Comment on “Invasive or non-invasive vagus nerve stimulation modulation of brain function and remodeling after stroke: a review”

Dear Editor, Stroke is a type of acute cerebrovascular disease, which is a group of diseases resulted from an abrupt rupture or blockage of blood arteries in the brain, which prevents blood flow to the brain and damages brain tissue. Atrial fibrillation, hypertension, diabetes, dissections, atherosclerosis, as well as other conditions are some of the major risk factors for stroke. Stroke can cause facial asymmetry, numbness in the limbs, loss of speech, and loss of coordination or balance. It primarily affects older and middle-aged people. Neurological abnormalities are the primary factors preventing stroke victims from reintegrating into society. The potential benefits of vagus nerve stimulation (VNS) for maintaining progress in neurological impairments are particularly intriguing. In order to determine research gaps in the field, clarify the mechanisms, and exhibit the safety and effectiveness of the therapeutic use of VNS, Zhang et al1 compiled the available data. They revealed that the VNS is a potentially effective treatment strategy for stroke rehabilitation (Table 1). Future research should focus on the use of VNS in treating hemorrhagic stroke, as it is currently unexplored. Table 1 - Summary of clinical studies applying non-invasive VNS in stroke populations. Author, year Design Stroke types Sample sizes Age Onset time Interventions Outcomes (EG, CG) (EG, CG) (EG, CG) Capone, 2017 RCT IS, ICH 7, 5 53.71 ± 5.88, 55.60 ± 7.12 93.71 ± 38.81 d, 46.00 ± 21.85 d Groups: taVNS + robotic therapy and sham; site: left external acoustic meatus at the inner side of the tragus; stimulator: electric stimulator (Twister—EBM) and two Ag-AgCl electrodes (5 mm in diameter); parameters: pulse frequency 20 Hz, duration 0.3 ms, repeated 5 min for 60 min. No adverse events; FMA scores were significantly better in the real group as compared to the sham group. Baig, 2019 - IS 12 64.2 ± 7.1 1.29 0.7–3.4, years (IQR) Groups: taVNS + upper limb training; site: left ear concha; stimulator: taVNS earpiece (NEMOS, Cerbomed); parameters: pulse width 0.1 ms, pulse frequency 25 Hz, pulse amplitude as maximally tolerated by the participant Improved sensory and motor function. Wu, 2020 RCT IS 10, 11 64.50 ± 9.97, 61.82 ± 10.63 36.30 ± 9.23 d, 35.55 ± 6.47 d Groups: taVNS and sham; site: left cymba concha; stimulator: taVNS (Bohua, Weihai, China); parameters: 600 pulses, pulse frequency 20 Hz, duration 0.3 ms, lasting 30 s, every 5 min. One case of skin redness; Significant improvements in upper limb motor function in the taVNS group. Chang, 2021 RCT IS, ICH 18, 18 59.02 ± 1.98 2.16 ± 0.39 years Groups: taVNS + robotic therapy and sham; site: left cymba conchae; stimulator: taVNS (Feinstein Institutes for Medical Research and the MIDI Product Development Corporation); parameters: current intensity 0.1–5.0 mA, single500 ms bursts, frequency 30 Hz, pulse width 0.3 ms. Well-tolerated and no serious adverse events; Robot training improved the motor capacity of both groups, and taVNS, decreased spasticity. Arsava, 2022 RCT IS, ICH 44, 25 71.0 ± 14.0, 71.0 ± 11.0 4.3 (3.5, 5.5) h, 4.0 (3.5, 4.7) h Groups: standard dose, high dose, and sham; site: left neck; stimulator: handheld stimulator (gammaCore®, electroCore, Inc., USA); parameters: sine waves 5–25 kHz, stimulation intensity 0–24 V (individualized titration strengths), each stimulation 2 min, repeat 1 (standard dose) or 2 h (high dose). NIHSS at 24 h, death, irritation or skin reaction, acute coronary syndrome, new ischemic lesion, > 30% increase in hemorrhage volume, and severe adverse device event (tcVNS vs. sham and high vs. standard-dose, difference was not statistically significant); study clarified safety, feasibility, and potential efficacy of tcVNS in ischemic and hemorrhagic stroke. Badran, 2023 RCT IS, ICH 9, 7 57.33 ± 8.28, 58.71 ± 6.45 3.22 ± 3.14 years, 4.51 ± 3.93 years Groups: motor activated auricular vagus nerve stimulation and unpaired taVNS; site: binaural cymba conchae and tragus; stimulator: motor activated auricular VNS (Digitimer DS7A); parameters: When movement is detected, the electrical nerve stimulator delivers electricity (1–3 mA), pulsed 25 Hz for a 5 s. No adverse events; FMA-UE improved in both groups, but more so in motor activated auricular VNS group. Wang, 2024 RCT IS, ICH 20, 20 55.0 ± 11.0, 57.0 ± 11.0 3.20 ± 2.04 m, 4.15 ± 1.60 m Groups: 0taVNS + task-oriented training and sham + task-oriented training; site: left auricular cymba concha; stimulator: taVNS (tVNS501, RISHENA Co., Ltd., Changzhou, China); parameters: 500 μs square pulses, 25 Hz, 30s, current intensity 6.55 ± 1.57 mA. No adverse events; significant improvements in upper limb motor function and activation of brain regions were seen in the taVNS group. CG, control group; EG, experimental group; FMA, Fugl-Meyer assessment; FMA-UE, Fugl-Meyer assessment-upper extremity; ICH, intracerebral hemorrhage; IS, ischemic stroke; RCT, randomized controlled study; taVNS, transcutaneous auricular vagus nerve stimulation; tcVNS, transcutaneous cervical vagus nerve stimulation; VNS, vagus nerve stimulation. The architecture of the brain network determines the effectiveness along with the specific functions of information integration across various brain regions. Functional remodeling may therefore be impacted by structural remodeling, and vice versa. Specifically, by facilitating synaptic plasticity via various pathways, VNS may drive brain functional remodeling. Neurotransmitters that support various cognitive and behavioral processes, including attention, memory, and arousal, are secreted by noradrenergic neurons in the locus coeruleus, cholinergic neurons in the basal forebrain as well as serotonergic neurons in the raphe nuclei. These neurotransmitters target a variety of subcortical and cortical brain structures. Specifically, VNS activates the norepinephrine, serotonin, as well as the cholinergic neurotransmitter systems, promoting synaptic remodeling and thereby improving neurological deficits after stroke. Furthermore, in rat models of stroke based on middle cerebral artery occlusion, VNS stimulation has been shown in multiple studies to be beneficial in facilitating synaptic regeneration and remodeling. The potential mechanism may involve the upregulation of brain-derived neurotrophic factor, PPAR-γ, α7nAChR and growth differentiation factor 11, all of which exert an essential role in facilitating synaptic regeneration and reorganization. In order to accelerate brain functional remodeling, research should be conducted to identify ways to increase the expression of the aforementioned variables and improve synaptic plasticity in addition to developing VNS therapies. The use of VNS to treat hemorrhagic stroke has not yet been thoroughly investigated; further research is required to identify the optimal stimulation parameters, timing, indications of functional impairment, and therapeutic efficacy. In addition to boosting sensory-motor function reshaping in patients with stroke, future research should also focus on treating other stroke sequelae, for example language barriers, cognitive deficits, anxiety, audiovisual deficits, as well as swallowing and sleep disorders. The creation of personalized intervention programs can be guided by real-time feedback on the temporal and spatial features of network modifications and interaction with existing brain remodeling techniques2.