Gray matter in the brain: Differences associated with tinnitus and hearing loss Kris Boyen a, b, * , Dave R.M. Langers a, b , Emile de Kleine a, b , Pim van Dijk a, b a Department of Otorhinolaryngology/Head and Neck Surgery, University of Groningen, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands b Graduate School of Medical Sciences, Research School of Behavioural and Cognitive Neurosciences, University of Groningen, The Netherlands article info Article history: Received 9 December 2011 Received in revised form 20 February 2012 Accepted 21 February 2012 Available online 15 March 2012 abstract Tinnitus, usually associated with hearing loss, is characterized by the perception of sound without an external sound source. The pathophysiology of tinnitus is poorly understood. In the present study, voxel- based morphometry (VBM) was employed to identify gray matter differences related to hearing loss and tinnitus. VBM was applied to magnetic resonance images of normal-hearing control subjects (n ¼ 24), hearing-impaired subjects without tinnitus (n ¼ 16, HI group) and hearing-impaired subjects with tinnitus (n ¼ 31, HI þ T group). This design allowed us to disentangle the gray matter (GM) differences related to hearing loss and tinnitus, respectively. Voxel-based VBM analyses revealed that both HI and HI þ T groups, relative to the controls, had GM increases in the superior and middle temporal gyri, and decreases in the superior frontal gyrus, occipital lobe and hypothalamus. We did not find significant GM differences between both patient groups. Subsequent region-of-interest (ROI) analyses of all Brodmann Areas, the cerebellum and the subcortical auditory nuclei showed a GM increase in the left primary auditory cortex of the tinnitus patients compared to the HI and control groups. Moreover, GM decreases were observed in frontal areas and mainly GM increases in limbic areas, both of which occurred for hearing loss irrespective of tinnitus, relative to the controls. These results suggest a specific role of the left primary auditory cortex and the additional involvement of various non-auditory brain structures in tinnitus. Understanding the causal relation between these GM changes and tinnitus will be an important next step in understanding tinnitus mechanisms. Ó 2012 Elsevier B.V. All rights reserved. 1. Introduction Tinnitus, the perception of sound without an external source, is a common disorder. Prevalence estimates generally range from 7 to 20% (Hoffman and Reed, 2004). Tinnitus may be mild but may also have a devastating impact on the ability to function in daily life, leading many patients to seek medical attention (Lockwood et al., 2002). A variety of additional symptoms is often reported, including stress, anxiety, depression, insomnia and irritability (Møller, 2000; Hébert and Lupien, 2007; Langguth et al., 2011). Approximately 40% of the patients with a primary complaint of tinnitus suffers from hyperacusis, an intolerance to loud sounds, as well (Baguley, 2003). The underlying pathophysiology of tinnitus is still poorly understood. Aging or loud-noise exposure, both of which may lead to hearing loss, are often associated with tinnitus. Since the asso- ciated hearing loss usually has a peripheral origin, the generator of tinnitus initially was thought to lie in the inner ear. However, since dissection of the vestibulocochlear nerve does not eliminate the tinnitus in the majority of subjects (House and Brackmann, 1981; Berliner et al., 1992), an important role in the generation of tinnitus is currently attributed to mechanisms in the central auditory system. Further support for tinnitus generation in the central auditory system is provided by a number of studies that employed positron-emission tomography (Arnold et al., 1996; Giraud et al., 1999; Wang et al., 2001; Langguth et al., 2006) and functional magnetic resonance imaging (Melcher et al., 2000, 2009; Lanting et al., 2008), demonstrating changes in the inferior colliculus, thalamus and auditory cortex (for reviews see Lanting et al., 2009 and Adjamian et al., 2009). Imaging studies further indicate that non-auditory brain areas may play a role in tinnitus. The limbic system in particular has been shown to exhibit abnormal activity in tinnitus patients (Andersson et al., 2000). If tinnitus is based on functional properties of the brain, there are presumably neuroanatomical correlates of tinnitus as well. A relatively new method to study the neuroanatomy of the human brain is voxel-based morphometry (VBM). VBM was introduced to * Corresponding author. Department of Otorhinolaryngology/Head and Neck Surgery, University of Groningen, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. Tel.: þ31 50 3637157; fax: þ31 503638875. E-mail addresses: k.boyen@umcg.nl (K. Boyen), d.r.m.langers@umcg.nl (D.R.M. Langers), e.de.kleine@umcg.nl (E. de Kleine), p.van.dijk@umcg.nl (P. van Dijk). Contents lists available at SciVerse ScienceDirect Hearing Research journal homepage: www.elsevier.com/locate/heares 0378-5955/$ e see front matter Ó 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.heares.2012.02.010 Hearing Research 295 (2013) 67e78