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Keywords
Stroke
Acupuncture
Neurologic recovery
Rehabilitation
Neurologic dysfunction
1. Introduction
Stroke, resulting from cerebral ischemia and hypoxia, leads to ischemic necrosis or softening and subsequent neurological dysfunction. It is the most prevalent form of cerebrovascular disease globally, accounting for approximately 87 % of all cerebrovascular incidents. Stroke is marked by high rates of morbidity, recurrence, disability, and mortality, contributing to a generally poor prognosis. As a leading cause of neurological impairment and death among the elderly, stroke demands global attention (Hankey, 2017; Wang et al., 2020). The condition not only causes irreversible neuronal damage but also triggers a cascade of pathological events, including energy depletion, excessive glutamate (Glu) release, free radical production, inflammation, and ultimately widespread excitotoxic cell death. This chain of events severely disrupts neuronal network function(Durukan and Tatlisumak, 2007). Following neurological damage, 50–70 % of stroke survivors experience sequelae such as hemiparesis, spasticity, dysphagia, sensory dysfunction, cognitive deficits, hemianopsia, and aphasia, significantly impacting their physical and emotional well-being(Coleman et al., 2017; Hankey, 2017). Consequently, there is a growing focus on identifying effective treatments to ameliorate neurological dysfunction, although current therapeutic options remain limited.
Acupuncture is an ancient Chinese therapeutic technique that entails the insertion of needles into the skin or deep tissues at specific anatomical locations, known as acupoints, to restore homeostasis and prevent and treat disease. It may involve various acupuncture methods or enhanced stimulation via electrical currents, such as motion-style acupuncture or electroacupuncture (Hesketh and Zhu, 1997). Acupuncture has gained widespread use as an effective, low-cost treatment for post-stroke rehabilitation with minimal adverse effects. Clinical and experimental evidence indicates that acupuncture ameliorates post-stroke neurological dysfunction through multiple mechanisms. For instance, acupuncture activates endogenous recovery processes and induces ischemic tolerance responses(Hermann and Chopp, 2012), alongside exhibiting anti-inflammatory(Xu et al., 2021), antioxidant(Wang et al., 2019), and anti-apoptotic properties(Sun et al., 2020). Additionally, it has been shown to significantly promote neurological recovery by enhancing vascular(Wu et al., 2021) and nerve regeneration(Deng et al., 2016) and stimulating the release of neurotrophic factors that offer neuroprotection(Zheng et al., 2020). In the context of post-stroke rehabilitation, acupuncture has demonstrated efficacy in improving hemiparesis(Zheng et al., 2020), spasticity(Lim et al., 2015), dysphagia(Cui et al., 2020), neuralgia(Xu et al., 2020), and cognitive dysfunction(Zheng et al., 2020), Moreover, it has been beneficial in regulating mental and psychological conditions(Hung et al., 2019), with numerous stroke patients exhibiting marked neurological improvement following treatment (Sharififar et al., 2018).
Over the past two decades, significant advancements have been made in the treatment of the hyperacute and acute phases of stroke. Consequently, it is imperative to shift our focus toward interventions that actively promote post-stroke rehabilitation. In clinical post-stroke rehabilitation, modulating neurological recovery through therapeutic techniques such as noninvasive brain stimulation, acupuncture, and task-oriented training is crucial(Hermann and Chopp, 2012; Li et al., 2008). This strategy is predicated on the fact that patients in the acute phase of stroke are infrequently encountered in clinical settings and necessitate urgent care, whereas those in the recovery or sequelae phases exhibit a greater variety of needs. Sequelae are often accompanied by a spectrum of neurological dysfunctions, including motor, swallowing, sensory, and mental and psychological impairments (Fig. 1). This paper systematically reviews the efficacy and mechanisms of acupuncture in improving neurological function during the post-stroke sequelae stage, aiming to identify new therapeutic options for clinical practice.
Fig. 1
2. Motor dysfunction
Motor dysfunction after stroke is typically categorized into abnormal involuntary movements with hyperactivity and those characterized by a paucity or delay in movements, each exhibiting a distinct trajectory. During the acute phase of stroke or the immediate days following the event, dyskinesias commonly manifest as lateralized flaccid paralysis. This initial flaccidity often evolves into lateralized dystonia and spasticity as the condition progresses(Ghika-Schmid et al., 1997).
2.1. Post-stroke hemiparesis
2.1.1. Clinical studies of acupuncture in post-stroke hemiparesis
In the context of post-stroke hemiparesis, a condition characterized by the diminished capacity to control motor functions on the side opposite the cerebral infarction, we observe a prevalent and enduring complication of cerebrovascular accidents. This condition, persisting for durations ranging from weeks to years, significantly impedes the recovery process following a stroke. Clinically, post-stroke hemiparesis is typified by muscular flaccidity, sluggish limb movements, and an overarching inability to adequately control the affected limb for daily activities(Sathian et al., 2011). whose recovery depends to a large extent on the restoration of upper limb motor function, a domain where acupuncture therapy, a Traditional Chinese Medicine (TCM) modality, has been extensively employed(Xu et al., 2018). A clinical trial led by Wang explored the modulation of brain area activation/inhibition through acupuncture using rs-fMRI. This involved assessing inter-subject correlation (ISC) and inter-subject functional correlation (ISFC) in stroke patients. Results indicated that acupuncture at the "GB34" point induced ISFC in various brain regions associated with motor and sensory imagery of upper and lower limbs, hands, face, tongue, and larynx. Notably, this response was more pronounced in the early stages of stroke (within one month) and diminished in the subsequent period (1–3 months)(Wang et al., 2022). In animal models, specifically in the context of the middle cerebral artery occlusion (MCAO) and MCAO + electroacupuncture groups, behavioural changes were quantified using the ladder-rung walking test. Concurrently, rs-fMRI was utilized to delineate the resting state network (RSN) of the brain. The RSN, an ensemble of brain regions that remain active in the absence of explicit tasks or stimuli, has been previously associated with the recuperation of motor function following acute ischemic stroke(Jeong et al., 2012). Following a 7-day electroacupuncture treatment regimen, subjects in the electroacupuncture group demonstrated markedly lower scores in the ladder-rung walking test compared to the MCAO group, indicating enhanced motor function. Furthermore, electroacupuncture substantially augmented activities within four key RSNs: the sensorimotor network (SMN), interoceptive network (IN), default mode network (DMN), and salience network (SN). Notably, within the SMN, increased activity of the corpus callosum on the contralateral side was observed. The IN exhibited heightened activity in the affected side's optic cortex. In the DMN, there was enhanced activity in the ambiguous nucleus of the AcbSh and the contralateral somatosensory cortex. In the SN, significant elevation in motor cortex activity on the contralateral side was recorded. These findings underscore the potential of electroacupuncture in ameliorating motor dysfunction in the affected limb post-stroke, with the SMN, IN, DMN, and SN playing pivotal roles in the treatment's effectiveness(Li et al., 2022).
In another randomized controlled trial (RCT) involving 120 stroke patients, participants were allocated into control and scalp acupuncture groups. The primary outcomes, assessed through manual muscle testing (MMT) and Fugl-Meyer assessment (FMA), focused on restoring muscle strength in the affected limb of hemiplegic patients. After a 2-week treatment period, both groups exhibited improvements in FMA and MMT scores; however, the scalp acupuncture group showed superior results. Additionally, this group demonstrated more significant enhancements in ADL ratings, Barthel Index (BI), and NIHSS scores. These findings suggest that scalp acupuncture can notably improve activities of daily living (ADL) in post-stroke hemiplegic patients by enhancing muscle strength(Wang et al., 2020). Additionally, patients with mild clinical impairment (National Institutes of Health Stroke Scale [NIHSS] scores of 2–4) showed more extensive brain area responses to acupuncture compared to those with moderate-to-severe impairment (NIHSS scores of 5–15), particularly in the contralateral upper and lower limb cortices. These findings highlight the clinical efficacy and modulatory characteristics of acupuncture in post-stroke hemiparesis patients, providing valuable insights for optimizing acupuncture therapeutic regimens(Wang et al., 2022).
2.1.2. Basic research of acupuncture in post-stroke hemiparesis
2.1.2.1. Acupuncture promotes neural circuit remodeling through CST repair
The corticospinal tract (CST) is the principal motor conduction pathway originating from the cerebral cortex, intricately linked either directly or indirectly to spinal cord motor neurons. It serves as a pivotal conduit for neural communication between the brain and the spinal cord, orchestrating the body's voluntary movements. The extent to which an infarct impinges on the CST is intimately associated with a patient's motor function and subsequent recuperative prospects. Research has demonstrated that patients whose CST is minimally involved in or merely adjacent to the infarct zone exhibit comparatively milder clinical manifestations and a more favourable recovery trajectory(Doughty et al., 2016). Conversely, patients with a substantial portion or the entirety of the CST traversing the infarct zone endure more severe motor impairments and face a grimmer prognosis(Kunimatsu et al., 2003). Fostering neuroplasticity within the impaired CST and its regulatory mechanisms might represent a novel therapeutic avenue for addressing post-stroke motor deficits. In this context, Zhang's establishment of a rat model of MCAO is particularly enlightening. This model elucidated that a higher modified Neurological Severity Score (mNSS) – indicative of more profound neurological impairment, including motor dysfunction – was significantly prevalent in the model group. Post-TTC staining revealed conspicuous infarct foci. Intriguingly, the application of electroacupuncture on the "ST36" and "PC6" acupoints led to a notable reduction in both the mNSS and infarct volume compared to the model group. This finding underscores the potential of electroacupuncture treatment in mitigating motor function impairment following a stroke(Zhang et al., 2022).
Moreover, electroacupuncture therapy has been shown to enhance the expression of neuroplasticity-associated proteins, specifically GAP-43 and SYN, in the cerebral cortex. This enhancement promotes axonal sprouting from the CST at cervical levels C1-C4, thus facilitating both cortical neuroplasticity and the regenerative activation of CST axons(Zhang et al., 2022). (Fig. 2) These processes are critical in mitigating motor dysfunction following a stroke. Beyond CST remodelling, acupuncture substantially contributes to neural repair. The fractional anisotropy (FA) metric, derived from MRI, serves as an indicator of nerve fibre density and functionality. Research by Zhao et al. demonstrated that combining scalp acupuncture with low-frequency repetitive transcranial magnetic stimulation significantly increases the FA value in the CST after a stroke(Zhao et al., 2018). This intervention not only promotes CST repair in hemiplegic patients but also improves their neurological and motor functions, as well as their daily living capabilities. Neurotrophic factors, essential for the survival, differentiation, and regeneration of nerve cells post-injury(Markosyan et al., 2020), include pivotal elements such as Nerve Growth Factor (NGF)(Li et al., 2017), Brain-Derived Neurotrophic Factor (BDNF) (Park et al., 2020), Ciliary Neurotrophic Factor (CNTF) (Jin et al., 2015), and Glial cell line-Derived Neurotrophic Factor (GDNF) (Zhang et al., 2019). Remarkably, electroacupuncture treatment at the "GB30" point has been demonstrated to increase BDNF expression in motor neurons on the paralyzed side in rats with unilateral CST injury. This elevation in BDNF correlates with compensatory axonal growth, functional recovery of the impaired limb, and changes in the pattern of BDNF expression. This suggests that electroacupuncture augments CNS plasticity through BDNF upregulation, enabling contralateral axons to sprout across the median line and form new neural connections with the paralyzed side. Such mechanisms effectively reconstruct neural circuits and restore function in the affected limb(Zhu et al., 2022).
Fig. 2
2.1.2.2. Acupuncture modulates neuronal excitability to improve muscle tone
Following a cerebrovascular insult, the muscular system contralateral to the cerebral lesion exhibits distinct pathophysiological characteristics, primarily characterized by flaccid hemiparesis and spasticity(Sheffler and Chae, 2015). Flaccid hemiparesis, defined by muscular paralysis and laxity opposite the site of the cerebral lesion, is marked by reduced muscle strength. This condition leads to atypical postures, impaired muscle extension, and a deficit in voluntary movement control (Mehta et al., 2012). Clinically, the Hmax/Mmax ratio, indicative of the proportion of reflexively activated motor units and reflecting the excitability of motor neurons in the anterior horn of the spinal cord, is routinely utilized to gauge motor neuron excitability in hemiplegic patients(Ansari and Naghdi, 2007; Schieppati, 1987). This ratio correlates with changes in muscle tone in these patients. Clinical observations have shown that hemiplegic patients with increased Hmax/Mmax ratios following acupuncture treatment experience reduced or normalized muscle tone. In contrast, those with decreased ratios demonstrate a mild increase or normalization in muscle tone. These results suggest that acupuncture may exert a bidirectional regulatory effect on muscle tone in hemiplegic patients, highlighting its potential therapeutic value in the neuromuscular rehabilitation of stroke survivors(Du et al., 2016)(Fig. 2).
2.2. Post-stroke spasticity (PSS)
2.2.1. Clinical studies of acupuncture in PSS
PSS is one of the major complications after stroke, which can lead to debilitating symptoms such as pain, compromised posture, mobility challenges, limited range of motion, and hygiene issues(Huang et al., 2023). In clinical settings, the management of PSS encompasses a spectrum of interventions ranging from nonpharmacologic and pharmacologic strategies to invasive neurosurgical procedures(Winstein et al., 2016). Most clinical guidelines advocate for nonpharmacological interventions, such as stretching and splinting, particularly for mild manifestations of PSS(Rodgers et al., 2021). Botulinum toxin-A injections are commonly employed for moderate to severe cases. However, the efficacy of these injections is temporally limited to 2–3 months and is accompanied by constraints, including high costs and potential systemic side effects like muscle flaccidity, lethargy, and cognitive impairments(Lindsay et al., 2014). Acupuncture, a component of TCM, presents itself as a novel alternative therapeutic modality. Clinical studies have demonstrated its efficacy in enhancing muscle strength(Yan and Hui-Chan, 2009) and mitigating spasticity(Zhao et al., 2009), thereby significantly improving motor function in post-stroke patients. In an RCT, 60 patients suffering from post-stroke lower limb spasticity were randomly assigned to one of three groups: a combination of electroacupuncture and biofeedback, a standalone biofeedback group, and a rehabilitation therapy group. Over a six-week treatment period, patients exhibited notable improvements in lower limb functionality, as quantified by FMA scores and muscle strength ratings of the affected anterior tibialis muscles. All three groups, including the electroacupuncture with biofeedback, standalone biofeedback, and rehabilitation therapy groups, showed increased FMA scores and muscle strength, coupled with decreased clinical spasticity index (CSI) scores post-treatment. Notably, the improvements in the electroacupuncture + biofeedback and biofeedback groups surpassed those observed in the rehabilitation therapy group. In terms of functional mobility, enhancements in step frequency and speed were noted across all groups. Additionally, the maximum dorsiflexion and plantarflexion angles of the affected ankle joints improved post-treatment, with the electroacupuncture + biofeedback group exhibiting the most significant therapeutic impact(Huang et al., 2022). These findings underscore acupuncture's efficacy in ameliorating both lower and upper limb spasticity. Further corroborating the effectiveness of acupuncture, another study involving 66 PSS patients compared the outcomes of a rehabilitation therapy group and a combination group receiving both rehabilitation therapy and acupuncture. After a 4-week intervention, both groups showed positive effects on PSS, as evidenced by reduced Modified Ashworth Scale (MAS) scores, decreased Glu levels, and increased FMA scores, BI scores, and γ-aminobutyric acid (GABA) levels. However, the combined therapy group demonstrated superior results in the between-group comparison(Zhang et al., 2023). Additional research, such as the study by Qi et al., highlights the impact of treatment sequencing or combination. After six months, significant improvements in muscle hypertonicity and motor function were observed across all treatment groups, including rehabilitation alone, scalp acupuncture with rehabilitation, and head acupuncture groups; the group receiving scalp acupuncture in conjunction with rehabilitation therapy showed the most pronounced efficacy(Qi et al., 2018).
2.2.2. Basic research of acupuncture in PSS
2.2.2.1. Acupuncture maintains homeostasis by modulating neurotransmitter expression
The pivotal role of neurotransmitters in modulating stroke-induced neurogenesis has been comprehensively delineated in contemporary research(Fricker et al., 2018; Kasaragod et al., 2022; Liu et al., 2022). This equilibrium at both cellular and neural network levels is quintessential for the brain's effective processing of information, subsequently orchestrating cognitive and behavioural functions. (Zhou and Yu, 2018). Among these neurotransmitters, the excitatory neurotransmitters - Glu and the inhibitory neurotransmitters - GABA are particularly noteworthy for their integral roles in modulating brain behavioural functions, influencing a spectrum of motor skills ranging from basic locomotion to intricate tasks such as writing. Their significance has been increasingly recognized in stroke research(Liu et al., 2023; Manto et al., 2012; Paparella et al., 2023). Recent studies have elucidated that, in the context of a stroke, interventions such as acupuncture can catalyze the release of GABA while concurrently mitigating the neurotoxicity of Glu. This dual action effectively curtails neuronal cell death and ameliorates neurological dysfunctions(Zhang et al., 2011). In MCAO rats, acupuncture notably decreased the neurological deficit score (Zea Longa score) and muscle tone in the affected limbs. The potential mechanism underlying this effect involves a reduction in type I muscle fibres in the spastic muscles and alterations in neurotransmitters in the brainstem, including GABA, GABA_Aγ2, and GABA_A receptors(Sun et al., 2022). A seminal study by Liu demonstrated that acupuncture treatment, specifically at the "GV26" acupoint, can preserve neurotransmitter homeostasis post-stroke. This intervention notably diminished the excessive release of Glu in the cerebrospinal fluid compared to control models while sustaining the endogenous inhibitory prowess of GABA, thereby imparting a neuroprotective shield against stroke-induced injuries(Liu et al., 2019). Another study highlighted that targeting the "DU14," "BL26," and "RN12" acupoints in MCAO rats resulted in a marked decrease in Glu expression in the brainstem, coupled with an upregulation of GABA expression (Fig. 2). This intervention notably ameliorated the spasticity in stroke-affected limbs by improving muscle tone, underscoring the therapeutic potential of neurotransmitter modulation in stroke recovery(Liu et al., 2014).
2.2.2.2. Acupuncture adjusts muscle fiber ratio to improve muscle tone
It is crucial to recognize that PSS extends beyond neurological disturbances to encompass structural muscular alterations. These changes include an increased proportion of connective tissue, a reduction in muscle segment numbers, and a contraction in their lengths(Trompetto et al., 2014). The muscle contralateral to the lesion after stroke may show flaccid hemiparesis in the early stages of the disease; as the condition progresses, there is a loss of the muscle's adaptive length-tension relationship, which can precipitate spasmodic episodes(Li, 2017).
The development of spasticity is commonly associated with an increased proportion of type I muscle fibres (Ito et al., 1996). The use of standard muscle relaxants, such as botulinum toxin-A, has been effective in reducing excessive muscle tone, primarily through the decrease of type I muscle fibres in the gastrocnemius, thus enhancing the prevalence of type II muscle fibres in individuals with post-stroke spasticity(Valentine et al., 2016). In animal research, studies conducted by Sun et al. have demonstrated that acupuncture treatment can mimic the effects of muscle relaxants by reducing type I muscle fibres in the gastrocnemius muscle, significantly improving muscle structure and reducing spasticity in rats afflicted with post-stroke spasticity(Sun et al., 2022)(Fig. 2). Clinically, musculoskeletal ultrasound technology has recently become prominent in evaluating spasticity post-stroke. Its capability to display musculoskeletal parameters objectively reflects the morphology of spastic muscles, including pennation angle (PA), fascicle length (FL), and muscular thickness (MT). Lin et al. found significant increases in PA, FL, and MT on the affected side following acupuncture treatment compared to pre-treatment values, with improvements surpassing those seen in the rehabilitation training group(Lin et al., 2020).
In summary, the main mechanisms of acupuncture for post-stroke motor dysfunction in either hemiparesis or spasticity involve the promotion of CST neural remodelling, modulation of neuronal excitability and muscle structure, and maintenance of neurotransmitter homeostasis (Fig. 2).
3. Dysphagia
"Dysphagia" is clinically characterized as an impediment in the passage of liquids or pills from the oral cavity to the oesophagus. Among neurological etiologies, stroke is the foremost cause of dysphagia, with symptoms often manifesting as diminished pharyngeal propulsive pressure, aberrant upper oesophagal sphincter relaxation pressure, or a combination thereof(Lan et al., 2015; Lee et al., 2017). Typically emerging within the initial 2–4 weeks post-stroke, the prevalence of post-stroke dysphagia (PSD) has been reported to reach as high as 80 %(Mourao et al., 2016). Recent data indicate an escalation in the incidence of mild dysphagia, now affecting up to 91 % of stroke patients, thereby underscoring its status as the most common post-stroke complication and necessitating heightened clinical awareness(Falsetti et al., 2009).
3.1. Clinical studies of acupuncture in PSD
Current understanding, based on previous research, suggests that PSD results from damage to cortical and subcortical structures in the brain, with cortical reorganization playing a crucial role in the restoration of swallowing function. Insights from transcranial magnetic stimulation (TMS) studies reveal that the pharyngeal musculature is represented bilaterally yet asymmetrically in the cortex(Hamdy et al., 1996). Consequently, stroke lesions affecting the "dominant swallowing hemisphere" can lead to unilateral hemispheric PSD, as documented in the seminal work of Leder, (1998). Moreover, comparative analyses of stroke patients have demonstrated that non-dysphagic individuals with post-cerebral hemisphere stroke exhibit more pronounced pharyngeal cortical activity in the contralateral cerebral hemisphere relative to their dysphagic counterparts(Leder et al., 1998). This distinction underscores the complexity of neurophysiological changes in stroke and their direct impact on swallowing functions, thereby highlighting the need for tailored therapeutic approaches to address this prevalent and consequential post-stroke complication(Hamdy et al., 1998). These results highlight the pivotal role of contralateral cerebral cortex reorganization in the recuperation of swallowing function post-stroke. An RCT investigating this phenomenon utilized a combination of TMS and electromyography to assess the resting motor threshold (RMT) and motor-evoked potentials (MEP) of the hyoid bone in subjects. The study revealed that electroacupuncture at the "RN23" and "DU16" points markedly diminished bilateral RMT and concurrently increased the latency and wave amplitude of bilateral MEP. These findings indicate that EA can instantaneously augment the excitability of the bilateral swallowing motor cortex, thereby enhancing PSD recovery(Tang et al., 2022). In patients with PSD following cortical hemisphere injury, acupuncture treatment has been demonstrated to facilitate recovery, ameliorate swallowing dysfunction, and enhance overall quality of life. A significant statistical difference was observed between the mean baseline scores of The Royal Brisbane Hospital Outcome Measure for Swallowing (RBHOMS) and the scores at the end of the treatment period (p≤0.006). Additionally, a noteworthy difference was found between the pre-treatment RBHOMS scores and those recorded upon completion of the treatment (p≤0.042). Furthermore, the Chinese version of the Swallow Quality-of-Life Questionnaire (CSWALQOL) was employed for a pre-and post-treatment analysis, registering a significant improvement in the swallowing quality-of-life scores following acupuncture treatment (p < 0.01)(Chan et al., 2020). These outcomes collectively underscore the efficacy of acupuncture in the rehabilitation process of PSD, particularly in patients with cortical hemisphere injuries, and its potential to significantly improve both functional outcomes and patient well-being.
3.2. Acupuncture improves PSD through two neural conductions
3.2.1. Acupuncture improves PSD from motor nerve conduction
The efficacy of acupuncture in modulating cerebral cortex activity has been substantiated in PSD model rats. The downstream motor nerve conduction essential for voluntary swallowing primarily originates from the primary motor cortex (M1). Electroacupuncture treatment at the "RN23" point was observed to enhance the local field potential of M1 in the non-infarcted hemisphere. This stimulation activates neurons integral to swallowing function, particularly pyramidal cells, thereby augmenting motor conduction for voluntary swallowing in the non-infarcted area. Consequently, there is an improvement in blood flow to M1 and the swallowing muscles on the non-infarcted side. This is accompanied by an increase in motor conduction velocity (MCV) of the hypoglossal nerve, enhancement of the electromyography signals of the mandibuloglossus muscle, reduction in the paralysis of swallowing muscles, the release of substance P, and restoration of the ability to drink water. Furthermore, electroacupuncture promotes functional compensation in the non-infarcted M1, enhancing the excitability of the hypoglossal nerve and contributing to the autonomic control of swallowing, thereby ameliorating symptoms of PSD(Ye et al., 2023). A recent study has identified a cluster of excitatory neurons in layer 5 of M1, which, in mice, regulate swallowing function by modulating hyoid muscle activity. Focal ischemia in M1 was found to mirror the pathological manifestations of PSD, characterized by diminished drinking ability and impaired electromyographic response of the hyoid muscle. Post-electroacupuncture intervention, significant activation was noted in the excitatory neurons of layer 5 of M1 in the contralateral hemisphere. Additionally, neurons in the parabrachial nucleus (PBN) and the nucleus of the solitary tract (NTS), both influenced by M1, were also significantly activated(Yao et al., 2023).
3.2.2. Acupuncture improves PSD from sensory nerve conduction
The aforementioned research primarily focused on the motor nerve conduction effects of electroacupuncture on the motor cortex-hypoglossal nerve pathway in a PSD animal model without delving into the upstream sensory nerve conduction dynamics. To bridge this gap, Yuan embarked on a study to elucidate the impact of electroacupuncture on sensory nerve conduction. Employing a PSD model in rats, the study revealed that electroacupuncture treatment notably enhanced blood perfusion and neuronal activity within the primary sensory cortex (S1) area. This augmentation in S1 activity corresponded with a significant improvement in the swallowing function of the rats. A critical element in this sensory nerve conduction pathway is the transient receptor potential channel vanilloid subfamily 1 (TRPV1), predominantly expressed in sensory neurons. Post-electroacupuncture treatment, an up-regulation in TRPV1 expression and blood perfusion was observed near the acupuncture point "RN23." However, in mice exhibiting diminished TRPV1 function, a decrease in blood perfusion at the "RN23" point was noted, yet there were no substantial changes in the blood perfusion and neuronal activity in the S1 area. These findings suggest that while electroacupuncture may enhance PSD recovery by activating sensory nerve conduction, the role of TRPV1 near the "RN23" point appears to be primarily confined to regulating local blood perfusion, not extending to the transmission of electroacupuncture signals to the central nervous system (CNS)(Yuan et al., 2023). Collectively, these studies corroborate that compensatory cortical function on the contralateral side is pivotal for improving swallowing function in rats with PSD. Furthermore, they substantiate the theory that acupuncture's efficacy in PSD amelioration extends beyond motor nerve conduction to include sensory pathways. This dual pathway involvement offers a comprehensive and necessary experimental foundation for the neuromodulatory application of acupuncture in treating PSD in clinical settings. (Fig. 3)
Fig. 3
4. Sensory dysfunction
Post-stroke pain (PSP), a frequently encountered and challenging sequela of cerebrovascular accidents, is often characterized by "severe, persistent, paroxysmal, and often intolerable pain on the lesion's side, which remains refractory to conventional analgesic therapies(Langhorne et al., 2000)." PSP's underlying pathophysiological mechanisms are multifaceted, encompassing both neuropathologic and injurious aspects. This complexity is further reflected in its common subtypes: central post-stroke pain (CPSP) and hemiplegic shoulder pain (HSP) (Widar et al., 2002). Understanding the nuanced mechanisms and clinical presentations of these subtypes is crucial for developing effective strategies to manage and alleviate PSP, thereby enhancing patient care and quality of life in the post-stroke period(Hansen et al., 2012).
4.1. CPSP
CPSP is a neuropathic pain syndrome originating from stroke-induced widespread lesions in the central somatosensory system, encompassing the brain, brainstem, and spinal cord(Andersen et al., 1995; Blasi et al., 2015). CPSP manifests as sudden, transient, and intense neuropathic pain, frequently described as burning, throbbing, or tingling, predominantly affecting the side of the body impacted by the stroke(Canavero and Bonicalzi, 1998).In clinical practice, CPSP is conventionally managed with pharmacological interventions, including analgesics, antidepressants, and anticonvulsants. However, these medications often present challenges such as resistance and potential for addiction(Doshi et al., 2021). Acupuncture, noted for its simplicity, minimal invasiveness, and low cost, has been reported to match the efficacy of oral carbamazepine in treating CPSP, offering significant analgesic effects with fewer side effects(Xu et al., 2020). In their research, Ma et al. developed a rat model of CPSP by injecting cobra venom into the ventral posterior lateral nucleus (VPL) and utilized "LI11" and "LI10" as acupuncture points. After 21 days of electroacupuncture treatment, a notable increase in the mechanical pain threshold of the rats was observed. Transcriptomic analysis linked electroacupuncture treatment with the modulation of the oxytocin signalling pathway, cAMP signalling pathway, and GABA synaptic pathway in CPSP model rats(Ma, B.F. et al., 2022). ADCY1, identified as a key target in chronic pain management, was found to be intricately associated with these pathways(Zhuo, 2012)(Fig. 4). Notably, ADCY1 expression was significantly elevated in the CPSP group compared to the sham group, with electroacupuncture intervention effectively reversing this alteration(Ma, B.F. et al., 2022). Moreover, studies have highlighted the crucial role of neuronal cell apoptosis and abnormal astrocyte activation in CPSP pathogenesis(Chiang et al., 2012). Tian et al. discovered that electroacupuncture could attenuate pain by inhibiting neuronal cell apoptosis and abnormal astrocyte activities, with different electroacupuncture frequencies eliciting distinct mechanisms. Specifically, 2 Hz low-frequency electroacupuncture effectively reduced neuronal apoptosis, while 15 Hz high-frequency electroacupuncture curbed abnormal astrocyte activation, outperforming the fluoxetine group in efficacy. These insights may pave the way for novel therapeutic approaches in the clinical management of CPSP, broadening the horizon of neuropathic pain treatment strategies(Tian et al., 2016).
Fig. 4
4.2. HSP
HSP predominantly manifests on the side of the body impacted by the stroke. The research identified two principal mechanisms that contribute to the development of HSP: frozen shoulder and shoulder subluxation. A frozen shoulder, characterized by restricted shoulder motion often secondary to PSS, leads to stiffness and pain during movement. Shoulder subluxation, often resulting from muscle flaccidity or reduced muscle tone on the lateral aspect of the shoulder, causes the muscles supporting the joint to weaken. This weakening hinders the ability to maintain the humeral head within the glenoid fossa of the shoulder socket(Razaq et al., 2016). While oral analgesics remain the primary treatment modality for HSP, their long-term usage is marred by various side effects, including gastrointestinal reactions, bleeding, and potential addiction. In contrast, acupuncture, traditionally considered a second-line treatment, has garnered attention in numerous clinical studies for its substantial pain-relieving effects, particularly in managing post-stroke shoulder subluxation and lateralized shoulder pain(Lin et al., 2022; Noor et al., 2022). The proposed mechanisms of acupuncture’s efficacy encompass the amelioration of shoulder adhesions, enhancement of muscle strength, and reduction of shoulder tension, thereby alleviating HSP(Chen et al., 2000; Li et al., 2012). An RCT involving 34 HSP patients assessed the impact of electroacupuncture versus sham electroacupuncture. After a two-week treatment regimen, both groups exhibited significant reductions in pain intensity, as measured by the Visual Analog Scale (VAS). However, the electroacupuncture group demonstrated superior efficacy in pain alleviation. Musculoskeletal ultrasound evaluations indicated notable reductions in shoulder subluxation indices in both groups, including measurements of the acromiohumeral distance (AHD), acromion-greater tuberosity (AGT), and acromion-lesser tuberosity (ALT)(Fig. 4). Despite these improvements, no significant difference was observed between the electroacupuncture and sham electroacupuncture groups(Sui et al., 2021). These findings echo previous research underscoring acupuncture’s beneficial role in HSP management, including improvements in pain thresholds and shoulder function(Itoh et al., 2014). A recent study further reinforced these outcomes, illustrating the electroacupuncture group’s superiority over the electrical interferential current stimulation (IFC) group in terms of pain intensity reduction and some improvement in shoulder mobility(Eslamian et al., 2020). Collectively, these studies highlight acupuncture’s potential as a viable and effective alternative for HSP treatment, offering a promising avenue for patients seeking relief from this debilitating post-stroke condition.
5. Multifaceted dysfunctions in post-stroke patients
A considerable segment of individuals who have experienced a stroke encounter not only physical impairments but also crucial mental and psychological sequelae. Approximately 20 %-30 % of these patients grapple with conditions such as post-stroke depression, post-stroke cognitive impairment (PSCI), and post-stroke aphasia (PSA). These conditions profoundly diminish the quality of life for stroke survivors and pose a significant challenge in the realm of stroke treatment. This underscores the need for a holistic approach that addresses both the physical and psychological ramifications of this cerebrovascular event(Douiri et al., 2013; Thiel and Zumbansen, 2016).
5.1. Post-stroke depression
Post-stroke depression emerges as the most prevalent and onerous psychiatric complication following a cerebrovascular event(Taylor-Rowan et al., 2019). To advance the understanding and therapeutic approaches for post-stroke depression, recent investigations have concentrated on its underlying mechanisms(Robinson and Jorge, 2016). Emerging studies suggest that the development of post-stroke depression might be associated with reduced levels of monoamine neurotransmitters (such as serotonin, norepinephrine, and dopamine), aberrant neurotrophic responses, inflammatory activation stemming from hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and glutamatergic-mediated excitotoxicity. These insights pave the way for more nuanced and effective treatment strategies for post-stroke depression(Loubinoux et al., 2012; Medeiros et al., 2020). The integration of acupuncture into the therapeutic landscape for post-stroke depression has garnered increasing attention, with studies indicating its potential to modulate the pathophysiological mechanisms underlying post-stroke depression(Hung et al., 2019; Zhang et al., 2020b). An RCT revealed that electroacupuncture significantly ameliorated various clinical indices, including the Hamilton Rating Scale for Depression (HRSD), Zung Self-Rating Depression Scale (SDS), NIHSS, BI, and TCM scores. Notably, the efficacy of electroacupuncture appeared to be directly proportional to the duration of treatment, underscoring its benefits not only in alleviating depressive symptoms but also in improving ADL(Cai et al., 2022). In an animal model investigation, Sun et al. established a rat model of post-stroke depression through a combination of MCAO and chronic unpredictable mild stress. Targeting acupuncture points "GV20", "GV26", "GV24", and "DU14", the study observed significant enhancements in depression-like behaviours in rats post-28 days of treatment, as evidenced by the sucrose water consumption experiment and the open-field test. Intracranially, acupuncture markedly reduced neuronal ultrastructural damage in the CA1 area of the hippocampus and elevated levels of norepinephrine, serotonin (5-HT), and dopamine(Sun et al., 2019). These findings substantiate the link between monoamine neurotransmitters and post-stroke depression and suggest that acupuncture can ameliorate post-stroke depression symptoms by augmenting the expression of these neurotransmitters. Further research focusing on the "Si Guan" acupoint in electroacupuncture treatment demonstrated parallels in antidepressant efficacy between electroacupuncture and fluoxetine. Both interventions significantly increased the hippocampal expression of BDNF and its receptor TrkB after 21 days, hinting at a shared mechanism involving the activation of neurotrophic pathways(Kang et al., 2021). Moreover, the role of oxidative stress and inflammation in post-stroke depression pathogenesis has been highlighted. Cai et al. demonstrated that electroacupuncture notably attenuated the expression of pro-inflammatory cytokines like IL-6 and TNF-α while enhancing glutathione (GSH) levels for its antioxidative action. Concurrently, electroacupuncture uplifted 5-HT expression and improved depression-like behaviours in animal models, reinforcing the antidepressant efficacy of electroacupuncture. This points to a mechanism where electroacupuncture exerts its therapeutic effects by mitigating inflammation and oxidative stress in post-stroke depression(Cai et al., 2019).
5.2. PSCI
PSCI is a neurological condition characterized by cognitive deficits that emerge or become apparent 3–6 months post-stroke, distinct from any pre-existing cognitive decline(Rost et al., 2022). PSCI is typically marked by diminished capabilities in abstract reasoning, memory, and orientation. Currently, the therapeutic landscape for PSCI remains narrow, with no specifically approved medications(Alawieh et al., 2020; Stuckey et al., 2021). While some drugs used in Alzheimer’s disease (AD) and vascular dementia treatment, such as cholinesterase inhibitors (e.g., donepezil), have shown promise, conclusive evidence for their effectiveness in PSCI is still lacking(Battle et al., 2021; Blennow et al., 2006). Intriguingly, recent investigations suggest that acupuncture, particularly at points innervated by the trigeminal nerve, may modulate cognitive functions(Zhang et al., 2020a). In a study by Zheng, electroacupuncture was applied to two scalp acupoints, "EX-HN3" and "GV20," connected to the trigeminal nerve. The study evaluated spatial learning and cognitive memory in rats using the Morris water maze and the novel object recognition test. Over a 14-day treatment period, rats in the MCAO group exhibited prolonged time to locate the platform during the Morris water maze training and decreased time spent in the target quadrant during the probe trial compared to the control group. In the novel object recognition test, the MCAO group showed a negative discrimination index. However, the electroacupuncture group demonstrated a reversal of these impairments in both tests, suggesting a potential therapeutic avenue for PSCI.
Recent studies have illuminated the potential of electroacupuncture in mitigating cognitive deficits associated with stroke, particularly in spatial learning, memory abilities, and recognition functions(Zheng et al., 2020). Notably, electroacupuncture targeting the "GV20" and "DU24" acupoints has been shown to substantially ameliorate cognitive dysfunction in MCAO rat models. Following cerebral ischemic injury, the CA1 region of the hippocampus in rats displayed pronounced inflammation, aligning with the understanding that neuroinflammation contributes to cognitive dysfunction. Electroacupuncture treatment significantly inhibited the expression of pivotal inflammatory pathway proteins, including NF-κB, along with its downstream elements, such as IL-1, TNF-α, iNOS, and COX-2(Lin et al., 2023). This suggests that electroacupuncture's improvement of cognitive dysfunction post-stroke may be attributed to its suppression of hippocampal inflammation. Furthermore, disruptions in cerebral energy metabolism, encompassing anomalies in cerebral blood circulation, mitochondrial oxidative metabolism, and glucose utilization, are recognized as key factors impacting PSCI(Camandola and Mattson, 2017). Studies have indicated that acupuncture can beneficially influence these pathways by significantly augmenting intracortical cerebral blood flow(Ma et al., 2020). It also enhances mitochondrial bioenergetic parameters, including the mitochondrial respiratory control rate and membrane potential, boosts the activity and expression of hippocampal mitochondrial respiratory complex enzymes (complexes I, II, and IV), and attenuates oxidative stress injury(Li et al., 2016). Additionally, acupuncture has been observed to increase activities of hexokinase, pyruvate kinase, and glucose 6-phosphate dehydrogenase in the brain, thereby enhancing glucose metabolism(Zhao et al., 2011). Synaptic plasticity, the foundation of neural network learning and memory, is often compromised following a stroke, leading to synaptic signalling and structural damage, which results in cognitive decline and memory impairment(Murphy and Corbett, 2009). Research conducted by Ma demonstrated that acupuncture could mitigate synaptic damage post-stroke. This is achieved by increasing the number of synapses, restoring synaptic morphology, structure, and transmission, and enhancing synaptic plasticity, thus alleviating cognitive impairments associated with stroke(Ma et al., 2022).
5.3. PSA
Aphasia, an acquired impairment of language abilities following brain injury, specifically denotes a disorder in language processing at various levels, including morphological, phonological, syntactic, or lexical-semantic(Cichon et al., 2021). Approximately 30 % of stroke patients develop aphasia, predominantly in the brain's dominant hemisphere (for instance, the left cerebral hemisphere in right-handed individuals), where language functions are typically localized(Fridriksson and Hillis, 2021). Despite the diverse treatment modalities available for PSA, such as pharmacotherapy, behavioural interventions, and stimulation techniques(Cichon et al., 2021), acupuncture has emerged as a prevalent therapeutic option(Zhang et al., 2021). It has demonstrated significant improvements in various facets of verbal function, including abilities in repetition, speaking, reading, comprehension, and writing(Tang et al., 2019). To further understand the neural underpinnings of acupuncture's efficacy in PSA, researchers have employed rs-fMRI to assess changes in brain functionality pre- and post-acupuncture. Studies by Xiao and others have revealed that electroacupuncture elicits notable activations in regions spanning the frontal, temporal, parietal, and limbic systems. Remarkably, the brain activation patterns induced by electroacupuncture closely align with those triggered by image-naming tasks(Xiao et al., 2016). This includes significant activity in the left inferior frontal gyrus (Broca's area), a crucial region implicated in verbal fluency and the organization of verbal expression. These findings underscore the potential of electroacupuncture in re-engaging and possibly rehabilitating language processing circuits impaired by stroke(Li et al., 2018).
In the realm of PSA treatment, recent investigations have unearthed compelling insights into the effects of acupuncture on brain connectivity and neuroplasticity. Xu's research notably illuminated that during electroacupuncture stimulation of the "HT05" and "GB39" points, there is an increased frequency of dynamic connections among the cerebellar, default mode, and language networks compared to baseline rest. These intricate networks are recognized for their pivotal roles in an array of language and cognitive functions(Xu et al., 2022). Delving deeper into the molecular mechanisms underlying PSA, studies suggest that functional recovery in patients is intricately linked to neuroplasticity. This encompasses the recovery and reorganization of residual neural networks within the damaged brain regions, as well as the compensatory mechanisms involving neural pathways or mirror regions of language function in the hemisphere contralateral to the infarct(Stefaniak et al., 2020; Xing and Bai, 2020). Acupuncture has been shown to counteract apoptosis in neuronal cells within the hippocampus of the affected brain regions, thereby reducing secondary neuronal cell damage and promoting the repair of damaged neurons, suggesting a cerebroprotective role of acupuncture[(Ye et al., 2017). Moreover, acupuncture positively influences synaptic plasticity. This is achieved through the activation of the brain-derived neurotrophic factor (BDNF)/TrkB signalling pathway(Pei et al., 2021) and by elevating acetylcholine levels in the contralateral brain hemisphere. It also promotes NMDA delivery to glutamatergic and dopaminergic cells and induces long-term potentiation (LTP), further substantiating its therapeutic potential in the rehabilitation of PSA(Chavez et al., 2017; Lin and Hsieh, 2010).
6. Summary of main acupoints
Stroke can lead to a variety of sequelae, including motor disorders, swallowing disorders, sensory disorders, as well as psychiatric and psychological disorders. This review summarizes the commonly used acupoints for the various dysfunctions associated with stroke (Table 1). Motor Dysfunction: "ST36" and "GB34" are the main points used for acupuncture or electroacupuncture. Additionally, scalp acupuncture targeting the bilateral anterior parietal-temporal oblique region is commonly employed. The parietal anterior temporal oblique region shows clear therapeutic effects on central limb motor dysfunction, with "ST36" and "GB34" often used to treat muscle flaccidity in the lower limbs. These acupoints are effective for opening the meridians, activating collaterals and muscles, soothing tendons, and facilitating joint movement. The mechanism involves improving muscular structure, promoting neural remodelling, and enhancing brain functional connectivity. Swallowing Dysfunction: The primary treatment point is "RN23" on the renal vessel. "RN23" is used for dysphagia, aphasia, loss of voice, hoarseness, and other pharyngeal and stomatognathic disorders. Its therapeutic effect is achieved by improving the swallowing response signal and localized blood flow in the cortex. Sensory Dysfunction: Sensory dysfunction is divided into central and shoulder pain. There are fewer studies on central pain due to the non-specific nature of the pain location, leading to a lack of specific acupoints. Shoulder pain is mainly treated using local acupoints "TE14" and "LI15." These points relieve pain by dredging the meridians and channels of the shoulder and activating blood circulation. They are effective in treating paralytic conditions such as shoulder and arm pain, upper limb paralysis, and shoulder joint contracture. Additionally, they play an analgesic role, strengthen muscular structure, and prevent shoulder joint dislocation. Mental and Psychological Disorders: "GV20" is used as the point for the governor-vessel meridian due to its role in governing the brain, considered the house of the original spirit. The Du meridian enters the collaterals and brain, and acupuncture at "GV20" helps wake up the brain and open the mind. "GV20" is a high-frequency point for treating depression and cognitive disorders. It significantly improves the inflammatory response and metabolic disorders in the brain and maintains the integrity of the hippocampus and white matter areas. The heart meridian, primarily treating cardiothoracic and psychosomatic disorders, utilizes "HT05" for conditions like aphasia, dysarthria, and hoarseness. "HT05" plays a key role in improving language function by activating Broca's area and facilitating the dynamic connectivity of the neural-linguistic network. These therapeutic strategies highlight the multifaceted role of acupuncture in addressing the diverse sequelae of stroke, offering targeted interventions that improve functional outcomes and enhance the quality of life for stroke survivors.
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