The paraventricular thalamus (PVT) is a key midline node of the dorsal thalamus involved in many behaviors, such as fear (Zhao et al., 2025), reward and motivation (Zorab et al., 2025; Minère et al., 2025), drug addiction (Zhu et al., 2023), feeding (Ye et al., 2023), homeostatic behavior (Ye et al., 2023; Penzo and Gao, 2021), and sleep-wakefulness (Ren et al., 2018). Clinical evidence has shown that injuries in the paramedian region of the thalamus (the homologous area of the rodent PVT) disrupt consciousness ranging from drowsiness to coma in patients (Hermann et al., 2008; Schmahmann, 2003; Luigetti et al., 2011). In rodents, inhibiting PVT activity suppressed consciousness, whereas increasing PVT activity facilitated wakefulness (Ren et al., 2018). These observations indicate that the PVT is a critical brain nucleus involved in controlling sleep-wakefulness. Interestingly, natural sleep and general anesthesia share the common characteristic of reversible unconsciousness, and many studies indicate that they are modulated via common neural mechanisms (Bao et al., 2023; Jiang-Xie et al., 2019; Yang et al., 2022). Recently, an increasing number of studies have investigated the role of PVT in general anesthesia. Their findings suggest that PVT is closely related to consciousness under volatile isoflurane (Bu et al., 2022; Ao et al., 2021), sevoflurane (Li et al., 2022; Wu et al., 2024), desflurane (Zhao et al., 2021), and intravenous propofol (Wang et al., 2023). Although the current evidence reaches the consensus that increased PVT activity accelerates emergence from general anesthesia, there is disagreement regarding the anesthesia induction process. Additionally, the involved neuronal populations and circuits also diverge. In 2024, Gao et al. (2024) reviewed recent advances in the neural mechanism of general anesthesia-induced unconsciousness. While this paper included descriptions of the PVT’s role in general anesthesia, it provided only a partial summary of optogenetic and chemogenetic findings and omitted several key studies (Ao et al., 2021; Wu et al., 2024; Zhao et al., 2021; Zhao et al., 2024) concerning the PVT’s involvement in general anesthesia. Therefore, it remains meaningful to conduct a focused review on the PVT’s specific role in general anesthesia. Here, we systematically searched databases (PubMed, Web of Science, Embase, the Cochrane Library, and Google Scholar) from inception to 15 August 2025, using the keywords “PVT,” “paraventricular thalamus,” “general anesthetics,” and “general anesthesia.” The objective was to specially summarize the modulatory effects of PVT under general anesthesia, independent of the experimental techniques employed (Table 1). We also illustrated the common brain circuits involved in PVT whose contributions are not currently known to occur during the regulation of general anesthesia (Figure 1). This study complies with the TITAN Guidelines 2025 for AI reporting (Agha et al., 2025).

Current evidence demonstrates that the activity of the PVT^Glu plays a pivotal role in regulating emergence from both volatile and intravenous general anesthesia, suggesting that the PVT may serve as a common target of general anesthetics. However, the contribution of PVT to the induction process of general anesthesia remains controversial. Most studies indicate no association between PVT activity and isoflurane anesthesia induction (Bu et al., 2022; Ao et al., 2021; Zhao et al., 2021) because manipulation of PVT activity does not influence induction time. Like these findings in the PVT, several brain regions or circuits that selectively affect the emergence period from isoflurane but not the induction process have been identified; these regions include the parabrachial nucleus–lateral hypothalamus or the parabrachial nucleus–BF circuit (Lu et al., 2023), serotonergic neurons in the DRN (Yang et al., 2019; Li et al., 2021), dopaminergic neurons in the VTA (Li et al., 2019), the BF (Zhang et al., 2016), orexinergic neurons in the perifornical hypothalamus (Kelz et al., 2008), and the olfactory tubercle (Yang et al., 2021). Therefore, other regions that affect both isoflurane induction and emergence may contribute more than the PVT to isoflurane induction, such as the ventrolateral preoptic nucleus (Moore et al., 2012), supraoptic nucleus (Jiang-Xie et al., 2019), and ventral periaqueductal gray (Liu et al., 2020). Interestingly, one study revealed that GABAergic transmission in the pontine reticular formation influenced the induction of propofol or isoflurane but not emergence in rats (Vanini et al., 2014). Nevertheless, studies have revealed that the PVT is involved in both the induction and emergence of sevoflurane ^{16 17}, desflurane (Zhao et al., 2021), and propofol (Wang et al., 2023) anesthesia. These results suggest that the molecular targets within the PVT or its upstream and downstream circuits involved in the induction of anesthesia by isoflurane differ from those involved in the process of other anesthetics. These findings indicate that induction is not a simple reverse process of recovery for isoflurane, at least in terms of the mechanism related to PVT. Hysteresis/neural inertia is suggested to be the underlying reason (Friedman et al., 2010). Hysteresis/neural inertia demonstrates an intrinsic tendency of the central nervous system to resist transitions from unconscious to conscious states, which cannot be solely explained by pharmacokinetics (Joiner et al., 2013). We speculated that the PVT might be an important area contributing to hysteresis/neural inertia under isoflurane-induced general anesthesia. Notably, poor experimental methods might influence the accuracy of the data. For example, high doses of general anesthetics might induce a rapid loss of the righting reflex, which makes it difficult to detect a notable difference in the induction time. Furthermore, a lack of temperature monitoring or thermal insulation measures under general anesthesia can cause hypothermia and influence the assessment. Therefore, well-designed studies are still needed to confirm the role of PVT in isoflurane induction.

The specific molecular mechanism by which general anesthetics commonly suppress the activities of PVT^Glu remains largely unknown because existing studies on the role of PVT in volatile and intravenous anesthesia remain limited. It is suggested that the ion channels and receptors expressed in the PVT might serve as important targets of general anesthetics. Recent evidence has shown that NALCN of glutamatergic neurons and Kir4.1 channels in astrocytes are key molecular targets that mediate the effects of sevoflurane on the activity of the PVT (Wu et al., 2024). More future studies are needed to clarify the molecular mechanisms. In addition, although the LC-PVT (Ao et al., 2021), PVT-BNST (Li et al., 2022), PVT-nucleus accumbens (Wu et al., 2024), and PVT-PFC (Zhao et al., 2024) circuits have been shown to regulate the effects of volatile anesthesia, the upstream and downstream pathways through which the PVT controls consciousness levels under general anesthesia are largely unknown. However, whether the abovementioned circuits regulate the general anesthesia induced by propofol is unclear. Future studies need to determine whether the classical circuits involved in the PVT, such as the mPFC-PVT (Lucantonio et al., 2021; Yamamuro et al., 2020), PVT-central amygdala (Ma et al., 2021; Keyes et al., 2020), and zona incerta-PVT (Ye et al., 2023; Zhang and van den Pol, 2017) (Figure 1), are associated with the actions of general anesthetics. Notably, other influences might exist between various PVT circuits, such as the diverse subpopulations and subregions in the PVT and its upstream and downstream targets (Kirouac, 2025), the various ion channels or receptors expressed in neurons or glial cells of the PVT and its involved circuits (Wu et al., 2024; Zhao et al., 2024; Mulkey et al., 2022), and potential sex differences (Zhang et al., 2022; Braithwaite et al., 2023). Furthermore, the interactions between various PVT circuits and the tertiary projection loop remain largely unknown and need to be elucidated in future studies. For example, sleep-promoting projections might inhibit the activities of PVT-involved circuits and weaken their effects on consciousness levels under general anesthesia (Ren et al., 2024). Given PVT circuits’ involvement in diverse physiological functions, assessing whether PVT manipulation induces abnormal phenotypes (e.g., respiratory or cardiovascular changes) is crucial. Such phenotypic alterations could potentially influence the actions of general anesthetics.

Despite accumulating animal evidence of the involvement of the PVT in emergence from general anesthesia, data concerning the contribution of the PVT to general anesthesia in humans are limited. Notably, emerging clinical evidence highlights the therapeutic potential of another thalamic region-the subthalamic nucleus (STN). Specifically, deep brain stimulation (DBS) of the STN has been established as an effective treatment for patients with Parkinson’s disease experiencing disabling motor response fluctuations (Hol et al., 2021; Roldán et al., 2025; de Dos Reis Paula et al., 2024). Furthermore, DBS can be safely performed under general anesthesia with reduced procedure duration compared to awake states (Gadot et al., 2023). However, no clinical studies have yet investigated the effects of DBS on consciousness levels during general anesthesia. This gap presents an intriguing opportunity to explore whether DBS targeting the PVT in comatose patients could enhance consciousness under anesthesia, given that clinical studies have reported that injuries in the thalamic paramedian region (the homologous area of the rodent PVT) lead to decreased consciousness levels or coma in patients (Hermann et al., 2008; Schmahmann, 2003; Luigetti et al., 2011) (Bassetti et al., 1996; Montagna et al., 2002). These findings underscore the translational potential of PVT-related mechanisms from rodent models to clinical applications. For example, monitoring PVT activity may provide a more sensitive indicator of general anesthesia depth than bispectral index value. More importantly, direct stimulation of the human PVT might facilitate emergence from delayed general anesthesia or from coma. However, the inhibition of PVT activity might reduce the consumption of general anesthetics and opioids, which will decrease the related complications and is safer for debilitated patients. Notably, a recent study (Bian et al., 2021) showed that noninvasive ultrasound stimulation of the ventral tegmental area facilitated mouse emergence from isoflurane anesthesia, suggesting the possibility of noninvasive manipulation of the PVT in clinical patients.

Several limitations exist in our work. First, existing studies on the role of PVT in volatile and intravenous anesthesia remain limited, more future studies are needed to clarify the molecular mechanisms. Second, sex differences might be notable in the regulation of PVT in general anesthesia, evidenced by that males are more sensitive to general anesthetics than females (Zhang et al., 2022; Braithwaite et al., 2023). Brain regions are suggested to be implicated in the sex differences in response to anesthetics. For instance, the estrogen receptor alpha of the medial preoptic area contributes to the differentially sensitive to sevoflurane between male and female mice (Zhang et al., 2022). Current study had yet investigated whether sex differences exist in the regulation of PVT in general anesthesia. Finally, despite progress in elucidating the anesthetic mechanisms of PVT in animal models, its clinical translation faces multiple challenges. There are significant structural and functional differences between the human and mouse PVT, making research findings from animal models difficult to directly apply to humans. Moreover, there is a lack of precise technical methods to target specific neuronal populations in the human PVT, and techniques for real-time monitoring of PVT neuronal activity in clinic remain underdeveloped. Additionally, direct intervention in the PVT may lead to unpredictable neurological side effects. Of note, studies on consciousness regulation will undergo rigorous ethical scrutiny. These factors constitute the predominantly practical barriers to clinical translation.

On the basis of the literature, we conclude that the PVT serves as a key emergence-promoting brain region under both volatile and intravenous general anesthesia. However, current evidence regarding the pivotal role of PVT in general anesthesia primarily come from rodent studies, and clinical data about the structural and functional aspects of the human PVT are urgently needed to facilitate the translation. The molecular mechanisms by which PVT contributes to the regulation of general anesthesia remain largely unknown, though recent studies have identified NALCN in PVT glutamatergic neurons and Kir4.1 in PVT astrocytes as potential targets for general anesthetics. Future studies will aim to identify more specific targets, such as ion channels, neurotransmitters as well as the receptors that modulate the actions of general anesthetics.