approved, effective and well-tolerated long-term therapy for chronic and treatment-resistant depression. Further sham-controlled studies over a longer observational period are desirable". Mechanism of action The vagus nerve is the tenth cranial nerve and arises from a series of rootlets in the medulla; it carries both afferent (80%) and efferent (20%) fibers. It has the longest and widest distribution of all the cranial nerves and functions as a bidirectional link between the brain and peripheral organs. Afferents from the vagus nerve project to the nucleus tractus solitarius which subsequently communicates with other regions of the brain including the dorsal raphe nucleus, locus coeruleus, amygdala and other areas. There are multiple potential mechanisms which may account for the efficacy of VNS in treating epilepsy and other conditions including: 1. There is evidence that VNS results in cortical desynchronization in epilepsy patients who had a favorable clinical response relative to those who did not. This makes sense given that seizures consist of abnormal hypersynchronous activity in the brain. 2. Multiple lines of evidence suggest that inflammation plays a significant role in epilepsy as well as associated neurobehavioral comorbidities such as depression, autism spectrum disorder and cognitive impairment. There is evidence that VNS has an anti-inflammatory effect through both peripheral and central mechanisms. 3. VNS can change the activity of several neurotransmitter systems involving serotonin, norepinephrine and GABA. These neurotransmitters are involved in both epilepsy and other neuropsychiatric conditions such as depression and anxiety. 4. VNS may alter the functional connectivity in several brain regions and enhance synaptic plasticity to reduce excitatory activity involved in seizures. It has also been shown to change the functional connectivity of the default mode network in depressed patients. Adverse events There are two categories of adverse events associated with VNS: (1) those related to the surgical procedure and (2) those related to stimulation. A large 25-year retrospective study of 247 patients found a surgical complication rate of 8.6%. The common adverse events included infection in 2.6%, hematoma at the surgical site in 1.9% and vocal cord palsy in 1.4%. The most common stimulation related side effect at 1 year following implantation are hoarseness in 28% and paraesthesias in the throat-chin region in 12%. At the third year the rate of stimulation related adverse effects decreased substantially with shortness of breath being the most common and occurring in 3.2%. In general, VNS is well tolerated and side effects diminish