Neuromodulation technologies improve functional recovery after brain injury: From bench to bedside

Abstract

Spontaneous recovery frequently proves maladaptive or insufficient because the plasticity of the injured adult mammalian central nervous system is limited. This limited plasticity serves as a primary barrier to functional recovery after brain injury. Neuromodulation technologies represent one of the fastest-growing fields in medicine. These techniques utilize electricity, magnetism, sound, and light to restore or optimize brain functions by promoting reorganization or long-term changes that support functional recovery in patients with brain injury. Therefore, this review aims to provide a comprehensive overview of the effects and underlying mechanisms of neuromodulation technologies in supporting motor function recovery after brain injury. Many of these technologies are widely used in clinical practice and show significant improvements in motor function across various types of brain injury. However, studies report negative findings, potentially due to variations in stimulation protocols, differences in observation periods, and the severity of functional impairments among participants across different clinical trials. Additionally, we observed that different neuromodulation techniques share remarkably similar mechanisms, including promoting neuroplasticity, enhancing neurotrophic factor release, improving cerebral blood flow, suppressing neuroinflammation, and providing neuroprotection. Finally, considering the advantages and disadvantages of various neuromodulation techniques, we propose that future development should focus on closed-loop neural circuit stimulation, personalized treatment, interdisciplinary collaboration, and precision stimulation.

Keywords: functional recovery; invasive electrical stimulation; neuromodulation; noninvasive electrical stimulation; stroke; transcranial magnetic stimulation; transcranial photobiomodulation; transcranial ultrasound stimulation; traumatic brain injury.

Figure 1

Schematic of non-invasive electrical stimulation techniques for brain injury. (A) tDCS is a low-intensity technique that applies continuous, direct current to enhance (anodic tDCS) or inhibit (cathodic tDCS) cortical excitability. (B) tACS is a unique form of non-invasive brain stimulation. Sinusoidal alternating electric currents are delivered to the scalp, primarily affecting cortical neurons. tACS modulates brain function by entraining brain oscillations and inducing long-term synaptic plasticity. (C) taVNS is a device that provides non-invasive electrical stimulation in the area where the vagus nerve is distributed in the ear. (D) FNS is proposed as a novel treatment for brain injury by dilating cerebral arteries and enhancing cerebral blood flow. (E) TNS is a novel medical treatment in which mild electrical signals stimulate branches of the trigeminal nerve (the largest cranial nerve) to modulate the activity of targeted brain regions, improving cerebral blood flow and brain oxygen tension. (F) TSS is a new method of spinal stimulation that applies high-intensity stimulation to the skin, allowing the stimulation to reach the spinal cord and improve the function of the patients. (G) NMES is a technique that stimulates nerves and muscles with low-voltage electrical currents to promote muscle contraction and functional recovery. Created with Adobe Photoshop. AC: Alternating current; DC: direct current; FNS: facial nerve stimulation; NMES: neuromuscular electrical stimulation; tACS: transcranial alternating current stimulation; taVNS: transcutaneous auricular vagus nerve stimulation; tDCS: transcranial direct current stimulation; TNS: trigeminal nerve stimulation; TSS: transcutaneous spinal stimulation.

Figure 2

Invasive electrical stimulation techniques for brain injury. (A) CS involves the implantation of electrodes in the epidural space, allowing for stable electrode placement and long-term stimulation. (B) DBS is a precise neurosurgical method in which one or more electrodes are implanted in specific areas of the brain. Accurate electrical pulses are delivered to targeted brain regions to achieve therapeutic effects. (C) VNS involves intermittent chronic stimulation of the vagus nerve via a generator connected to an implanted electrode, aiming to provide therapeutic benefits through low-frequency stimulation. (D) Epidural stimulation can also be applied at the spinal level for therapeutic purposes. (E) BCI systems measure brain activity and translate it into commands for computers or other devices. This technology enables users to control machines solely through thought. Electroencephalography is the most commonly used platform for BCI research. BCI: Brain–computer interface; CS: cortical stimulation; DBS: deep brain stimulation; VNS: vagus nerve stimulation.

Figure 3

Neuromodulation technologies based on magnetism and sound. (A) TMS is a noninvasive treatment that uses a magnetic coil to influence the natural electrical activity in the brain. (B) TUS emerges as a promising new technology that is both noninvasive and deep in its bioeffects. TUS utilizes piezoelectric transducers to generate ultrasonic waves that focus deeply within the brain. These ultrasonic forces provide a deeper penetration range and enhanced focal resolution. Created with Adobe Photoshop. TMS: Transcranial magnetic stimulation; TUS: transcranial ultrasound stimulation.

Figure 4

Neuromodulation technologies based on light. (A) Optogenetics is an elegant approach to precisely controlling and monitoring the biological functions of a cell, group of cells, tissues, or organs with high temporal and spatial resolution, using optical systems and genetic engineering technologies. (B) tPBM is a non-invasive and non-thermal technique that modulates brain activity using low-power light at a near-infrared wavelength between 620 and 1100 nm or LED delivered through the skull or eyes. LED: Light-emitting diode; tNILS: transcranial near-infrared laser stimulation; tPBM: transcranial photobiomodulation

Figure 5

Mechanism of neuromodulation technologies in promoting functional recovery. Different neuromodulation techniques based on electricity, magnetism, sound and light exhibit remarkably similar mechanisms, including promoting neuroplasticity, enhancing neurotrophic factor release, improving cerebral blood flow, suppressing neuroinflammation, and providing neuroprotection. BCI: Brain-computer interface; CS: cortical stimulation; DBS: deep brain stimulation; FNS: facial nerve stimulation; NMES: neuromuscular electrical stimulation; SCS: spinal cord stimulation; taVNS: transcutaneous auricular vagus nerve stimulation; tDCS/tACS: transcranial direct/alternating current stimulation; TMS: transcranial magnetic stimulation; TNS: trigeminal nerve stimulation; tPBM: transcranial photobiomodulation; TSS: transcutaneous spinal stimulation; TUS: transcranial ultrasound stimulation; VNS: vagus nerve stimulation.