The mechanism of action of VNS therapy for epilepsy remains largely unclear because of the complicated nature of the disease. This notwithstanding, large amounts of scientific research have yielded promising theories (Shafique, Dalsing 323). For instance, it is believed that the VNS disrupts the hypersynchronous electrical activity in the brain. Continual stimulation of the vagus nerve, by an implantable electrical device might result in bilateral activity of the brain circuits.
The neuroanatomical connections provide support for this theory. Sensory neuron fibers, which comprise about 80% of the axons in the cervical vagus nerve, terminate on and thus directly innervate the ipsilateral medulla and the nucleus tractus solitarius, both of which are located in the brain stem. According to Alan Guberman, positron emission studies have shown that electrical signals inputted into these nuclei are "conveyed to widespread bilateral regions of the cerebral cortex, diencephalon, and limbic system." The activation of certain neural regions and inactivation of others is believed to disrupt the massive neural discharge that leads to epileptic seizures (Guberman).
Depression
Shortly following the approval of VNS therapy for treatment of drug-resistant epilepsy, researchers noticed an unexpected beneficial effect of the therapy. The epileptic patients felt a significant mood improvement. Further research revealed that the decrease of seizure frequency was not related to the mood improvement. This remarkable side effect opened the door for depression treatment using the VNS therapy (George et al 56).
The mechanism of action of the VNS therapy for depression is also unknown; however, it is better understood than the corresponding VNS function in epileptic patients. It is believed that the VNS therapy modulates neurotransmitters and brain structures that are thought to be involved in mood regulation. The left vagus nerve directly innervates the nucleus tractus solitarius, which is connected to areas of the brain that control mood, appetite, sleep, and motivation ("Vagus Nerve Stimulation"). An electrical signal from the vagus nerve can be projected to these areas through the nucleus tractus solitarius. During the VNS therapy, the positron emission tomography imaging suggests activity in the following regions of the brain: locus coeruleus, raphe nuclei, amygdala, hypothalamus, orbitofrontal cortex, cingulate gyrus, and thalamus.
Each brain part plays a role in mood regulation and depression. Like antidepressant drugs, the VNS therapy increases the availability of neurotransmitters in the brain. Locus coeruleus is the primary source of norepinephrine-producing neurons, while the raphe nuclei are the major sites of serotonin production. The amygdala is the center for generating fear and anxiety, while the hypothalamus regulates emotions and behavior. The orbitofrontal cortex also regulates emotions, and may control the autonomic nervous system. The cingulate gyrus is involved in self-perceived conflict and response to pain. Finally, the thalamus is responsible for cooperative social behaviors. Like pieces in a jig-saw puzzle, these individual brain regions each play a role, fitting neatly into producing the overall symptoms of depression. The VNS therapy has been shown to stimulate an activity within each of these brain structures, an understanding of which provides clues for deciphering the mechanism of treatment of depression ("Vagus Nerve Stimulation").
