Non-invasive therapeutics for neurotrauma: a mechanistic overview

Abstract

Traumatic brain injury is a leading cause of death and a major risk factor for the development of both memory and motor disorders. To date, there are no proven interventions to improve patient outcome after neurotrauma. A promising avenue of treatment has emerged in the use of non-invasive therapies for recovery after brain injury. A number of non-invasive brain stimulation techniques have been developed, such as transcranial direct current stimulation, transcranial magnetic stimulation and vagus nerve stimulation, as well as low intensity ultrasound stimulation and photobiomodulation therapy. However, standardized treatment regimens have not been developed. There is a clear need to better understand the underlying mechanisms of non-invasive therapeutics on brain injury pathology so as to more effectively guide treatment strategy. Here we review the current literature of non-invasive therapies in preclinical neurotrauma and offer insight into the potential mechanism of action and novel targets for the treatment of traumatic brain injury.

Keywords: blood brain barrier (BBB); inflammation; non-invasive brain stimulation (NIBS); plasticity; transcranial direct current electrical stimulation; traumatic brain injury.

Figure 1

Molecular targets of transcranial electrical stimulation. Anodal and cathodal tDCS deliver a monophasic square waveform, while tACS delivers an alternating sinusoidal wave. All tES protocols produce an electric field which modulates neural activity via the regulation of ionic channel dynamics, leading to transcription changes in cellular signaling, and upregulation of growth factors which promote adult hippocampal neurogenesis and angiogenesis. tES produces anti-inflammatory effects via the up-regulation of eNOS which prevents tight-junction protein breakdown, preserving blood-brain barrier integrity.

Figure 2

Molecular targets of transcranial magnetic stimulation. TMS produces a magnetic field which is capable of inducing LTP and LTD plasticity. Where high-frequency stimulation produces an excitatory effect and low-frequency stimulation inhibiting neural circuits. Regulating synaptic function through LTP-LTD plasticity leads to the stabilization of neural circuits following injury. TMS also attenuates neuroinflammation and preserve the blood-brain barrier integrity by the reduction of pro-inflammatory cytokines and apoptosis preventing further peripheral immune cell infiltration.

Figure 3

Molecular targets of Low-intensity ultrasound stimulation. Low intensity ultrasound stimulation targets the mechanoreceptor Piezo1. Piezo1 detects changes in the mechanical force of the cellular microenvironment. Piezo1 helps to regulate intracellular calcium homeostasis and preventing further inflammatory signal cascade.

Figure 4

Molecular targets of photobiomodulation. Photobiomodulation enhances ATP production via cytochrome c activity in the mitochondrial membrane, improving calcium homeostasis and protecting against oxidative stress as well as stimulating growth factor transcription and cell proliferation.

Figure 5

Molecular targets of vagus nerve stimulation. VNS stimulation initiates several anti-inflammatory processes from the periphery. Targeting the water channel Aquaroin-4 as well as reducing pro-inflammatory cytokines and oxidative stress. VNS also stimulates the release of the gastrointestinal peptide ghrelin, which supports neuronal function and recovery.

Figure 6

Mechanisms of action for non-invasive therapeutics in traumatic brain injury. Non-invasive therapies enhance the expression of Brain-Derived Neurotrophic Factor (BDNF) and its receptor, Tropomyosin receptor kinase B (TrkB), leading to improved synaptic plasticity and neuronal survival. This pathway plays a crucial role in the recovery and reorganization of neural networks following TBI. Therapeutics promote the proliferation and differentiation of neural progenitor cells in the hippocampus and other brain regions, contributing to the generation of new neurons. This process supports cognitive function and recovery of memory and learning abilities impaired by TBI. By modulating blood-brain barrier permeability, non-invasive interventions facilitate the clearance of excess fluid and inflammatory molecules from the brain parenchyma. This reduction in edema and inflammation mitigates secondary injury processes and supports overall neural health. The combined effects of these mechanisms underscore the potential of non-invasive therapeutic strategies to enhance recovery and improve outcomes in patients with traumatic brain injury.