Targeted sounds and VNS (Vagus Nerve Stimulation) to desensitize the overactive neural networks thus calming tinnitus.... Full research link Abstract The functional organization of cortical and subcortical networks can be altered by sensory experience. Sensory deprivation destabilizes neural networks resulting in increased excitability, greater neural synchronization and increased spontaneous firing in cortical and subcortical neurons. This pathological activity is thought to generate the phantom percept of chronic tinnitus. While sound masking, pharmacotherapy and cortical stimulation can temporarily suppress tinnitus for some patients, these interventions do not eliminate the pathological activity that is responsible for tinnitus. A treatment that could reverse the underlying pathology would be expected to be effective in alleviating the symptoms, if not curative. Targeted neural plasticity can provide the specificity required to restore normal neural activity in dysfunctional neural circuits that are assumed to underlie many forms of tinnitus. The forebrain cholinergic system and the noradrenergic system play a significant role in modulating cortical plasticity. Stimulation of the vagus nerve is known to activate these neuromodulatory pathways. Our earlier studies have demonstrated that pairing sounds with either nucleus basalis of Meynert (NB) stimulation or vagus nerve stimulation (VNS) generates highly specific and long lasting plasticity in auditory cortex neurons. Repeatedly pairing tones with brief pulses of VNS reversed the physiological and behavioral correlates of tinnitus in noise exposed rats. We also recently demonstrated that VNS modulates synchrony and excitability in the auditory cortex at least in part by activation of muscarinic acetylcholine receptors, suggesting that acetylcholine is involved in the mechanism of action of VNS. These results suggest that pairing sounds with VNS provides a new avenue of treatment for some forms of tinnitus. This paper discusses neuromodulation as treatment for tinnitus with a focus on the potential value of pairing VNS with sound stimulation as a treatment of chronic tinnitus.