Transcutaneous Auricular Vagal Nerve Stimulation and Disorders of Consciousness: A Hypothesis for Mechanisms of Action

Abstract

Disorders of consciousness (DoC) are the hallmark of severe acquired brain injuries characterized by abnormal activity in important brain areas and disruption within and between brain networks. As DoC's therapeutic arsenal is limited, new potential therapies such as transcutaneous auricular vagal nerve stimulation (taVNS) have recently been explored. The potential of taVNS in the process of consciousness recovery has been highlighted in recent studies with DoC patients. However, it is not clear how taVNS plays a role in the recovery of consciousness. In this article, we first describe the neural correlates of consciousness, the vagus nerve anatomy and functions, along with the results of functional magnetic resonance imaging studies using taVNS. Based on consciousness recovery and taVNS mechanisms, we propose the Vagal Cortical Pathways model. This model highlights four consecutive pathways (A. Lower brainstem activation, B. Upper brainstem activation, C. Norepinephrine pathway, and D. Serotonin pathway) likely to have an impact on patients with a brain injury and DoC. Additionally, we suggest six different mechanisms of action: (1) Activation of the ascending reticular activating system; (2) Activation of the thalamus; (3) Re-establishment of the cortico-striatal-thalamic-cortical loop; (4) Promotion of negative connectivity between external and default mode networks by the activation of the salience network; (5) Increase in activity and connectivity within the external network through the norepinephrine pathway; and (6) Increase in activity within the default mode network through the serotonin pathway. This model aims to explain the potential therapeutic effects that taVNS has on brain activity in the process of consciousness recovery.

Keywords: brain injury; brain network; disorders of consciousness; functional magnetic resonance imaging; non-invasive brain stimulation; post-coma; transcutaneous auricular vagal nerve stimulation.

Figure 1

The Vagal Cortical Pathways model: overall four consecutive pathways of the transcutaneous auricular vagal nerve stimulation. By stimulating the auricular branch of the vagus nerve, it leads to (A) the activation of the trigeminal nucleus and tractus of the solitarius nucleus located in the lower brainstem (gold arrows). Their activation leads to (B) the activation of the locus coeruleus and the raphe nuclei localized in the upper brainstem (red arrows). Then, (C) the locus coeruleus produces norepinephrine and modulates global brain activity (pink arrows). Finally, (D) the raphe nuclei produce serotonin, which also targets the brain, especially some structures of the limbic system and the frontal cortex (blue arrows).

Figure 2

taVNS' specific potential effects on consciousness recovery processes. This figure illustrates the effects of proposed pathways of transcutaneous auricular vagal nerve stimulation on a damaged brain causing disorders of consciousness, leading to six mechanisms of action. By stimulating the auricular branch of the vagus nerve, taVNS activates the caudal part of the trigeminal nucleus and of the tractus solitarius in the lower brainstem. Their neurons synapse and activate the locus coeruleus and the raphe nuclei in the upper brainstem which synthetize NE and serotonin respectively. 1) Both nuclei are part of the ascending reticular activating system (ARAS, purple rectangle), have a direct effect on arousal, and 2) project directly to the thalamus. Through their excitatory neurotransmitters and direct projections, it leads to 3) re-establishment of the cortico-striatal-thalamic-cortical loop (dashed arrows), 4) promotion of negative connectivity between external network (red diamonds) and internal network (blue diamonds) because of a higher activity of the salience network, 5) increase in external network activity and strength connectivity through NE projections, and 6) increase in DMN activity through serotonin projections. Purple rectangles represent brainstem nuclei, green round shapes represent subcortical structures and diamonds represent cortical structures, in blue the intrinsic network and in red the external network. ACC: anterior cingulate cortex, ARAS: ascending reticular activating system, DMN: default mode network, lateral FC: lateral frontal cortex, loop c-s-t-c: cortico-striatal-thalamic-cortical loop, mPFC: medial prefrontal cortex, PCC: posterior cingulate cortex, taVNS: transcutaneous auricular vagal nerve stimulation.