointestinal bleeding (SRGB) is clinically significant as it leads to hemodynamic instability, heightened ventilation requirements, elevated rates of hospitalization, and augmented mortality rates (4–6).

Numerous studies have demonstrated a prominent role of the dopaminergic system in specific gastrointestinal functions (7, 8). In addition, stress affects both central and peripheral dopaminergic activity, thereby further regulating the effects of stress-induced gastroduodenal mucosal injury. As one of the three principal dopaminergic pathways in the central nervous system, the nigrostriatal pathway primarily comprises cell bodies in the substantia nigra pars compacta (SNpc), which project to the caudate putamen and the central nucleus of the amygdala. Studies have reported that damage to the nigrostriatal pathway could promote the development of gastric erosions (9, 10).

Computed tomography (CT), as a reliable and safe indicator, is being increasingly applied to clinical research pertaining to both cerebral ischemic and hemorrhagic diseases. The Hounsfield unit (HU) value serves as an indicator of water uptake in infarcted tissue. Increased water absorption leads to a decrease in the HU value (11). Studies have established a correlation between the HU value and cerebral vasospasm or delayed cerebral ischemia in patients affected by aSAH (12). The Alberta Stroke Program Early Computer Tomography (ASPECT) score employs a scoring method that evaluates early ischemic changes on CT scans in the areas of the brain supplied by the middle cerebral artery (MCA). It also computes the mean HU value of the region containing the caudate, internal capsule, lentiform nucleus, and insula. Currently, the ASPECT score can be automatically generated by an artificial intelligence system known as Rapid, which acts as a bridge for assessing the relationship between the caudate and SRGB.

Elevated intracranial pressure post-aSAH can cause a decline in cerebral perfusion pressure. Thus, we aimed to determine whether a relationship between the caudate and SRGB exists using the HU value in the ASPECT score.

In the current study, we have identified the predictive effect of the right caudate HU value in forecasting the development of SRGB following aSAH. Our main findings were as follows (1): the overall incidence of SRGB was 17.9% in our single-center cohort (2); endovascular coiling and right caudate HU values were predictors for SRGB (3); a HU value ≤25.1 in the right caudate was the predictive cutoff value for SRGB.

The HU value in the ASPECT score system quantitatively reflects the degree of tissue X-ray absorption, reliably detecting ischemic changes in brain tissue (14). Previous research on the ASPECT score has primarily focused on ischemic stroke in the MCA territory. Although aSAH is a hemorrhagic stroke, the main risk factor of this disease is ischemia. It has been found that the ASPECT score has important clinical application value for aSAH. Specifically, it significantly correlates with functional outcomes in patients with delayed cerebral ischemia following aSAH (1). Notably, our sensitivity analysis excluded patients with MCA aneurysm and still observed that the right caudate HU value significantly correlated with the development of SRGB, emphasizing the broader utility of the ASPECT score as a clinical tool.

SRGB refers to acute lesions of the gastrointestinal system in patients suffering from serious injuries, illnesses, and other stressful situations. In the process of SRGB, the metabolism of central monoamine neurotransmitters is accelerated. Norepinephrine, dopamine, γ-aminobutyric acid, serotonin, and acetylcholine may all be involved in the induction of SRGB. Previous research indicated that dopamine plays a significant role in gastric mucosal erosions. The central nervous system has three major dopaminergic pathways: the nigrostriatal pathway, mesolimbic pathway, and mesocortical pathway (15). First, the nigrostriatal pathway originates from the SN and projects to the caudate putamen and the central nucleus of the amygdala (10, 16). Second, the mesolimbic pathway receives input from neurons in the lateral ventral tegmental area (VTA) and projects to the nucleus accumbens, olfactory tubercle, septum, amygdala, and hippocampus (9). Eventually, the mesocortical pathway also descends from the VTA but includes ascending projections that follow a more medial route. Research has revealed that bilateral microinfusions of N-methyl-D-aspartate (NMDA), a highly specific neurotoxic agent, into the substantia nigra (SN) led to gastric erosions 24 h after surgery. Furthermore, a decrease in dopamine levels within the caudate 24 h after the NMDA infusion into the SN was observed (15). Additionally, Strang found that the incidence of duodenal ulcers is higher in Parkinson’s disease patients than in the general population. This phenomenon is primarily attributed to decreased dopamine and/or hypofunction in the substantial nigra-striatum of the central nervous system (17). Therefore, we hypothesize that hypoperfusion of the caudate nucleus following aSAH contributes to the hypofunctioning dopaminergic system, which plays a crucial role in the pathogenesis of SRGB. Our study demonstrated no effect of the left caudate HU value on SRGB in the multivariate Cox regression analysis. However, this phenomenon may be due to the different functions of the left and right insula. The issue requires further study.

In a previous study involving 627 patients with aSAH, the overall incidence of gastrointestinal bleeding was reported to be 4.9% (18). However, in our study, the incidence rate of SRGB was notably higher, at 17.9%. This trend aligns with findings regarding the incidence of SRGB after intracranial hemorrhage, which has widely varying incidence rates, ranging from low (0.3%) to high (32.3%). The discrepancies may be attributed to the varied ways in which SRGB is defined and documented across studies. For instance, in a previous study, the authors defined SRGB as the occurrence of any of the following events within 24 h of reported gastrointestinal bleeding (1): blood transfusion requirement (2); hemoglobin reduction of 2 gm/dl or greater; or (3) an abrupt systolic blood pressure reduction of ≥20 mmHg (18). Furthermore, regional disparities, differences in medical resources and care, and varying physician perspectives may further contribute to these differences.

aSAH often necessitates complex, multimodal treatment delivered by a diverse range of medical professionals. Currently, endovascular intervention (EVI) has emerged as the primary treatment modality. However, EVI carries a risk of thromboembolic events, which are estimated to occur in 2.4–5.2% of cases. Consequently, antiplatelet medications are frequently administered during endovascular treatment to prevent thromboembolism (19). Unfortunately, this preventative mechanism comes at the cost of a heightened risk of SRGB. Prostaglandins are essential for protecting the gastric mucosa. They increase mucosal blood flow, promote the proliferation of gastric epithelial cells, and stimulate mucus and bicarbonate secretion. Therefore, inhibition of prostaglandin synthesis by antiplatelet drugs makes gastric mucosa prone to ulceration and bleeding in a highly acidic environment. Furthermore, the acidic environment in the stomach causes aspirin to remain non-ionized, allowing it to accumulate in the gastric mucosal cells. It can alter the cells’ permeability and lead to ulceration (20). The use of anticoagulant or antiplatelet drugs has been listed as a risk factor for SRGB. Thus, it seems reasonable to assume that patients treated with endovascular coiling have an increased risk of SRGB.

Our study is the first study to demonstrate the clinical value of using the right caudate HU value in the ASPECT score to predict SRGB in patients with aSAH. It is easily obtained by the Rapid system in clinical practice. Therefore, our research findings can be used for patient care and preoperative assessment by neurosurgeons, intensive care unit (ICU) physicians, and other medical personnel. With early detection, doctors can take early preventive medication. In addition, the correlation between the right caudate HU value and SRGB provides further clinical evidence of the interplay between dopaminergic pathways and the gastrointestinal tract.

In this large observational cohort, the right caudate HU value is a predictor for SRGB of aSAH patients. Our findings provide further evidence for the relationship between the gastrointestinal system and the brain.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.

This study received ethical approval from the Institutional Review Board of Beijing Tiantan Hospital (KY 2021–008-01). The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements.

XC and YuanZ: conception, design, and reviewed submitted version of manuscript. KY, KW, RunL, FL, YC, HH, and RuiL: acquisition of data. KW and KY: drafting the article. KY, FL, YC, and QH: statistical analysis. YJ, YunZ, and TL: administrative, technical, and material support. XC, and YuanZ: study supervision. All authors, analysis, interpretation of data, contributed to the article, and approved the submitted version.

This study was supported by the National Key Research and Development Program of China (Grant Nos. 2021YFC2501101 and 2020YFC2004701), the National Natural Science Foundation of China (Grant Nos. 82071296, 81671129, and 81471210), the Beijing Municipal Administration of Hospitals Incubating Program, Beijing, China (Grant No. pX2020023), and the Natural Science Foundation of Beijing, China (Grant No. 7204253).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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