In our opinion, the key to understanding tinnitus pathophysiology lies in understanding how the auditory and limbic systems interact. The present study reports, for the first time, functional differences in the NAc of patients with chronic tinnitus. Furthermore, this hyperactivity in NAc correlates with the magnitude of structural changes in the vmPFC in these same patients. We conclude, therefore, that a dysregulation

of limbic and auditory networks may be at the heart of chronic tinnitus. A complete understanding and ultimate cure of tinnitus may depend on a detailed understanding of the nature and basis of this dysregulation. Given PLX-4720 supplier the paucity of effective treatments for tinnitus, this field of research is in need of new and testable ideas, and the model we propose will certainly benefit and evolve from future research. For example, although we report moderate correlations between functional activity in primary auditory cortex and limbic regions in tinnitus patients, additional studies are needed to directly assess the nature of connectivity between these and other limbic and auditory regions.

We have proposed topographic inhibitory influence HA-1077 datasheet of the thalamic reticular nucleus (TRN) on auditory thalamic (i.e., MGN) transmission as a candidate noise-cancellation site in this network (Mühlau et al., 2006 and Rauschecker et al., 2010); however, further research is needed to test the site(s) of limbic-auditory interaction relevant for tinnitus, particularly next in animal models of tinnitus. Limbic corticostriatal structures (i.e., vmPFC and NAc) have also been linked to disordered appraisal of hedonic state in drug addiction (Ahmed and Koob, 1998) and emotional state in mood disorders (Mayberg, 1997). Both these conditions are associated with structural abnormalities in vmPFC

(Drevets et al., 1997, Koenigs and Grafman, 2009 and Tanabe et al., 2009) similar to the ones we report in individuals with chronic tinnitus. Adjacent mPFC and cingulate structures, along with other limbic regions, have also been implicated in chronic pain (DaSilva et al., 2008, Geha et al., 2008 and Kuchinad et al., 2007), which too may involve the inability to suppress unwanted sensory signals. Converging evidence regarding common mechanisms shared between these and similar disorders will further our understanding of the limbic system and its influence on perception. Tinnitus, as a relatively circumscribed condition, may facilitate better understanding of limbic dysregulation in many of these disorders. Twenty-two volunteers (11 tinnitus patients, 6 female; 11 controls, 7 female) were recruited from the Georgetown University Medical Center community and gave informed written consent to participate in this study. Tinnitus patients ranged widely in age (20–64 years; SD = 16.0 years) and were on average 44.