Table 4 Overview of preclinical vagus nerve stimulation (VNS) studies

Smith et al. [177]

VNS to increase cognitive and motor recovery after TBI

Motor and cognitive function

57 male Long-Evans hooded rats, lateral FPI (left hemisphere, moderate TBI), awake during VNS

0.5 mA, 20 Hz, 30 s trains of 0.5 ms biphasic pulses, 30 min intervals

Starting 2 h post-injury, for 14 days

Smith et al. [178]

VNS for functional recovery after TBI

Motor and cognitive deficits

48 Long Evans hooded rats, FPI (moderate TBI), awake during VNS

0.5 mA, 20 Hz, 30 s trains of 0.5 ms biphasic pulses, 30 min intervals

Starting 24 h post-injury, for 14 days

Neese et al. [184]

VNS to protect GABAergic neurons after TBI

Reduction of GABAergic neurons

24 male Long Evans hooded rats, unilateral FPI (severity unclear), awake during VNS

0.5 mA, 20 Hz, 30 s trains of 0.5 ms biphasic pulses, 30 min intervals

Starting 24 h post-injury, for 14 days

Clough et al. [182]

Effects of VNS on development of cerebral edema

Cerebral edema

19 male Long Evans hooded rats, unilateral FPI (moderate TBI), awake during VNS

0.5 mA, 20 Hz, 30 s trains of 0.5 ms biphasic pulses, 30 min intervals

Starting 2 h post-injury, for 48 h

Zhou et al. [183]

Neuroprotective effects of VNS

Brain edema

28 adult male New Zealand rabbits, brain explosive injury (firecracker with charge quantity of 50 ± 5 mg black powder, severity unclear), conscious during injury (unclear for VNS)

10 V, 5 Hz, 5 ms pulses, for 20 min

Starting 1 h post-injury, for 20 min

Pruitt et al. [179]

VNS with physical rehabilitation to enhance recovery

Motor function

28 adult female Sprague–Dawley rats, CCI to cortex (3 m/s impact, severity unclear), awake during VNS

0.8 mA, 30 Hz, 500 ms trains of 15 biphasic pulses, 100 µs phase duration

Starting on day 9 post-injury, within 45 ms of successful trials, alongside rehabilitation

Dong and Feng [180]

VNS to promote wakefulness after TBI

DoC

120 Sprague–Dawley rats (half male, half female), weight drop (400 g dropped from 40 to 44 cm, severity unclear), anesthetized during VNS

1 mA, 30 Hz, 0.5 ms pulses, for 15 min

Once, directly after TBI

Dong et al. [181]

VNS for wake-promotion after TBI

DoC

120 male Sprague–Dawley rats, weight drop (400 g dropped from 40 to 44 cm, severity unclear), anesthetized during VNS

1 mA, 30 Hz, 0.5 ms pulse width, for 15 min

Once, directly after TBI

Smith et al. [177]

Left vagus nerve, cervical part

Skilled forelimb reaching, beam walk, inclined plane, forelimb flexion, locomotor placing, Morris water maze, histology

Behavioral recovery, cognitive recovery, histologic changes (lesion cavity size, neurodegeneration, hippocampal pyramidal neuron death, reactive astrocytosis)

Not investigated

VNS improves the rate of recovery and performance of rats in a FPI model as shown in multiple behavioral and cognitive tests

Smith et al. [178]

Left vagus nerve

Injury severity, skilled forelimb reaching, beam walk, forelimb flexion, locomotor placing, Morris water maze, histology

Duration of apnea and unconsciousness, behavioral and cognitive recovery, lesion analysis (tissue loss near injury), neurodegeneration (FluoroJade)

Not investigated

VNS facilitates rate of recovery and final level of motor and cognitive performance following FPI, can be applied starting 2–24 h post-injury

Neese et al. [184]

Left vagus nerve, cervical part

Histology

Number of GAD positive cells in cerebral cortices and hippocampal hilus

Not investigated

FPI induces a significant loss of GAD-like immunoreactive cells, VNS has an overall protective effect on GABAergic neurons

Clough et al. [182]

Left vagus nerve, cervical part

Beam walk, locomotor placing

Vestibulomotor function, motor coordination, coordination of limb placing, regional brain water content

Not investigated

Chronic, intermittent VNS in rats attenuates development of cerebral edema

Zhou et al. [183]

Right vagus nerve

CT imaging, blood analysis, histology

Cranial CT images, TNF-α, IL-1β and IL-10 serum concentrations, histological parameters (pathological manifestations, brain water content)

Not investigated

VNS reduced levels of TNF-α and IL-1β, increased levels of IL-10, and reduced degree of cerebral edema, VNS may exert neuroprotective effects against explosive injury

Pruitt et al. [179]

Left vagus nerve, cervical part

Two 30 min behavioral training sessions (pull task) per day (5 days per week, starting 7 days after VNS implantation, for 6 weeks), histology

Pull task performance, mean maximal pull force, motor recovery, lesion size

Not investigated

VNS paired with physical rehabilitation enhances recovery of forelimb function and pull strength after TBI

Dong and Feng [180]

Left vagus nerve, cervical part

OX1R antagonist injection, assessment of consciousness, ELISA, western blot analysis, immunohistochemistry

Behavior and consciousness levels 1 h after TBI, orexin-A and OX1R expression in prefrontal cortex at 6, 12 and 24 h after TBI

Not investigated

VNS might promote wakefulness in comatose TBI rats through upregulation of orexin-A and OX1R expression in prefrontal cortex, VNS is a promising method to wake patients from TBI-induced coma

Dong et al. [181]

Left vagus nerve, cervical part

OX1R antagonist injection, assessment of consciousness, western blot analysis, immunohistochemistry

Degree of consciousness (I–VI), protein concentration in brain tissue (excitatory and inhibitory neurotransmitter receptors), brain section visualization

Not investigated

VNS could promote arousal and improve consciousness after TBI, potential treatment for comatose individuals affected by TBI