Numerous studies on depression have confirmed that noradrenergic and serotonergic neurons involved in emotional regulation in the brain are located in the brainstem. Its axons pass through the hypothalamus, basal ganglia, corpus callosum, and radial crown, and finally reach the frontal cortex. 5-HT and NE are both monoamine neurotransmitters, mainly involved in depression, anxiety, self-injury suicidal behavior, and sleep disorders. When stroke destroys the above related structures, it can cause a decrease in NE and 5-HT levels, and patients are more prone to depression (4). Some scholars have found that the concentration of serotonin metabolites in cerebrospinal fluid of patients with PSD is reduced (8). Combined with clinical application of antidepressants such as selective serotonin reuptake inhibitors (SSRIs), it is effective in the treatment of PSD. It was further confirmed that the occurrence of PSD is associated with a decrease in monoamine neurotransmitters (9).

Studies have found that the occurrence of PSD is related to neurotransmitters such as glutamate (Glu) and gamma-aminobutyric acid (GABA). Hypoxia-induced hypoxia causes a decrease in ATP and changes in membrane permeability leading to K+ efflux and Ca2+ influx, leading to an increase in excitatory amino acids such as glutamate, while re-uptake is blocked, excitatory amino acids accumulate outside the cell, leading to post-synaptic Excessive excitation, degeneration, and necrosis of neurons. Increased Glu leads to post-synaptic neurons, excessive excitability, ulceration, and necrosis. Patients with PSD are often accompanied by changes in the level of glutamate in the frontal lobe. PSD patients have a significantly elevated glutamate/creatinine ratio in the frontal lobes and anterior cingulate gyrus. This change is associated with the Hamilton Depression Scale (HDRS) is associated with patients with high scores (10). Wang et al. used MRI spectroscopy studies to show that patients with PSD have higher glutamate levels than stroke patients without PSD (11). The mechanism of PSD is related to the imbalance of GABA expression, and a decrease in GABA can lead to a low level of NE (12).

Inflammation refers to the defense response of living tissue to the stimulation of biological, physical, chemical, and other damage factors. Various inflammatory factors refer to cytokines involved in the inflammatory response, and are hydrophilic specific polypeptides or small molecular proteins secreted by activated immune cells. When inflammation occurs in the body, inflammatory factors inactivate the phosphorylation of the inhibitor of nuclear factor kappa B (IκB) resulting in a decrease in the inhibition of nuclear factor kappa B (NF-κB) by IκB, which causes NF-κB to enter the nucleus and bind to specific NF-κB. Inducing the transcription of related genes and promoting the expression of genes, causing an increase in anxiety and other depressive behaviors. IL-1, IL-2, IL-6, and TNF-α are mainly produced by mononuclear macrophages, which are involved in the inflammatory response and promote the immune response. Both IL-10 and IL-13 are important inhibitory cytokines, mainly produced by Th2 cells, which inhibit the production of pro-inflammatory cytokines, suppress immune responses, and protect nerves. Inflammation plays a protective role in maintaining the homeostasis of the body. However, if it is overreacted, it can damage normal tissues and organs. Studies have found that inflammation under certain conditions can damage the internal balance of the body, causing metabolic disorders, leading to abnormal secretion of neurotransmitters, resulting in depression (13). Spalletta et al. believe that the occurrence of PSD may be related to immune activation, leading to increased secretion of cytokines, and proposed a “cytokine hypothesis.” After stroke, astrocytes and microglia in the central nervous system produce cytokines and their receptors, including IL-1, IL-6, TNF-α, and IFN-γ. The phenomenon of immune activation and increased cytokines (14).

Studies have suggested that inflammatory factors may cause depression through neurodegeneration, decreased regeneration, decreased ω-3 fatty acids, decreased levels of tryptophan, and elevated levels of metabolites. Inflammatory factors interact with each other to form a network system that regulates immune responses (15, 16). Inflammatory factors can increase the activity of indoleamine-2,3-dioxygenase (IDO), increase the metabolism of tryptophan, and increase the concentration of quinolinic acid and kynurenine. The level of serotonin precursors synthesized by tryptophan is reduced, causing a decrease in serotonin concentration and accelerating depressive symptoms in patients (17, 18).

Yang et al. studies found that IL-18, IL-1, IL-6 play an important role in the occurrence, development and prognosis of PSD (19). Kim et al. performed polymorphisms of pro-inflammatory cytokine genes such as IL-1β, IL-6, IL-8, TNF-α, and polymorphisms of anti-inflammatory cytokines such as IL-4 and IL-10 in patients with PSD. The results showed that the IL-10-1082A/A genotype was closely related to PSD, and the IL-4 + 33C/C genotype was only associated with heavy PSD (20). After a year of follow-up of PSD patients, Su et al. found that IL-10 levels in the depression group were significantly lower than those in the non-depressed group, and IL-10 levels were negatively correlated with depression. IL-10 may have antidepressant effects (21). Spalletta et al. believe that stroke promotes the release of inflammatory factors such as C-reactive protein (CRP), interleukin-1(IL-1), tumor necrosis factor-α (TNF-α), IL-6. These factors stimulate and produce a toxic effect on the monoamine neurotransmitter system. As a result, its function declines, causing depression to occur (22). Increased expression of TNF-α, IL-1β, and cortisol releasing factor was found in the hippocampus of PSD rats, and interaction between cortisol releasing factor and TNF-α signaling pathway was found in PSD (23). Studies by Reichenberg et al. have shown that induction of TNF-α production by experimental stimulation can induce depression and cognitive function changes in humans (24).

Studies have shown that inflammation can affect the function of the hypothalamic-pituitary-adrenal axis (HPA), promote the metabolism of monoamine transmitters, and induce depression (14). Pro-inflammatory factors activate HPA and promote excessive secretion of cortisol, and excess cortisol damages nerve cells through cytotoxicity. Abnormal activity of the HPA and hypothalamus-pituitary-thyroid axis (PHT), leading to elevated plasma cortisol. Elevated plasma cortisol induces the production of tryptophan pyrrolase and aminotransferase in the liver, which both degrade blood tryptophan (5-HT precursor) and tyrosine (NE precursor), resulting in 5-HT and NE synthesis are reduced, promoting, or aggravating the occurrence and development of PSD (25–27). Persistent and excessive secretion of cortisol can inhibit hippocampal neuronal regeneration and reduce neural plasticity in the pre-frontal cortex, leading to PSD.

Vitamin D is a neurosteroid hormone, 25-hydroxyvitamin D is its main form in the blood circulation (42). Vitamin D is derived from food, especially from fish oil, which is synthesized on the skin and is affected by light. Vitamin D receptor (VDR) is located in an important area of the brain associated with depression and emotional behavior, such as cingulate gyrus, hippocampus, thalamus, hypothalamus, and substantia nigra (43). VDR is also present in immune cells and has an immunomodulatory effect (44). Vitamin D can regulate neurotransmitters such as serotonin in the brain through tryptophan-hydroxylase 2, vitamin D deficiency may lead to central morphological changes and decreased synthesis of neurotransmitters such as norepinephrine and dopamine (45). Studies by Puchacz et al. showed that vitamin D is involved in the regulation of the expression of the tyrosine hydroxylase gene, which catalyzes the production of levodopa by tyrosine in dopamine biosynthesis (46). Studies have found that vitamin D levels are negatively correlated with inflammatory markers, and the relationship between depression and inflammatory response can be regulated by the immune system (47). In the central nervous system, vitamin D acts as a neuroprotective factor through its antioxidant activity to increase the efficiency of neuronal projection and regulate the synthesis of neurotransmitters. A meta-analysis found that low vitamin D levels are associated with depression levels and are the biological basis for depression susceptibility (48). Studies have shown that supplemental reduced vitamin D levels contribute to the improvement of depressive symptoms in patients with depression, but different studies have also been reported (49). Han et al. also believe that vitamin D levels are positively correlated with PSD within 24 h after stroke onset (50). A prospective randomized controlled clinical trial by Shaffer et al. found that vitamin D supplementation helps prevent PSD. High serum vitamin D levels protect patients from PSD, and recent randomized controlled trials have shown that vitamin D supplementation can improve depressive symptoms in patients (51, 52).

Some studies have concluded that high homocysteine levels are significantly associated with PSD. Stroke patients with high levels of homocysteine are relatively more prone to PSD (53). High homocysteine (Hhcy) has a direct toxic effect on blood vessels, causing further damage to the cerebral blood vessels, leading to the occurrence of depression (54). Hhcy affects the production and metabolism of monoamine neurotransmitters such as DA, 5-HT, NE, etc. These neurotransmitters play an important role in the pathogenesis of depression (55). Liu et al. studied 18 patients with ischemic stroke and selected three core regions of DMN (left parietal cortex, pre-frontal cortex, posterior cingulate ganglion/wedge anterior cortex). Then, the difference between the patient and the normal person ReHo was compared, and the ReHo of the posterior cingulate cortex of all stroke patients was found to be reduced. The functional connectivity (FC) analysis was performed using the posterior cingulate cortex for the region of interest, and the FC values of posterior cingulate cortex and anterior cingulate were found to be reduced (56).

Resting-state functional magnetic resonance imaging (rs-fMRI) indirectly reflects the functions of brain local and neural networks through signal changes, which have the advantages of non-invasiveness and reproducibility. Since the early 1990s, it has had an important impact on the development of neuroscience and psychology. In recent years, it has also begun to be used in the research of diseases such as PSD, and has gradually become one of the important means for studying the physiological and pathological activities of brain function. At present, the commonly used analytical methods for rs-fMRI are as follows: Regional homogeneity (ReHo), Amplitude of low-frequency fluctuation (ALFF), Functional connectivity (FC) (57). The most widely studied is the default mood network (DMN), which mainly involves the medial pre-frontal cortex, posterior cingulate gyrus/pre-wedge lobes, bilateral apical lobes (including angular gyrus), bilateral lateral temporal lobe, hippocampus, etc. Studies have shown that the default network is closely related to the monitoring of internal and external environments, the processing of emotions, introspection, the maintenance of thinking cognition, and the extraction of thought memories. A large number of studies have shown that there is an abnormality in the brain network under the resting state of depression, and DMN is an important neuropathological mechanism of depression (58, 59). Zhang et al. performed FC analysis on patients with cerebral infarction, and found that compared with non-PSD and normal people, PSD patients had changes in the right frontal gyrus and the left gyrus and the anterior cingulate gyrus. In addition, the FC values of the left temporal and anterior cingulate gyrus were significantly associated with the severity of depression (60). Liu et al. (56) studied 18 patients with ischemic stroke, and selected 3 core regions of DMN (left parietal cortex, pre-frontal cortex, posterior cingulate gyrus/anterior cranial cortex), and then compared patients and normal Human differences. The ReHo of the posterior cingulate cortex was found to decrease in all stroke patients, and the posterior cingulate gyrus was used as a functional area for FC analysis, and the FC value of the posterior cingulate gyrus and the anterior cingulate gyrus was found to be reduced (56). Zhang et al. studied 26 patients with PSD, and the results showed that the default emotional network, cognitive control network, and emotional network FC of PSD patients changed. The left lower parietal lobe, the left eyelid portion of the inferior temporal gyrus and the left anterior gyrus were significantly associated with the Hamilton Depression Rating Scale for PSD patients. Changes in the three neural networks may be associated with the development of PSD in the subacute phase of stroke (61).

At present, there are many studies on the relationship between PSD and stroke sites, but the conclusions are not the same. Current brain imaging studies of depression have shown that subcortical white matter damage leads to a susceptibility to depression by destroying certain neural circuits associated with emotions. Depression brain function changes mainly in the pre-frontal cortex, anterior cingulate gyrus, amygdala, ventral striatum, hippocampus, insula, thalamus, and basal ganglia. The pre-frontal cortex is thought to play a key role in cognitive and emotional activities, and functional abnormalities in these brain regions may present with affective and cognitive impairments. Current studies have shown that left hemisphere stroke is more prone to depression than right hemisphere stroke. The lesions near the frontal pole have a specific correlation with the degree of PSD. The lesions associated with PSD were: frontal lobe, left basal ganglia, and temporal lobe, and the incidence of lesions near the extreme was high (62). Carson et al. found that the occurrence of PSD was not related to stroke lesions after evaluation of related studies (63). PSD has nothing to do with the stroke site. The reasons for the difference between the two may be different sample sizes, differences in diagnostic criteria, ethnic differences, geographical differences, and so on (64). Vataja et al. found that the lesions of acute stroke were located in the left hemisphere, especially in the left anterior hemisphere, and their chance of developing depression was higher than in the right hemisphere. It is believed that the damage of the globus pallidus and the volume of injury are related to the diagnosis of depression within 3 months after stroke (65). Angeleri et al. observed the observation of the 3 years after the stroke, 3 years or more after stroke, the incidence of depression is not related to the lesion in the left or right hemisphere (66). Shimoda et al. observed the relationship between lesions and PSD at different time points after stroke. In the acute phase of stroke, PSD was associated with left anterior hemisphere lesions; at 3–6 months, PSD was related to the distance from the lesion to the frontal pole and lesion volume; and 1–2 years later, PSD was related to the distance from the right hemisphere lesion to the occipital pole and lesion volume (67).

Cognitive dysfunction is one of the common complications in stroke patients. Most studies have concluded that depression has a significant relationship with cognitive dysfunction. However, the specific relationship between the two is still controversial. Many studies have identified the most relevant factors for PSD and cognitive impairment: low education, speech impairment, stroke severity, and previous diabetes history (68). Murata et al. found that cognitive function improved with the improvement of PSD symptoms (69).

Regarding the gene hypothesis, there is clear evidence that the shortening of the promoter region associated with the serotonin gene is associated with severe PSD. Studies have shown that individuals and families with a history of depression may be one of the risk factors for major depression after stroke (70, 71). The expression of some genes is considered to be a risk factor for PSD. Brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of PSD. It has been suggested that the single nucleotide polymorphisms rs1778929 and rs1187323 in the tyrosine receptor kinase B (TrkB) gene of BDNF are significantly associated with PSD (72). Kim et al. evaluated 222 stroke patients and followed up for 1 year. The increase in methylation status of 5-HTTLPR (The serotonin transporter-linked polymorphic region, 5-HTTLPR) SS genotype was associated with PSD. Higher levels of BDNF gene methylation were associated with PSD occurring at follow-up (73). The serotonin transporter gene (SLC6A4) has also been shown to play an important role in the pathophysiology of PSD. Studies have found that 2 weeks after stroke, higher SLC6A4 promoter methylation status is independently associated with PSD and is more pronounced 1 year after stroke, and is significantly associated with worsening depressive symptoms within 1 year (74). Studies have shown that apolipoprotein E (APOE) polymorphism is associated with PSD, APOE rs429358 polymorphism increases the probability of PSD, APOE rs429358-C allele may be post-stroke nerve Functional recovery is harmful (75).