In accordance with the temporal evolution of relevant literature in this field, we observed a consistent upward trajectory in the overall quantity of publications. Notably, over the past decade, the number of publications has significantly surpassed historical figures, with four years registering a count equal to or exceeding 10, all occurring post-2016. Given our literature inclusion cutoff date of November 21, 2023, we acknowledge that our analysis may not fully capture the publication landscape for the current year. Nevertheless, based on the observed trends (Fig. 2), we have reasonable grounds to anticipate sustained high activity in the field throughout 2023.

In the journal analysis aspect, CEPHALALGIA ranks first in NP, g-index, h-index, and total link strength, and it also holds impressive rankings in other indicators. Therefore, we believe CEPHALALGIA has exerted the greatest influence. JOURNAL OF HEADACHE AND PAIN consistently holds a leading position in multiple analyzed metrics, underscoring its undeniable influence in the field. The highest NC and Average Citations associated with JOURNAL OF NEUROSCIENCE indicate the superior quality of its published works, widely recognized within the scholarly community. Considering the total link strength, JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM appears to warrant strengthened collaborative relationships. The annual publication trends further highlight the commendable growth and dominant position of CEPHALALGIA in the field in recent years. The evolving dynamics of journal publications over time suggest that JOURNAL OF HEADACHE AND PAIN and Neurobiology of Disease may be worth noting in this field recently (Fig. 3 and Table 1). Figure 4 unveils primary citation pathways, providing valuable insights for novice researchers embarking on studies in this field.

In the realm of author analysis, considering all encompassed metrics, we assert that PIETROBON D and DALKARA T wield significant influence in this field. Notably, EREN-KOCAK E, with a relatively lower NP count (N = 4), attains the third-highest NC (N = 405) and the highest Average Citations (N = 101.25), indicative of widespread recognition for the quality of their publications. The total link strength indicates that all eight scholars maintain close collaborative relationships with fellow specialists in the domain. The yearly variation in authors’ publication output reveal that PIETROBON D and CONTI F have exerted sustained influence in the domain. Furthermore, the evolving dynamics of journal publications over time suggest that CONTI F, among others, may be emerging as noteworthy and promising contributors in the field (Fig. 5 and Table 2).

The analysis of regions and countries reveals the most intricate and expansive collaboration network between Europe and North America, centered around the United States. The United States exhibits overwhelming dominance, boasting the highest number of links, total link strength, NP, and NC, thereby establishing extensive connections across regions. Italy, with its second-ranking NP and NC, coupled with rankings in other pertinent metrics, is deemed to exert substantial influence in this field. TURKEY holds the third position in NC and boasts the highest Average Citations, indicating that its published works are of high quality and widely recognized. While CHINA holds the third position in NP, considering its NC, Average Citations, and Total Link Strength, we suggest there is room for improvement in the quality of its publications, and fostering collaborative relationships could be beneficial. The evolving trends in country/region publication dynamics over time reveal recent vibrancy in the contributions of countries/regions such as CHINA in this field (Fig. 6 and Table 3).

Considering the outstanding performance of UNIV PADUA and CNR across various rankings, we unequivocally identify them as institutions wielding significant influence in this field. Among these, HACETTEPE UNIV boasts the highest NC and secures the second position in terms of Average Citations. UNIV CALIF LOS ANGELES achieves the highest Average Citations with a relatively lower NP. Hence, we posit that publications affiliated with HACETTEPE UNIV and UNIV CALIF LOS ANGELES demonstrate a higher quality. Notably, CHONGQING MED UNIV appears to benefit from strengthening collaborative efforts with other institutions. The annual variation in institutional publication output suggests that institutions such as UNIV POLITECN MARCHE, JICHI MED UNIV, and IRCCS may be noteworthy in this field recently (Fig. 7 and Table 3).

Analyzing and interpreting pivotal publications, along with the results of keyword and reference analysis in this field, allows for a more in-depth understanding of its historical development trajectory. This process proves beneficial in gaining insights into both the past and present aspects of the field. We employed historiographic analysis using the R package ‘bibliometrix’ to identify and visually analyze 10 milestone publications within this field. Subsequently, we annotated the primary content and key information of these publications based on the original images, ultimately presented in Fig. 10. Combining the primary information from the 10 identified publications, we observed that all studies primarily focused on CSD, Na + /K + -ATPase, or FHM2. The majority of these investigations involved animal experiments, predominantly conducted in mouse models. A study revealed an increased susceptibility to CSD in FHM2 caused by a mutation in the α2 subunit of Na + /K + -ATPase. This research highlights the interrelation among these factors, laying a robust foundation for subsequent related studies [9]. Researchers predominantly focused on calcium waves associated [29], Casein kinase Iδ [30], PANX1 channels [31], dynamics of ionic shifts [32], the glutamate system [33, 34], K + clearance [34, 35], and migraine-related epileptiform activity [36]. One publication delineates the association between different subtypes of Na + /K + -ATPase and a spectrum of behavioral alterations [37]. In addition to the milestone publications mentioned above, research in this domain has also delved into numerous other facets. Several publications provide comprehensive summaries of the glial–neuronal interaction in migraine [20, 38] and the role of dysfunctional astrocytes [39]. Researchers have focused on different phases of migraine, including the aura phase [40] and the interictal phase [41]. The investigated subjects encompass mitochondrial function [42], insulin-like growth factor-1 [43], the CGRP system [44, 45], brain glycogen [46], 5-hydroxytryptamine receptor subtypes [47], and Na + /HCO3-cotransporter [48]. The cells, tissues, and sites under investigation include meningeal cells [49], neocortex [50], occipital regions [41], trigeminal ganglia, and brain vessels [45]. In addition, topics such as sleep [46], inflammation [51], and female-related factors [41] have garnered attention from researchers.

Principal contents of the top 10 milestone publications

The most common keywords highlight the primary focus of researchers in this field, emphasizing the pathophysiological mechanisms of different types of migraines. Researchers place a significant emphasis on animal studies, evaluating the impact on the blood–brain barrier and hemodynamics in the central nervous system. Their attention spans across various genes and proteins, the status of multiple cell types, and signal transduction. In addition, there is a notable interest in CSD. In the period around 1999–2010, researchers prominently focused on migraines with aura and FHM, underscoring the pivotal role of CSD and placing emphasis on observing hemodynamic changes. Investigations delved into the cellular and molecular aspects within the brain and cortex, exploring relevant mechanisms. Simultaneously, glutamate and CGRP gained increasing attention as crucial factors in the migraine process. In the period around 2010–2015, researchers developed a keen interest in ATP and brain energy metabolism. The application of genome-wide association techniques saw a gradual increase over time. Through predominantly in vivo experiments using mice, investigations were conducted into astrocyte elevated gene 1 and activity-modifying protein 1. Simultaneously, researchers focused on symptoms such as headache and pain. From approximately 2015 to 2020, new focal points emerged, including alpha2 isoforms, glutamate transporters, and calcium channels. Mechanistic explorations regarding depolarization, neuronal activity, and depression saw an increasing trend. The crucial role of animal models in pathophysiological research was further acknowledged during this period. As of 2023, research pertaining to satellite glial cells has captured the attention of scholars. In addition, researchers have turned their focus towards studying the prefrontal cortex, trigeminovascular system, and other organizational structures. Emerging research priorities include neuropathic pain, stimulation, and NMDA receptor-related investigations. The clustering of keywords underscores the diverse directions of research, encompassing migraine symptoms, mechanisms, organizational structures, influencing factors, and various types of migraines. The primary symptoms of migraine, particularly pain, have consistently been the focus of extensive research. FHM and migraine with aura stand out as two prominent subtypes garnering substantial attention from researchers. Notably, CSD plays a pivotal role in these migraine types, attracting significant interest. Researchers have also delved into the impacts of the blood–brain barrier (BBB) and the effects of medications. In addition, investigations into brain metabolism and blood flow have been pivotal areas of study (Fig. 8 and Table 4).

The prevalence of citations highlights researchers’ focus on investigating the pathophysiological mechanisms of migraine [52,53,54]. CSD remains a focal point of scholarly attention in this field [31, 55]. “Three studies, employing murine models, focused on Glutamate system defects, K + clearance, and CSD in association with astrocytes in FHM [9, 33, 34]. One publication predominantly investigated the inflammatory response of the Microglial NLRP3 inflammasome in central sensitization of chronic migraine [56]. In addition to the nine most frequently cited references encompassing prominent research areas, our comprehensive review of other references reveals that researchers in this field have also placed significant emphasis on topics such as aura, neuroimaging, the trigeminal vascular system, Genome-Wide Association Studies, CGRP, and satellite glial cells [10, 57,58,59]. Cluster analysis of the references underscores diverse research domains, with researchers concentrating on specific pathophysiological mechanisms, notably vasoregulation, brain recovery, and brain energy metabolism. The critical role of K + clearance in the sustained functioning of the nervous system has also garnered considerable attention among researchers. Researchers have directed their attention towards the application of genetic technologies, particularly Genome-Wide Association Studies, and various cell types, with a focus on Microglia. In addition, analgesia has consistently served as a pivotal metric for assessing the efficacy of migraine treatment (Fig. 9 and Table 5).

The results of keyword and reference clustering analysis highlight the primary areas of interest for researchers. Combining these findings with our understanding of the field, we succinctly summarize several major research hotspots, including CSD, Aura and Brain Blood Flow, FHM, BBB and Medication, Brain Metabolism, and the Brain’s Glymphatic System (BGS).

CSD is a distinctive abnormal phenomenon. It initiates with widespread depolarization of cortical neurons and glial cells, followed by a gradual reduction in activity. It propagates at a speed of approximately 3–4 mm/min, potentially reaching the parietal and/or temporal lobes [60, 61]. The widespread depolarization signifies a pronounced alteration in the concentration of various ions both inside and outside the cells. These changes result in cell swelling, significantly impacting the composition of the extracellular space. Notably, K + and glutamate receptors, particularly N-methyl-D-aspartate receptors, play crucial roles in the initiation of CSD [62, 63]. During the CSD process, various substances, including ions, vasoactive substances, inflammatory mediators, and neurotransmitters, are intricately linked to vasodilation, plasma protein extravasation, mast cell degranulation, and other cellular processes. These interactions may potentially trigger migraines through pathways such as activating the trigeminovascular system and inducing neuroinflammation [64]. Current research evidence indicates that CSD might serve as a trigger for auras [60]. Furthermore, CSD has been shown to induce changes in blood vessel diameter [65]. Consistent with the higher prevalence of migraines in females compared to males, female mice exhibit a higher susceptibility to CSD than their male counterparts [66]. Beyond its association with migraines, CSD has also been implicated in other conditions, such as stroke and head trauma [67].

Currently, the role of astrocytes in CSD remains contentious, but some evidence suggests a connection between the two. Ca2 + waves in astrocytes occur almost simultaneously with depolarization of neurons during CSD [50]. Certain studies propose that astrocytes might be involved in the initiation of CSD [9, 68]. In addition, astrocyte networks likely play a crucial role in the regulation of K + and glutamate during CSD and the propagation of CSD [67, 69].

Approximately one-fourth to one-third of migraine sufferers experience an aura before, during, or even after a migraine attack [64]. An aura is a transient and reversible focal neurological symptoms, involving aspects such as vision, sensation, speech, movement, and brainstem functions. Typically, auras develop gradually over 5–20 min and gradually resolve within 60 min [2]. The current mechanisms of aura remain elusive, with the prevailing view suggesting a crucial role for CSD in its occurrence. In alignment with the abundance of vascular-related keywords present in keyword cluster #3, the initial association of CSD is with hyperemia. This hyperemia, appearing approximately 15 s after CSD onset, can persist for up to 3 min. Subsequently, hyperemia gives way to oligemia. The duration of this oligemia can extend up to 1 h or even longer [70]. Such oligemia may impact neurons and glial cells in various brain regions by inducing local tissue ischemia and hypoxia, consequently triggering the onset of an aura. Conversely, ischemia or hypoxia can also serve as triggering conditions for CSD [71]. “In addition, the drastic changes in intracellular and extracellular ion concentrations and the release of substances induced by CSD may also contribute to the aura of migraines. Presently, multiple imaging studies provide evidence that CSD and the associated hemodynamic changes are correlated with auras [64]. The controversy persists regarding whether auras trigger migraine attacks, with a hypothesis suggesting that pain and auras may represent two parallel phenomena [72]. Moreover, various substances produced during CSD, including vasoactive agents, can induce changes in cerebral blood flow through their impact on brain vasculature during the CSD process [64].

FHM is an exceptionally rare form of monogenic migraines, characterized by autosomal dominant transmission caused by pathogenic mutations in a single gene. FHM is notably distinguished from migraines with aura by the obligatory inclusion of motor symptoms during its aura manifestation, with the aura can even extend for several dozen hours. In addition, a crucial criterion for FHM diagnosis is that the patient must have at least one first-degree or second-degree relative diagnosed with FHM; otherwise, it is classified as sporadic Hemiplegic Migraine [2]. Mutations in ion transport genes CACNA1A, ATP1A2, and SCN1A respectively impact the encoding of Cav2.1 channels, α2 Na + /K + -ATPase, and Cav1.1 channels, leading to three distinct forms of FHM: FHM1, FHM2, and FHM3[73]. Based on our analysis, it is evident that the focal point of research in this field revolves around ATP1A2-related FHM2. In adult astrocytes, Na + /K + -ATPase expressed on the cell surface maintains K + balance in the synaptic cleft through K + clearance. This mechanism restricts neuronal excitability and sustains the transmembrane Na + concentration gradient, facilitating the reuptake of glutamate. In the context of FHM2, mutations lead to dysfunctional α2 Na + /K + -ATPase, potentially impairing the reuptake of K + and glutamate by astrocytes. Consequently, this dysfunction may contribute to a delayed recovery of neuronal excitability [73].

The BBB primarily consists of brain microvascular endothelial cells, the basement membrane surrounding endothelial cells, pericytes, and the foot processes of astrocytes. By restricting the passage of certain molecules, the BBB serves as a barrier between the systemic circulation and the central nervous system, the BBB plays a crucial role in protecting the brain and maintaining its homeostasis [74]. Astrocytes play a crucial role in both the homeostasis and homeostatic imbalance of the BBB. Astrocytes contribute to the maintenance of BBB stability through various substances, such as Sonic hedgehog [75] and Sphingosine 1 [76]. In addition, their influence on smooth muscle function impacts the regulation of cerebral microvascular blood flow associated with the BBB [77]. In various pathological conditions, astrocytes can undergo transformation into reactive astrocytes. These reactive astrocytes also play a crucial role in the BBB, such as contributing to its repair following neurological diseases [78, 79]. Due to the existence of the BBB, drug components that need to exert their effects in the brain must traverse this barrier. The primary mechanisms include diffusion, carrier-mediated transport, endocytosis, among others. However, the BBB is influenced by various factors such as inflammation, neuropeptides, and glutamate, leading to alterations in its permeability and other aspects [80]. which has been an unavoidable focus in migraine drug research.

According to the content of Cluster #4 “Brain Metabolism” in the keywords analysis, researchers in this field focus on various subjects, including SLC4A4, nitric oxide, pyruvate carboxylase, coenzyme Q10, among others. However, human metabolism is comprised of thousands of biochemical reactions. Confronted with the vast and intricate network composed of metabolic byproducts, associated proteins, and the genome resulting from various metabolic processes, elucidating the mechanisms within this complex system is undoubtedly a formidable task. Omic technologies, as a method for discerning key targets and analyzing vast datasets, offer a valuable tool to alleviate the challenges faced by researchers [81]. Human Genome-Scale Metabolic Models, constructed based on existing literature, represent a widely utilized computational framework in metabolic research. These models primarily focus on metabolic processes and encompass virtually all substances involved in metabolic reactions, contributing significantly to advancements in the field [82]. Genome-Scale Human Brain Modeling is a computational model primarily focused on the dynamics of the human brain, playing a significant role in the field [83]. The application of these advanced methods will aid researchers in elucidating the intricate relationships within metabolic networks and contribute to the generation of novel insights.

The BGS, distinct from the classical lymphatic circulation system, has garnered increasing attention recently [84]. It is, in fact, a complex network of perivascular spaces containing a significant volume of cerebrospinal fluid and interstitial fluid, surrounding brain vessels and communicating with the subarachnoid space. This network functions as the brain’s lymphatic circulation, maintaining homeostasis by clearing metabolic waste and various solutes from the brain [85]. The water transporter Aquaporin 4, located on the foot-like protrusions of astrocyte cells, plays a crucial role in the process of cerebrospinal fluid and interstitial fluid entering cervical lymphatics [86]. Neuroinflammation, CSD, and excessive CGRP are three mechanisms that have garnered widespread attention in the pathogenesis of migraine and aura. The BGS may exert influence on the aforementioned three mechanisms by regulating pro-inflammatory substances, CGRP, and relevant ion concentrations, thus significantly contributing to the processes of migraine and aura [87]. However, the significant role of the BGS in migraine research has not received adequate attention. We posit that in the future, the BGS may emerge as a focal point of investigation in this field.

Based on our analysis of relevant literature in the fiel