Application of stellate ganglion modulation in mental disorders and the future prospects of physical therapies

Abstract

The treatment of mental disorders faces significant challenges due to their complex etiology and the limitations of existing therapies. Neuromodulation has emerged as a promising approach for managing these conditions. Among the various neuromodulatory strategies, stellate ganglion modulation (SGM) specifically targets the sympathetic nervous system by inhibiting neural activity at the cervical stellate ganglion (SG). Stellate ganglion block (SGB), a chemical form of SGM achieved through local anesthetic injection into the SG, suppresses sympathetic nerve impulses to the head, neck, and upper limbs. Evidence suggests that SGB offers a favorable safety profile and demonstrates notable efficacy in treating post-traumatic stress disorder. Moreover, preliminary findings indicate its potential in managing depression and sleep disorders. Current hypotheses propose that SGB alleviates psychological symptoms via two pathways: ascending regulation, which modulates neuroendocrine activity and neuroinflammation, and descending regulation, which influences cardiovascular and digestive functions, thereby engaging the heart–brain and gut–brain axes. Recently, physical energy-based modalities for SGM, including electrical, magnetic, optical, thermal, and ultrasonic stimulation, have been explored as alternatives to conventional chemical modulation. Invasive physical methods such as electroacupuncture and radiofrequency ablation show preliminary efficacy and safety, while noninvasive approaches provide simpler and safer options, with some evidence of benefit in conditions such as arrhythmia. However, clinical validation in psychiatric populations remains limited. Despite the therapeutic promise of physical SGM, key questions persist regarding its mechanisms, efficacy, and safety in mental disorders. Future research should aim to expand preclinical studies, verify these techniques in psychiatric populations, standardize stimulation parameters, develop closed-loop feedback systems, and assess long-term outcomes.

1. Introduction

Mental illness is a major public health challenge worldwide, characterized by complex causes and unclear mechanisms, which place a substantial burden on society [1]. Since the 1950s, when chlorpromazine was recognized as an effective treatment for mental disorders [2], pharmacological therapies have remained the primary approach. Although these treatments can relieve symptoms and enhance patients’ quality of life, they have limitations, such as variable responses, side effects, and the risk of dependency [3]. These challenges have prompted the exploration and development of complementary or alternative therapeutic strategies.

Targeted stimulation of the nervous system is a promising approach for treating mental disorders [4]. Among these approaches, peripheral nervous system stimulation has attracted widespread attention owing to its safety and convenience [5]. Peripheral stimulation primarily targets the sympathetic and parasympathetic branches of the autonomic nervous system, both of which are highly relevant to psychiatric conditions [6]. Sympathetic nerve activation stimulates emotion-regulating regions, including the amygdala, hypothalamus, and hippocampus, leading to emotional responses [7]. Under stress, prolonged activation of the sympathetic system may cause overactivation of the amygdala and elevated levels of nerve growth factor (NGF) and norepinephrine (NE), which are linked to depression and anxiety symptoms [8].

The stellate ganglion (SG), a part of the cervical sympathetic nervous system (SNS) located between the C6 and C7 vertebrae, plays a key role in regulating autonomic functions such as heart rate, blood vessel constriction, and sweating [9]. The SG connects to the limbic system through multisynaptic descending and ascending circuits (Fig. 1). Descending projections originate from the prefrontal cortex and amygdala and extend to the hypothalamus and rostral ventrolateral medulla, where C1 neurons modulate sympathetic preganglionic neurons in the spinal cord that innervate the SG [10]. The locus coeruleus (LC), which receives input from limbic regions, projects noradrenergic fibers to both the SG and the basolateral amygdala (BLA) [11]. Ascending input from the SG influences the LC, which relays signals to the BLA and modulates fear memory [11]. These findings suggest an indirect but functional SG-to-limbic projection via the LC. SGM can elicit both excitatory and inhibitory effects through specific neural projections. Excitatory SGM is primarily used to induce arrhythmia models in animals [12], while clinical use typically involves inhibitory effects. In this article, all references to SGM pertain exclusively to its inhibitory application. Examples include stellate ganglion block (SGB), stellate ganglion radiofrequency ablation (SGA), and other physical therapies [13,14]. SGB was first explored by Dr. Murphey in 1944, who demonstrated that SG blockade was more effective in treating acute vascular injuries than traditional sympathetic nerve blockade. He proposed two distinct methods for performing an SG blockade, laying the foundation for contemporary techniques [15]. SGB involves injecting a local anesthetic into the SG to suppress sympathetic nerve impulses to the head, neck, and upper limbs [16]. It has been widely adopted for managing pain conditions, including hot flashes, migraines, facial pain, and upper-limb pain [16]. In addition to chemical modulation, SGM includes physical therapies, such as electrical stimulation, magnetic stimulation, and light therapy, primarily used in the treatment of ventricular tachycardia and pain syndromes. Research indicates that SGM can improve mood and induce positive sensations during pain management [13]. Since the 1990s, it has been recognized as a promising treatment option for mental disorders, with reports on SGB for psychiatric conditions steadily increasing. Lebovitz et al. reported that anxiety symptoms in patients with post-traumatic stress disorder (PTSD) treated with SGB disappeared and remained absent for up to 3 months [17]. Thus, SGM may represent a novel technique for treating psychiatric disorders. Subsequent studies have explored its application in PTSD, sleep disorders, and depression, as well as the underlying mechanisms.

Fig. 1.

Neural pathways connecting the stellate ganglion with central autonomic and limbic circuit. The multisynaptic circuits by which the stellate ganglion (SG) interfaces with central nervous structures including the descending pathways and the ascending pathways. Descending pathways originate in the prefrontal cortex (PFC) and amygdala (AMY), relaying through the hypothalamus (HYP) and rostral ventrolateral medulla (RVM); C1 neurons from these regions project to sympathetic preganglionic neurons in the spinal cord, which then innervate the SG. Ascending projections from the SG reach the locus coeruleus (LC), which sends noradrenergic fibers back to the basolateral amygdala (BLA) and other limbic regions, thereby modulating emotional processing and fear memory. The bifurcation into ascending and descending circuits is indicated by red and blue arrows, respectively, while solid gold lines represent known anatomical pathways.

In this review, we summarize the current evidence and potential mechanisms of SGM as a therapeutic strategy for mental disorders and discuss prospective applications of physical SGM in their treatment.

2. Application of SGB in mental disorders

2.1. Clinical evidence

2.1.1. PTSD

PTSD is the most extensively studied mental disorder treated with SGM (Table 1) [18]. Both psychotherapy and pharmacological treatments for PTSD have limitations, including long treatment durations and delayed effects, which reduce overall effectiveness [19]. For instance, psychotherapy often requires multiple sessions over weeks or months [19], and pharmacological treatments may take 4–8 weeks to show results, with up to 50% of patients discontinuing due to side effects or lack of efficacy [20]. Mulvaney et al. were the first to apply SGB for PTSD and observed significant relief in flashback symptoms along with a marked reduction in PTSD Checklist-Military Version scores in two patients [21]. Subsequent small-sample studies followed, though their findings were inconsistent. Hickey et al. and Alino et al. reported 13 PTSD cases that achieved remission after SGB treatment [22,23]. However, Hanling et al. reported different results. Their small double-blind randomized controlled trial found no significant difference in symptom relief between the SGB and control groups [24]. The trial has been criticized for methodological issues, including a small sample size, an inappropriate placebo, and excessive randomization of the placebo group, which may explain the lack of positive findings. Given that the frequency and anesthetic dose of SGB were consistent across studies, discrepancies in outcomes are more likely attributable to differences in patient characteristics and the limited sample sizes.

Table 1.

Clinical evidence of SGM for psychiatric disorders.

Mental disorders	First author, year	Study design	Sample size	Intervention frequency	Key findings	Conclusion
PTSD	Sean W et al., 2010	case report	n = 2	Single-session SGB.	Two patients' PCL-M scores dropped from 76 to 25 and 67 to 34.	SGB may be an effective treatment for post-traumatic stress disorder
PTSD	Anita Hicky et al., 2012	Case report	n = 9	Single-session SGB.	Five patients showed clinically significant symptom reduction. symptoms were reduced in two patients but were not clinically significant. The remaining two patients reported no significant changes.	SGB may be an effective and rapid treatment for post-traumatic stress disorder.
PTSD	Justin Alino et al., 2013	Case report	n = 4	Single-session SGB.	Mean PCL-M score of four patients decreased from 73.5 to 26.25.	SGB can alleviate PTSD symptoms
PTSD	Eugene G Lipov et al., 2013	Case report	n = 1	One SGB, then a second SGB 90 days later	Patients' PCL-M scores decreased by 57.7% and 25% after the first SGB and 90 days later, respectively	SGB may be effective in treating PTSD
PTSD	Sean W Mulvaney et al., 2014	Case report	n = 166	Single-session SGB.	At follow-up of 1 week, 1–2 months, and 3–6 months, most of the patients' PCL scores improved significantly, with an average decline of 22 points.	SGB is a safe and minimally invasive procedure that provides at least 3 months of relief from combat-related PTSD-related symptoms.
PTSD	Sean W Mulvaney et al., 2015	Case report	n = 11	Single-session SGB.	A significant decrease in PCL-M scores was also observed from baseline to follow-up (mean change: −29.18; [95% CI, −34.09 to −24.27])	SGB demonstrates its potential for effective treatment of PTSD symptoms.
PTSD	James H Lynch et al., 2016	Non-randomized clinical trial	n = 30	Single-session SGB.	PCL-M scores decreased from 48.69 to 32.15 1 week after surgery. 2–4 weeks after surgery, the mean score was 31.88.	SGB is effective in alleviating PTSD symptoms.
PTSD	Steven R Hanling et al., 2016	DBRCT (SGB group = 21, control group = 21)	n = 42	Single-session SGB.	No statistically or clinically relevant differences in results between the SGB and control groups.	Current evidence does not support widespread use of the approach in the clinic to treat PTSD.
PTSD	Kristine L Rae Olmsted et al., 2020	Multicenter RCT (SGB group = 74, control Group = 39)	n = 113	Single-session SGB.	CAPS-5 score change in the SGB group was −12.6 points, while the adjusted mean total symptom severity score change in the sham treatment group was −6.1 points.	SGB treatment effectively relieved symptoms within 8 weeks.
PTSD	Alan L Peterson et al., 2022	Non-randomized clinical trial	n = 12	SGB is performed every 2 weeks	SGB combined with prolonged exposure therapy, 90.9% of participants showed clinically significant PCL-5 changes at the final stage of treatment.	Combination therapy is effective in PTSD remission
PTSD	Jonathann Kuo et al., 2023	Case report	n = 1	SGB once, then a second SGB 2 week later	PCL-M score decreased from 57 to 15 after the first SGB, and the score did not change significantly after the second SGB, but the patient reported relief of symptoms.	Botox enhanced SGB as a treatment for PTSD to enhance and maintain the positive results of standard stellate ganglion block.
PTSD	Shannon M Blakey et al., 2024	Two analyses of the RCT	n = 113	SGB is performed every 2 weeks	Arousal and reactive PTSD symptom groups changed significantly, with the greatest reduction in symptom severity	SGB can relieve PTSD symptoms
PTSD	Christy Capone et al., 2024	Non-randomized clinical trial	n = 14	Single-session SGB.	In the mixed model, PTSD symptoms measured by the PTSD checklist were significantly reduced	SGB in combination with psychotherapy is feasible and acceptable for veterans and is expected to reduce symptoms in veterans with combat-related PTSD.
Sleep disorder	Eugene G Lipov et al., 2008	Non-randomized clinical trial	n = 13	Five patients had only one SGB and eight patients had two SGB	Number of nighttime awakenings decreased from an average of 19.5 per week to an average of 7.3 per week and continued to decrease over the remainder of the follow-up period.	Stellate ganglion block can reduce hot flashes and sleep disturbances in breast cancer survivors
Sleep disorder	K Haest et al., 2012	Non-randomized clinical trial	n = 34	Single-session SGB.	Odds ratios of improved sleep quality compared to baseline were 3.4 (95% CI 1.6–7.2) at week 1 and 4.3 (95% CI 1.9–9.8) at week 24.	SGB appears to be an effective short-term treatment
Sleep disorder	Jian Xu et al., 2022	Case report	n = 1	One SGB administered daily for 8 consecutive days.	Patient's ESS score decreased from 19 to 0.	It provides a new solution for EDS-related serious functional complications.
Sleep disorder	Decai Luo et al., 2023	RCT	n = 60 (SGB group = 30, control group = 30)	Single-session SGB.	On days 1, 2, and 5 after lumbar anesthesia, the score of deep sleep quality in the SGB group was significantly lower than that in the control group.	SGB alleviates POSD by inhibiting autonomic nervous system excitation.
Sleep disorder	Shiting Yan et al., 2023	RCT	n = 40 (SGB group = 20, control group = 20)	Single-session SGB.	One and two nights after surgery, the sleep efficiency was significantly improved.	SGB can improve POSD, reduce inflammatory response, maintain perioperative hemodynamic stability, and increase melatonin levels undergoing radical surgery for gastrointestinal malignancies.
Depression disorder	L J KARNOSH et al., 1947	Case report	n = 3	Single-session SGB.	Patient's mood improved after SGB.	Possibility of treating depression with SGB is suggested.
TRD	David Sussman et al., 2023	RCT	n = 10 (SGB group = 5, control group = 5)	One SGB, then a second SGB 2 weeks later	At every stage of follow-up, the SGB group had lower MADRS scores than the control group	Support the feasibility of SGB confirmatory trials in patients with TRD
Postpartum depression	Zhang et al., 2025	Non-randomized clinical trial	n = 98(SGB group = 56, escitalopram group = 42)	Daily treatments alternating sides, six treatments per course for three courses total.	The SGB group demonstrated significant reductions in HAMD, EPDS, PSQI scores. lower levels of ACTH, CRH and cortisol than the escitalopram group.	SGB is an effective treatment for postpartum depression, significantly alleviating depression symptoms, improving sleep quality, and reducing stress levels.
Anxiety disorder	James H Lynch et al., 2023	Retrospective analysis	n = 285	GAD-7 questionnaire was reviewed before surgery, 1 week and 1 month after surgery	At every stage of follow-up, GAD-7 scores in the SGB group were lower than the baseline	Larger prospective studies should be conducted to determine the efficacy of SGB therapy as a new treatment for generalized anxiety disorder and other anxiety disorders.
Anxiety disorder	Sean W Mulvaney et al., 2024	Case report	n = 1	Single-session SGB.	Anxiety increased significantly after left SGB and was subsequently improved by the right stellate ganglion block.	SGB can improve anxiety symptoms
Cognitive disorder	Hongji Zeng et al., 2024	RCT	n = 84 (SGB = 42, control = 42)	SGB once a day for a total of 20 sessions.	MMSE scores were improved and significantly different in the SGB group compared with the control group	SGB can significantly and safely improve cognitive function

PTSD, post-traumatic stress disorder; SGB, stellate ganglion block; PCL-M, PTSD check list – military version; CAPS-5, the clinician-administered PTSD scale for DSM-5; EDS, excessive daytime sleepiness; ESS, Epworth sleepiness scale; CI, confidence interval; PCL-5: PTSD checklist for DSM-5; POSD, postoperative sleep disorders; MADRS, Montgomery-Asberg depression scale; TRD, treatment-resistant depression; HAMD, Hamilton depression rating scale; EPDS, Edinburgh postnatal depression scale; PSQI, Pittsburgh sleep quality index; ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; GAD-7, generalized anxiety disorder 7-item scale; MMSE, mini-mental state examination.

In studies with larger sample sizes, the therapeutic effects of SGB were more consistent, suggesting that small sample sizes contribute significantly to variability in outcomes. Mulvaney et al. performed SGB at baseline in 166 patients and followed them for 6 months. Of 132 patients with more than 3 months of follow-up, 97 showed significantly reduced PCL scores and improved symptoms, including anxiety and traumatic flashbacks [25]. Olmsted et al. conducted a multicenter randomized controlled trial (RCT) with 113 military personnel with PTSD, randomly assigning patients to two groups. The SGB group received biweekly interventions, resulting in significant relief of pain and anxiety symptoms [26]. A secondary analysis by Blakey et al. found that SGB produced differential effects on PTSD symptoms, with the most pronounced improvements in reactive arousal clusters [27]. Additional evidence suggests that SGM may relieve anxiety. In a retrospective study, Lynch et al. assessed patients with PTSD receiving SGB using the Generalized Anxiety Disorder 7-item scale. Scores decreased significantly in two of three patients after treatment [28]. Overall, the clinical evidence supporting SGB for PTSD is substantial. However, its efficacy still requires validation in broader patient populations beyond military personnel.

2.1.2. Sleep disorder

More than one-third of adults experience insomnia, and approximately 40% of these individuals develop sleep disorders [29]. These disorders are associated with excessive activation of the SNS [30]. Evidence suggests that SGB may have therapeutic effects on postoperative sleep disorders (POSD). Two non-randomized clinical trials involving breast cancer survivors with POSD showed that SGB produced a lasting reduction in nighttime awakenings for at least 12 weeks, along with significant improvement in sleep quality [31,32]. An RCT in patients undergoing lumbar spine surgery found that those in the SGB group had significantly higher deep sleep quality scores than controls [33]. Another RCT in postoperative patients with gastrointestinal malignancies demonstrated improved sleep efficiency and increased melatonin levels after SGB [34]. Furthermore, Xu et al. reported a case in which SGB effectively treated hypersomnia [35]. Overall, current evidence indicates that SGB is a promising treatment for POSD and may be effective for primary sleep disorders. Nevertheless, its efficacy requires confirmation through large-scale trials.

2.1.3. Depression

Depression is a mental disorder characterized by mood disturbances and somatic symptoms, such as anhedonia, diminished interest, and palpitations [36]. Its prevalence is rising annually, and the risk of suicide may be up to 30 times higher than in the general population [37]. As with other mental disorders, the cause of depression remains unclear, and pharmacological treatments are often limited in effectiveness. The potential of SGB for depression treatment was first suggested in 1947, when three patients experienced symptom relief after bilateral SGB [38]. A small RCT of treatment-resistant depression (TRD), defined as inadequate response despite appropriate treatment, found reduced Montgomery-Asberg Depression Rating Scale scores in the SGB group [39]. This finding supports the feasibility of a confirmatory trial of SGB in TRD. Zhang et al. reported that patients with postpartum depression experienced significant reductions in Hamilton Depression Rating Scale, Edinburgh Postnatal Depression Scale, and Pittsburgh Sleep Quality Index scores after SGB, along with markedly decreased serum levels of adrenocorticotropic hormone (ACTH), corticotropin-releasing hormone, and cortisol [40]. However, firm conclusions cannot be drawn from this preliminary study owing to the small number of participants who completed treatment [41]. Overall, the evidence supporting SGB for depression is inconclusive, highlighting the need for larger RCT with long-term follow-up to evaluate both effectiveness and duration of symptom relief. Such studies could provide crucial evidence supporting SGB as a therapeutic option for depression.

2.2. Preclinical evidence

While emerging clinical reports suggest potential therapeutic effects of SGM, the current evidence is insufficient to establish it as routine clinical practice. Barriers to large-scale clinical validation include safety concerns, mechanistic uncertainty, and gaps in understanding heterogeneity. Consequently, preclinical studies serve as essential translational bridges (Table 2). Wang et al. found that in chronically stressed rats, SGB significantly reduced serum corticotropin-releasing factor, ACTH, and NE levels, and depressive symptoms were markedly alleviated in the sucrose preference test [42]. Dai et al. reported that sleep-deprived rats exhibited significantly prolonged escape latency in maze tests compared to controls, whereas SGB shortened this latency, indicating improved spatial memory. Sleep-deprived rats also exhibited significant weight loss, elevated hippocampal interleukin-6 (IL-6) and interleukin-1β (IL-1β) levels, aggravated neuronal damage, and reduced serum melatonin. Following SGB, weight and serum melatonin significantly increased, hippocampal damage was alleviated, and IL-6/IL-1β levels decreased [43]. Another study showed that SGB suppresses hippocampal microglia inflammation and enhances cognitive function in mice [44]. Together, these findings suggest that SGB may improve spatial memory by suppressing hippocampal inflammation, a recognized pathological basis for multiple diseases. A randomized cohort study using the UK Biobank demonstrated that elevated plasma IL-6 levels are associated with hippocampal cortical and subcortical atrophy and cognitive decline [45]. Previous studies have linked IL-6 to the pathogenesis of depression and schizophrenia [46]. Given the ability of SGB to reduce hippocampal IL-6 and IL-1β in animal models, it represents a promising immunomodulatory strategy for clinical translation in these conditions. In a recent study, PTSD model mice exhibited significantly reduced freezing time after SGB, indicating attenuated fear conditioning memory. Using combined chemogenetic and optogenetic manipulation, investigators demonstrated that SGB likely suppresses the LC-BLA pathway, thereby reducing conditioned fear memory in PTSD mice [11]. Studies confirm that the amygdala is the central hub for fear and anxiety. Electrical stimulation of the human amygdala can evoke conscious fear and anxiety, whereas drugs that enhance inhibitory neurotransmission in the amygdala (such as benzodiazepines or ethanol) alleviate anxiety and depression [47]. The LC circuitry mediates both acute and chronic pain processing, with analgesics such as pregabalin specifically targeting this nucleus [48]. Given the established roles of the LC and amygdala in mental disorders, interventions targeting these regions may become future therapeutic cornerstones. SGB concurrently reduces LC NE release and BLA neuronal excitability, potentially circumventing benzodiazepine dependence and pregabalin-associated central nervous system (CNS) adverse effects, thereby offering novel treatment options for therapy-resistant patients.

Table 2.

Preclinical evidence of SGM for psychiatric disorders.

Indications	First author, year	Study subjects	Sample size	Intervention frequency	Key findings	Conclusion
Depression disorder	Weiwei Wang et al., 2017	Rats	n = 48 (Sham Group = 12, SGB Group = 12, UCMS Group = 12, UCSG Group = 12)	Single-session SGB.	Compared to the UCMS group, the UCSG group demonstrated reduced anhedonia and lower serum cortisol levels.	SGB can reduce depression-like behaviors caused by chronic stress.
Cognitive disorder	Dongsheng Dai et al., 2021	Rats	n = 64 (Control Group = 16, SD Group = 16, SGB Group = 16, SGB SD Group = 16)	SGB once a day	Compared to the SD group, the SGB SD group exhibited significantly shortened maze test latency, reduced hippocampal IL-6 and IL-1β levels, and attenuated neuroinflammation.	Right stellate ganglion block can improve spatial learning and memory dysfunction in sleep-deprived rats, and its mechanism may be related to reducing the apoptosis and inflammation of hippocampus cells in sleep-deprived rats.
Cognitive disorder	Kun Yu et al., 2023	Rats	n = 105 (Control = 15, Control + TAK-242 = 15, Control + SGB = 15, Surgery = 15, Surgery + TAK-242 = 15, Surgery + SGB = 15, Surgery + SGB + LPS = 15)	Single-session SGB.	SGB significantly reduced the exploration time and crossed the platform more times.	Preoperative SGB may effectively prevent POCD by inhibiting TLR4/NF-κb mediated hippocampal microglial neuroinflammation.
Cognitive disorder	Xijin Deng et al., 2023	Rats	n = 184 (sham = 36, sham NS = 36, surgery = 36, SGB = 36)	Single-session SGB.	Compared to the surgery group, the SGB group demonstrated significantly less severe cognitive impairment and superior recovery outcomes.	SGB reduces the degree of cognitive impairment caused by surgical trauma by inhibiting the excitability of the sympathetic nerve and hypothalamic axis.
PTSD	Ziheng Wang et al., 2025	Mice	n = 40 (control = 10, SGB = 10, NS = 10, Sev = 10)	Single-session SGB.	The duration of freezing in the SGB group was significantly shorter than that in the other three groups.	SGB can relieve PTSD symptoms and the LC-BLA pathway was the potential mechanism.

SGB, stellate ganglion block; UCMS, unpredictable chronic mild stress; UCSG, combined UCMS with SGB; SD, sleep deprivation; NS: saline group; TAK-242, resatorvid, a small-molecule-specific inhibitor of Toll-like receptor 4 signaling; Sev, sevoflurane; LC, locus coeruleus; BLA, basolateral amygdala; IL, interleukin; POCD, postoperative cognitive dysfunction; TLR4/NF-κb: Toll-like receptors 4/nuclear factor kapa-B; LPS, lipopolysaccharide.

3. Potential mechanisms of SGB in improving mental disorders

Because psychiatric disorders are classified based on symptoms and share overlapping clinical features, the mechanisms underlying the therapeutic effects of SGB are likely common across multiple conditions. Current hypotheses suggest that SGB influences ascending sympathetic regulation, which modulates neuroendocrine activity and neuroinflammation in the brain, while descending sympathetic regulation affects the cardiovascular and digestive systems. Through these pathways, SGB may indirectly improve mental symptoms via the heart-brain and gut-brain axes (Fig. 2).

Fig. 2.

The potential mechanisms of SG modulation in improving mental disorders. SGB is proposed to regulate brain function through both ascending and descending sympathetic pathways. Ascending regulation influences central processes such as norepinephrine (NE) signaling, neuroinflammation in the hippocampus, and melatonin secretion from the pineal gland. Descending sympathetic outputs affect peripheral systems, including the cardiovascular and gastrointestinal systems, thereby indirectly modulating brain activity via the heart–brain and gut–brain axes. Solid arrows represent direct modulation via the sympathetic nervous system; dashed arrows indicate indirect modulation via alternative physiological pathways.

3.1. Neuroendocrine hypothesis

3.1.1. NE and NGF hypothesis

There are bidirectional neural projections between the SG and the LC [11]. The LC is the brain’s primary noradrenergic nucleus, sending widespread projections throughout the CNS [49]. NE interacts with receptors in brain regions involved in emotional processing, including the amygdala and hippocampus, influencing their activity and potentially contributing to anhedonia and other psychological symptoms [48]. Accordingly, pharmacological agents that target the NE system are widely used in the clinical treatment of depression, PTSD, and other mental disorders for affective symptoms [50]. Given the anatomical and functional connections between the SG and LC, it is hypothesized that SGB may exert therapeutic effects on affective symptoms in mental disorders such as PTSD and depression by modulating ascending noradrenergic pathways. However, clinical evidence on SGB’s effects on central noradrenergic circuits in psychiatric populations remains limited. Preclinical evidence supports this mechanism. Wang et al. demonstrated that SGB alleviates conditioned fear memory in a mouse model of PTSD by inhibiting the noradrenergic circuit from the LC to the BLA. Specifically, SGB reduced neural activity within the SG–LC pathway and decreased NE concentrations in the BLA. Moreover, optogenetic activation of the LC–BLA pathway reversed the fear-attenuating effects of SGB, indicating that modulation of central noradrenergic signaling is a key mechanism underlying its therapeutic effects [11].

Beyond direct neural projections, neurochemical mediators play a critical role in modulating sympathetic–central noradrenergic pathways, a process hypothesized to contribute significantly to the therapeutic effects of SGB in mental disorders [51]. NGF, primarily secreted by the amygdala, is a critical regulator of NE synthesis. Through interaction with the high-affinity TrkA receptor, NGF stimulates the production of NE and other neurotransmitters and neuropeptides, thereby influencing downstream autonomic and emotional regulation [52]. In patients with mental disorders such as PTSD, excessive amygdala activation increases NGF levels [53]. Elevated NGF is transmitted to the SG, leading to nerve ending sprouting, the formation of new neural pathways, and increased NE levels [53]. SGB may counteract this pathological process by inhibiting NGF–TrkA signaling in the SG. Preclinical studies have shown that local anesthetics used in SGB, such as lidocaine, suppress NGF-induced TrkA autophosphorylation and neurite outgrowth without inducing cytotoxicity. These findings suggest that blockade of NGF–TrkA signaling may underlie the therapeutic effects of SGB on sympathetic hyperactivity and NE dysregulation [54]. However, clinical evidence demonstrating that SGB suppresses NGF–TrkA signaling to alleviate sympathetic hyperactivity and NE dysregulation remains lacking and requires further investigation.

3.1.2. Melatonin hypothesis

Melatonin, a circadian hormone secreted by the pineal gland, plays a central role in regulating sleep–wake cycles and mood. Altered melatonin secretion has been observed in individuals with symptoms such as insomnia and depression, which are common across psychiatric conditions [55,56]. Pineal melatonin secretion is regulated by the suprachiasmatic nucleus and directly by the SNS [57]. Acting on melatonin receptors, melatonin governs sleep-wake rhythms [58]. Under chronic stress or heightened sympathetic activity, sustained adrenergic input to the pineal gland suppresses pinealocyte function, resulting in reduced melatonin secretion and disrupted circadian rhythms [59]. Studies have shown that melatonin levels are reduced or delayed in patients with mental disorders and tend to normalize following treatment [60]. By inhibiting sympathetic outflow, SGB may restore pineal gland function and re-establish physiological melatonin rhythms, thereby alleviating insomnia in sleep disorders and depression. Supporting this mechanism, Bruce et al. demonstrated that sympathectomy markedly altered melatonin levels in patients with hyperhidrosis and disrupted the normal diurnal rhythm of melatonin in both plasma and cerebrospinal fluid. These findings provide direct evidence that sympathetic innervation is essential for maintaining melatonin rhythmicity [61]. Collectively, these insights underscore the hypothesis that neuroendocrine mechanisms may underlie the therapeutic effects of SGB in mental disorders, warranting further investigation.

3.2. Neuroinflammatory hypothesis

Neuroinflammation is primarily mediated by microglia and astrocytes, leading to the release of pro-inflammatory cytokines and other signaling molecules [62]. These substances can reach the brain and disrupt neural function and emotional regulation circuits. Growing evidence indicates that neuroinflammatory processes contribute to the pathophysiology of various mental disorders [63]. Elevated levels of pro-inflammatory cytokines, including IL-1β, IL-6, IL-8, tumor necrosis factor-alpha (TNF-α), and C-reactive protein, have been consistently observed in patients with mental disorders, and these alterations are closely associated with the severity of affective symptoms [63,64]. SNS activity significantly influences systemic inflammatory cytokine levels. For example, central inhibition of the SNS has been shown to decrease peripheral TNF-α levels in hypertensive patients [65]. Additionally, increased sympathetic tone correlates with elevated plasma IL-6 concentrations in young non-pregnant women, supporting a link between SNS activity and pro-inflammatory cytokine levels [66]. SGB may exert therapeutic effects on affective symptoms of mental disorders by modulating these neuroinflammatory pathways. Preclinical evidence supports this hypothesis. In diabetic rats subjected to ischemic stroke, SGB reduced hippocampal expression of IL-6, IL-1β, and TNF-α, leading to improved neurological function [67]. In a rat model of central post-stroke pain with anxiety- and depression-like behavior, SGB reversed mechanical allodynia and affective symptoms by enhancing cerebral blood flow (CBF) and suppressing hypoxia-inducible factor-1α and NOD-like receptor thermal protein domain-associated protein three-mediated inflammatory signaling [68]. In rats with memory impairment, SGB inhibited the Toll-like receptor 4/nuclear factor kappa-B pathway and reduced hippocampal expression of IL-6, IL-1β, and caspase-3. These effects alleviated hippocampal cellular damage and improved cognitive function and insomnia [43,44], suggesting that SGB may modulate insomnia symptoms in mental disorders. Although preclinical studies strongly support the neuroinflammatory hypothesis, clinical evidence confirming that SGB alleviates psychiatric symptoms through this mechanism remains limited. Further clinical research is needed to clarify the contribution of neuroinflammation to the therapeutic effects of SGB in mental disorders.

3.3. Heart-brain axis hypothesis

The heart-brain axis is a well-established circuit connecting the frontal brain regions to cardiovascular autonomic functions through the limbic system, hypothalamus, and brainstem structures [69]. Heart rate variability (HRV), defined as fluctuations in the interval between successive heartbeats, is considered a surrogate marker of the balance between the brain and the cardiovascular system [70]. Chronic stress and traumatic events disrupt vagal stability, leading to reduced HRV and increased hyperarousal [71]. Evidence indicates that cardiac interventions can improve psychological symptoms [72]. For example, Lamb et al. reported that vagus nerve stimulation reduces the heart rate, improves the low-frequency to high-frequency (LF/HF) ratio of HRV, suppresses sympathetic excitability, and alleviates PTSD symptoms in veterans [73]. It is hypothesized that SGB may improve psychiatric symptoms by increasing HRV, producing an effect similar to vagus nerve excitation. A clinical study found that left-sided SGB significantly enhanced parasympathetic activity, indicated by increased HF power and a decreased LF/HF ratio in HRV parameters [74]. Preclinical evidence supports this mechanism. In healthy rats, SGB improved endothelial and cardiac function, enhanced CBF, and ultimately led to cognitive enhancement [75]. These findings suggest that SGB can regulate autonomic nervous system balance, potentially influencing CNS function via heart–brain autonomic pathways, and thereby alleviating hyperarousal in PTSD and anxiety symptoms in other mental disorders. However, the contribution of this mechanism to the therapeutic effects of SGB requires further clarification.

3.4. Gut-brain axis hypothesis

The gut–brain axis is a bidirectional communication network integrating neural, immune, and endocrine signals between the gastrointestinal tract and the CNS [76]. Neuroanatomically, the enteric nervous system, embedded in the gut wall, is innervated by both vagal and sympathetic efferents, with the SNS playing a key role in suppressing gastrointestinal motility and modulating mucosal immune responses [77,78]. Disruption of intestinal barrier integrity has been implicated in the pathophysiology of both affective and somatic symptoms in depression disorder. A randomized, double-blind, placebo-controlled trial showed that enhancing intestinal barrier function over 12 weeks significantly ameliorated depressive symptoms [79]. SGB is hypothesized to restore gastrointestinal barrier integrity, influence CNS function through gut–brain axis modulation, and thereby alleviate affective and somatic symptoms in mental disorders. In a hemorrhagic shock rat model, SGB significantly improved intestinal barrier function and survival, reduced gut permeability, and restored tight junction protein expression [80]. These effects were shown to depend on suppression of endoplasmic reticulum (ER) stress, as SGB downregulated ER stress markers and prevented intestinal injury, while ER stress agonists abolished the effect [81]. Clinical evidence also supports this mechanism. A meta-analysis by Wen et al. reviewing five RCT involving 274 patients undergoing surgery under general anesthesia, suggested that SGB facilitates gastrointestinal function recovery by modulating SNS activity, thereby enhancing gut motility and reducing postoperative complications [82]. In addition, an RCT conducted by Xue et al. indicated that SGB reduces early postoperative cognitive dysfunction in older patients undergoing laparoscopic gastrointestinal surgery [83]. However, direct causal evidence linking SGB-induced gastrointestinal improvements to CNS modulation via the gut–brain axis remains limited and requires further investigation.

4. Prospects for the application of physical SGM in the treatment of mental disorders

Physical SGM uses physical modalities to inhibit the SG, achieving effects similar to SGB. These modalities include electrical stimulation, magnetic stimulation, irradiation therapy, SGA, and ultrasonic stimulation (Fig. 3). Compared with conventional SGB, most of these techniques (except SGA) are less invasive and associated with fewer adverse effects, although their therapeutic effects are generally shorter in duration (Table 3). Although more invasive than traditional SGB, SGA offers the advantage of longer-lasting efficacy [14]. Currently, physical SGM is primarily applied in the treatment of neuropathic pain and ventricular arrhythmias. Its application in mental disorders remains limited, with only a few studies reporting benefits in patients with PTSD and depression accompanied by insomnia (Table 3). Nonetheless, these preliminary findings suggest that physical SGM holds promise as a novel neuromodulation strategy for psychiatric treatment. Further investigation is warranted to clarify the relative advantages and limitations of each physical SGM modality in the context of mental disorders.

Fig. 3.

Physical modulation techniques targeting the stellate ganglion. Six physical approaches which could be used to modulate the activity of the stellate ganglion (SG), achieving neuromodulatory effects like those of stellate ganglion block. These include transcutaneous electrical nerve stimulation, which applies low-frequency electrical currents to the cervical region; Electroacupuncture, which combines needle insertion with targeted electrical stimulation near the SG; Magnetic stimulation, which delivers pulsed magnetic fields to influence neural excitability; Irradiation therapy, which uses low-level red or near-infrared light to penetrate tissue and regulate SG function; Radiofrequency ablation, an invasive technique that thermally disrupts SG signaling via targeted radiofrequency currents; And ultrasonic stimulation, which applies low-intensity acoustic energy to modulate sympathetic output.

Table 3.

Comparative analysis of physical therapies: indications, technical parameters, and safety profiles.

Therapy	Indications	Stimulation parameters	Adverse effects	Contraindications	Technical difficulty	Advantages and disadvantage vs. SGB	First author, year
SGB	PTSD, sleep disorder, depression,	Unilateral stellate ganglion, 7 ml, 0.5% ropivacaine.	Horner's syndrome, pneumothorax, recurrent laryngeal nerve block	Anticoagulation or coagulation dysfunction, local infection, anatomical malformation, allergy to local anesthetic drugs	Invasive, precision-guided localization	/	Kristine L Rae Olmsted et al., 2020; Eugene G Lipov et al., 2008; Zhang et al., 2025
TENS	Muscle pain, effort angina, minor trauma	80 Hz, 150 μs pulse, 30 min	Local skin discomfort/pain	Pacemakers/ICDs; pregnancy; epilepsy; malignancy; DVT; fragile skin	Non-invasive, non-targeted localization	Fewer AE; narrower indications	Sluka KA et al., 2013; Mannheimer C et al., 1990
EA	Depression with insomnia	Three sessions/week (alternate days), 8 weeks	Hand numbness, hematoma, Local pain	Severe CV/hepatic/renal disease; Infection/ulcer at acupoints; pregnancy/lactation	Minimally invasive, precision-guided localization	Adaptable acupoints; Higher difficulty	Yin X et al., 2020; Yin X et al., 2022
Magnetic Stimulation	VT storm, MI-induced ventricular arrhythmia	20 Hz, < 1 ms pulse; 30 min/session, bid, 8 weeks	Hemodynamic compromise, Local discomfort	Pregnancy; lactation; cardiac disease; unhealed wounds; electronic/metal implants	Non-invasive, non-targeted localization	Fewer AE; narrower indications	Wang S et al., 2016; Markman TM et al., 2020; Markman TM et al., 2021
Light Therapy	Neuropathic pain, burning mouth syndrome, fibromyalgia	380–1100 nm; 15 min (1 pulse/s × 1 min, then 1 pulse/4 s × 14 min)	Local thermal injury	Active cancer sites; infection sites; pregnancy	Non-invasive, non-targeted localization	Fewer/low-incidence AE; narrower indications	Liao C-D et al., 2016; Liao C-D et al., 2017; Nakajima F et al., 2015
Radiofrequency Ablation	Electrical storm (ventricular arrhythmias), PTSD	2 Hz pulsed, 45 V, 6 min	Pneumothorax, hemothorax, horner's syndrome	Severe comorbidities; pregnancy; pacemakers/neurostimulators	Invasive, precision-guided localization	Better efficacy; high difficulty	Rao BH et al., 2023; Block T et al., 2023
Ultrasonic stimulation	ventricular arrhythmias	0.5–3 W/cm², 5–10 min	Treatment-related pain, transient erythema, edema, and mild ecchymosis	Malignancy; pregnancy; cardiac pacemakers	Non-invasive, non-targeted localization	Fewer AE; narrower indications	Wang S et al., 2020

SGB, stellate ganglion block; PTSD, post-traumatic stress disorder; TENS, transcutaneous electrical nerve stimulation; EA, electroacupuncture; AE, adverse events; DVT, deep vein thrombosis; ICD, implantable cardioverter-defibrillator; VT, ventricular tachycardia; MI, myocardial infarction; CV, cardiovascular.

4.1. Electrical stimulation

Current forms of electrical stimulation primarily include transcutaneous electrical nerve stimulation (TENS) and EA. TENS is widely used in clinical practice for rapid pain relief. It delivers a mild electric current to the body through electrode pads placed on the skin, typically at the pain site or at acupuncture points [84]. When targeting the SG, two adhesive electrodes are placed on one side of the neck: one near the sixth cervical transverse process at the base of the trapezius muscle, and the other in the supraclavicular region over the SG. This arrangement allows the TENS device to deliver electrical impulses intended to mimic the therapeutic effects of SGB. Stimulation is generally applied at a frequency of 80–100 Hz with a pulse width of 150–200 µs. The intensity (mA) is gradually increased to the maximum tolerated level without causing pain. Each session lasts less than 30 min. During stimulation, physiological responses such as increased skin temperature and enhanced blood flow are often observed, suggesting modulation of sympathetic nervous activity [[85], [86], [87]]. TENS applied at adjacent sites of the SG (C7 and T4) has also been found to relieve pain [85]. In addition, several studies have reported that TENS decreases circulating levels of adrenaline and NE [88]. This suggests that, similar to SGB, TENS may exert therapeutic effects on mental symptoms by modulating NE levels. Moreover, TENS may alleviate sympathetic overactivation, reduce vasoconstriction, and improve blood flow, blood oxygenation, and exercise tolerance [86,87]. Reduced CBF in specific brain regions has been linked to psychiatric disorders, including depressive symptoms and cognitive decline [89], as inadequate blood flow fails to meet the brain’s metabolic demands [90]. Thus, TENS may confer therapeutic benefits for psychiatric symptoms by improving CBF. However, despite its theoretical feasibility, current clinical evidence does not support the therapeutic efficacy of TENS targeting the SG in patients with mental disorders. Regarding risk–benefit considerations, TENS applied to the SG offers a faster onset of action with minimal adverse effects, typically limited to transient discomfort or pain at the stimulation site. In contrast, conventional SGB carries risks such as puncture-related injury, bleeding, pneumothorax, and allergic reactions to local anesthetics [91]. Safety concerns have also been noted in neuropathic pain studies. TENS is contraindicated in patients with cardiac implantable electronic devices, pregnant women, individuals with epilepsy, active malignancy, deep vein thrombosis, or compromised skin integrity [92]. Collectively, TENS demonstrates a superior safety profile compared with SGB; however, robust clinical evidence for psychiatric applications remains lacking, highlighting the need for rigorous translational research.

EA, an electrical stimulation therapy derived from acupuncture and rooted in traditional Chinese medicine, has recently gained attention as a potential treatment for mental disorders [93]. When applied to the SG, filiform acupuncture needles are unilaterally inserted in the lower cervical region, typically around the C6–C7 level of the cervical sympathetic chain. A specialized EA stimulator is subsequently connected to the needles to deliver electrical pulses. In clinical trials, stimulation used a continuous waveform (∼30 Hz) at an intensity set to patient tolerance (up to ∼20 V), with each session lasting approximately 30 min [94,95]. Yin et al. conducted a preliminary study on a small sample of patients, applying EA to acupuncture points related to the sympathetic system, such as Shenmen (HT7) and Sanyinjiao (SP6), for depression with comorbid insomnia. They found that patients receiving EA experienced significant improvements in sleep quality, which persisted for at least 12 weeks [94]. A subsequent large RCT involving 270 patients with depression and insomnia further supported these findings. Patients received EA for 8 weeks and were followed for an additional 24 weeks; results showed that EA significantly improved sleep quality [95]. Potential adverse effects of EA include hand paresthesia, hematoma formation, and pain at the stimulation sites [94]. For safety reasons, EA is generally contraindicated in patients with severe cardiovascular, hepatic, renal, or hematopoietic disorders, as well as during pregnancy. Patients with local skin infections, ulcers, or scars near treatment sites should also be excluded [95]. Electrical stimulation methods each have clear advantages and limitations. While TENS is associated with fewer adverse effects than EA, clinical evidence supporting its efficacy in mental disorders remains limited. EA, though linked to a higher rate of adverse reactions than TENS, has demonstrated therapeutic benefits in patients with depression and insomnia and maintains a better safety profile than SGB. Future clinical studies should rigorously evaluate the risk-benefit balance to optimize therapeutic strategies.

4.2. Magnetic stimulation

Magnetic stimulation, a noninvasive intervention, has been increasingly applied in the treatment of mental disorders in recent years [96]. Magnetic stimulation of the SG is performed by placing a coil at the lateral neck, near the C6 transverse process, close to the ganglion’s surface landmark [97]. Magnetic pulses are subsequently applied to activate or modulate the SNS via the SG. Studies have used standard TMS devices or repetitive peripheral magnetic stimulators to deliver focused pulses. Typical protocols employ low frequencies (∼0.9–1 Hz) at high intensity (approximately 80% of the individual motor threshold to avoid excessive neck muscle contraction), with the coil oriented over the ganglion. Sessions typically last 15–60 min [[97], [98], [99]]. In a canine model of acute myocardial infarction, intermittent low-frequency electromagnetic field stimulation at 1 Hz was applied to the left SG (LSG). Significant reductions in LSG neural activity, serum NE levels, and systolic blood pressure were observed after 30 and 90 min of stimulation [97]. Similarly, a small RCT and a case report by Markman et al. showed that sustained LF magnetic stimulation of the LSG improved ventricular tachycardia for at least 72 h, suggesting it may safely reduce the burden of ventricular tachycardia [99,100]. In general, low-frequency magnetic stimulation of the LSG can inhibit sympathetic nerve activity and reduce serum NE levels. Because PTSD, anxiety, and other mental disorders are often associated with elevated NE levels and tachycardia, these findings suggest that stimulation of the SG may represent a promising treatment option for such conditions. Similarly, although theoretically promising, current clinical evidence does not support the therapeutic efficacy of magnetic stimulation targeting the SG in patients with mental disorders. Adverse effects of magnetic stimulation are similar to those of TENS and primarily include hemodynamic compromise, local discomfort, or skin irritation at the stimulation site [100]. Given these safety concerns, magnetic stimulation is clinically contraindicated in patients with permanently implanted ventricular assist devices; metallic implants in the head or neck region (excluding dental implants); implanted drug pumps or neurostimulators; cochlear or ocular implants; pregnancy; or active malignancy within the stimulation field [99]. Overall, magnetic stimulation resembles TENS in demonstrating a relatively high safety profile and low incidence of adverse events. Therefore, further exploration of its applications in mental disorders is warranted to establish an optimal risk-benefit balance.

4.3. Irradiation therapy

SG light therapy (SG-LI), which includes low-level laser therapy, xenon light therapy, and linear-polarization near-infrared therapy, is a potential alternative to conventional SGB. SG-LI targets the cervicothoracic sympathetic ganglion at approximately 2–3 cm above the clavicle, in the jugular groove near the C6–C7 level. Clinical studies have applied red and near-infrared low-level light, such as diode lasers or polarized xenon lamps, transcutaneously over this region [[91], [92], [93]]. Reported treatment parameters vary; however, they typically involve wavelengths in the red to near-infrared range, low power densities delivering only a few joules per cm², and brief exposures of approximately 5–10 min per side, often applied bilaterally in one session [[91], [92], [93], [94]]. SG-LI may exert therapeutic effects by inhibiting sympathetic tone, reducing inflammation, and promoting vasodilation [91]. A randomized double-blind trial reported significant improvements in pain and HRV after 6 weeks of near-infrared radiation applied to the SG [92]. Momota et al. treated patients with burning mouth syndrome using high-waist-line polarized near-infrared irradiation of the SG and found that pain was significantly relieved in all cases without serious adverse reactions [94]. Nakajima et al. used xenon irradiation on the SG of patients with fibromyalgia and observed significantly lower visual analog scores for pain [93]. Overall, similar to SGB, SG-LI may exert therapeutic effects against mental symptoms by blocking the SG. SG-LI offers several advantages—including ease of administration, low complexity, high patient compliance, and minimal adverse effects—that make it a promising therapeutic option for psychiatric disorders. Reported adverse effects are rare; however, local skin lesions at treatment sites have been described [91]. As with TENS and magnetic stimulation, the application of SG-LI in mental disorders remains unexplored. For safety reasons, previous studies recommend avoiding SG-LI during pregnancy and in patients with active malignant tumors or local infections [95]. Future clinical research is necessary to establish its risk-benefit profile.

4.4. Radiofrequency ablation

SGA has been used in the treatment of arrhythmias. The procedure is performed under image guidance, typically ultrasound, computed tomography​, or fluoroscopy, to accurately target the SG at the C6–C7 level, adjacent to the transverse process and longus colli muscle. A radiofrequency needle is carefully advanced to this region via an anterolateral approach. A case report described the use of a 2 Hz pulsed current with a maximum voltage of 45 V for a total duration of 6 min, which was effective in alleviating PTSD symptoms [96]. Rao et al. applied conventional radiofrequency ablation of the SG in patients experiencing electrical storm (ES). During a mean follow-up of 22 months, none of the patients experienced recurrence, suggesting that SGA is both effective and safe for unstable ES [14]. In a rat model, left-sided SGA reduced the induction rate of ventricular tachycardia, NE levels, ventricular M1 macrophages, and inflammatory cytokines. These findings suggest that SGA may reduce ventricular arrhythmia by inhibiting macrophage polarization and activation induced by sympathetic hyperactivity [97]. Studies have also explored SGA in the treatment of mental disorders. Block et al. performed bilateral SGA in patients with PTSD who had relapse after SGB treatment and found that symptoms significantly improved, with effects lasting longer than those of SGB [96]. Based on current evidence, SGA has considerable potential as a therapeutic intervention for mental disorders. Because of its durability and irreversibility, SGA may overcome the short efficacy duration associated with SGB. However, owing to the complexity and invasiveness of the procedure, its use is limited and it is less preferable than other physical therapies in general practice. Compared with SGB, SGA is similarly invasive and may cause adverse events such as pneumothorax or allergic reactions to local anesthetics [14]. Current evidence advises against its use during pregnancy and in patients with cardiac pacemakers or other neuromodulatory implants [98]. Although available studies suggest potential applications of SGA in mental disorders [96], further research is warranted to refine therapeutic protocols and incorporate technical advancements that minimize risks, thereby improving its overall benefit-risk balance.

4.5. Ultrasonic stimulation

Low-intensity focused ultrasound (LIFU) has emerged as a promising modality for modulating the SNS, with preliminary evidence suggesting potential therapeutic benefits. For LIFU targeting the SG, the ultrasound transducer is positioned on the lateral side of the neck at the level of the C7 transverse process, approximately 3–4 cm above the clavicle, corresponding to the anatomical location of the cervicothoracic sympathetic ganglion. A therapeutic ultrasound device operating at a frequency of around 1 MHz is used to deliver low-intensity acoustic energy to the region [99,100]. The aim of this noninvasive intervention is to modulate sympathetic output by acoustically suppressing SG activity, thereby producing physiological effects similar to those of SGB. Stimulation is typically applied in pulsed or continuous mode at intensities of 0.5–3 W/cm², with each session lasting approximately 5–10 min [99,100]. Wang et al. demonstrated that LIFU applied to the LSG for 10 min prolonged the ventricular refractory period and reduced LSG neuroactivity, indicating an inhibitory effect on sympathetic nervous activity [99]. In contrast, Askin’s study using low-dose high-frequency (HF) ultrasound in the LSG found no significant improvements in pain relief, range of motion, grip strength, or upper limb disability, suggesting that low-frequency ultrasound may be more effective than HF treatments for inhibiting LSG activity [100]. These findings highlight the importance of selecting the appropriate frequency to optimize the effectiveness of ultrasound therapy for autonomic modulation. SG ultrasonic stimulation may modulate the heart–brain axis, thereby exerting therapeutic effects on mental disorders. However, current evidence for ultrasound therapy in mental disorders is not yet available. With respect to risk–benefit balance, reported adverse effects primarily include procedure-related pain, transient erythema, edema, and mild ecchymosis [99]. In prior studies, SG ultrasound was avoided in individuals with coagulopathies, autoimmune disorders, severe cardiovascular disease, diabetes mellitus, hepatic or renal impairment, active malignancies, and pregnancy [100]. Overall, ultrasound stimulation is comparable to magnetic stimulation and TENS, with a favorable safety profile and a low incidence of adverse events. Nevertheless, further investigation is needed to clarify its therapeutic potential in mental disorders and to establish an optimal risk–benefit balance.

4.6. Current challenges and future directions

Several challenges remain in applying physical modulation techniques to the SG in clinical settings. First, although evidence supports the efficacy of physical SGM in neuropathic pain and cardiac arrhythmias, and its theoretical applicability to mental disorders is supported by mechanistic similarities with SGB, clinical evidence on noninvasive physical neuromodulation for mental disorders remains limited. High-quality data from well-controlled trials are needed, particularly in psychiatric populations with standardized outcome measures. Second, the mechanisms by which SGM exerts therapeutic effects in mental disorders have not been clearly defined. Future studies should aim to clarify these mechanisms using validated animal models and clinical trials that incorporate advanced neuroimaging techniques, such as functional magnetic resonance imaging​, to identify both central and peripheral neurobiological changes associated with SGM. Third, the safe and effective range of treatment parameters for mental disorders, including stimulation intensity, frequency, duration, and intersession intervals, remains undefined. Systematic investigations are required to establish foundational treatment protocols and to characterize the relationships between stimulation parameters and clinical responses. Building on this foundation, future research may focus on developing closed-loop systems that automatically adjust stimulation settings in real time according to physiological signals, such as HRV or skin conductance. Fourth, most existing studies have examined short-term efficacy and acute adverse event profiles, whereas the long-term durability of SGM remains largely unexplored. Longitudinal clinical trials with extended follow-up are needed to determine whether the therapeutic benefits of SGM persist over time. These trials should also monitor potential long-term adverse effects that may not be captured in short-term studies.

5. Conclusion

Current evidence highlights the promising efficacy of SGM in the treatment of certain mental disorders, particularly PTSD. However, strong clinical evidence is lacking to confirm its efficacy and safety for other conditions such as depression and anxiety. Current hypotheses suggest that SGB may alleviate psychological symptoms through both ascending and descending pathways, thereby influencing brain function. Future studies are needed to rigorously validate these mechanisms and support the development of more targeted and effective therapeutic strategies. Furthermore, SGM methods, such as light therapy and magnetic stimulation, demonstrate significant therapeutic potential for mental disorders; however, further evidence is required to expand the clinical application of physical SGM.

CRediT authorship contribution statement

Yu’ang Liu: Writing – original draft. Linzi Liu: Writing – original draft, Funding acquisition. Zijing Deng: Data curation. Yifang Zhou: Data curation. Li Xiao: Writing – review & editing, Funding acquisition. Yanqing Tang: Writing – review & editing, Funding acquisition.

Biographies

Linzi Liu is a lecturer and psychiatrist in the Department of Psychiatry at Shengjing Hospital, China Medical University. Her research primarily focuses on developing and applying innovative methodologies in the diagnosis and therapeutic interventions for mental health disorders.

Yanqing Tang (BRID: 09620.00.75980) is a professor and chief psychiatrist in the Department of Psychiatry at Shengjing Hospital, China Medical University. Her research primarily focuses on the neuroimaging mechanisms underlying mental disorders and the identification of therapeutic targets.