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White matter tracts relating to hearing loss in LBC and UK Biobank Background Despite hearing being such a prevalent facet of ageing, relatively little is known about the neurobiological changes that accompany age-related hearing loss. Age-related bilateral changes in hearing (or presbycusis) can be characterised by reduced ability to perceive and discriminate different frequencies and a loss of fidelity that can affect operations such as speech comprehension (J. Wang & Puel, 2020) . (In the UK, more than 40% of people over 50 years old have hearing loss, rising to more than 70% of people over the age of 70; Royal National Institute for Deaf People, 2023). Age-related hearing loss is becoming more prevalent with estimations suggesting by 2050, one in every ten people will have disabling hearing loss (Deafness and Hearing Loss, 2023.). Tinnitus is characterised by phantom ringing in the ears - is estimated to occur in 1 in 7 adults (Deafness and Hearing Loss, 2023). Tinnitus can occur in clinically normal hearing ranges (≤20 dB hearing level) but there is evidence of cochlear damage in tinnitus sufferers; there is also evidence for outer hair cell damage causing tinnitus and elevated listening levels, which is a risk factor for later life hearing loss (Job et al., 2007; Roberts et al., 2010; Weisz et al., 2006). Both hearing loss and tinnitus have implications for social interaction, quality of life, and independent living among older adults and can herald cognitive decline and dementia (Loughrey et al., 2018). Beyond the elevated risk that presbycusis confers on cochlear sensory-neural cell degeneration, there is an increasing interest in the cerebral consequences for both hearing loss and tinnitus, with findings supporting region-specific differences or changes, which have been taken to support atrophic or ‘re-wiring’ accounts of diminished auditory input. Well-powered studies in older adults with concomitant structural and diffusion MRI (dMRI) are currently lacking and have potential to add to our understanding of the neurobiological bases of these ageing-related phenomena. Brain correlates of hearing loss Most cases of hearing loss are driven by changes in the inner ear, and less frequently in the middle ear (as opposed to a minority of cases directly arising from nerve degradation or damage), and several reports indicate that specific brain changes also accompany this phenomenon. It has been proposed that the degradation of the auditory input results in repurposing of the brain regions for recruitment into other types of processing such as visual processing (Glick & Sharma, 2020), though other studies (below) may also support the presence of subtle atrophic effects within the wider auditory network. Studies such as Glick and Sharma (2020) found that in older participants with age related hearing loss, the auditory cortex “rewired” for visual processing and after 6 months of wearing a hearing aid this process was reversed. This suggests the auditory network is far more plastic than previously believed and that without auditory input, the auditory cortex is instead used for visual processing (Ponticorvo et al., 2022). In hearing impaired participants there was significant increase in brain network degree centrality (DC) between the auditory network (superior temporal gyrus (STG), medial geniculate nucleus (MGN) and the visual network; Wei et al., 2021). This was positively correlated with the extent of the hearing impairment. However, there remains conflicting evidence about the extent to which white matter microstructural properties of the brain’s major which matter pathways differ with hearing loss. For example, acoustic radiation such as fractional anisotropy (FA) and mean diffusivity (MD) do not appear to differ among adults with hearing loss, compared to controls (Koops et al., 2021; Profant et al., 2014). On the other hand, Tarabichi et al., (2018) review of dMRI studies of auditory pathways in patients with sensorineural hearing loss found that FA values on the side of hearing loss were significantly reduced in the inferior colliculus (IC) and elevated at the lateral lemniscus compared to the normal hearing side. In unilateral hearing loss patients, greater grey matter volume have been reported in the somatosensory and motor systems, and lower volumes in the auditory (i.e., Heschl's gyrus) and visual systems (i.e., the calcarine cortex; Wang et al., 2016). These lower grey matter volumes in the primary auditory cortex (i.e., STG and Heschl's gyrus) correlated with poorer hearing ability. Additionally, the lower volumes in structures related to high-level cognitive control functions (i.e., dorsolateral prefrontal cortex and anterior cingulate cortex) correlated positively with hearing loss duration (X. Wang et al., 2016; Wei et al., 2021). The degree of hearing impairment was more significantly associated with mean DC values in the right than left ear hearing impairment (Wei et al., 2021). This is further supported by research which states that those with greater ageing-related hearing loss had lower grey matter cortical volume in the cingulate, superior temporal, superior and medial frontal gyri along with the occipital lobe and hypothalamus in hard-of-hearing compared to normal-hearing participants (Boyen et al., 2013; Husain et al., 2011). This is, however, in contrast to Rosemann and Thiel (2020), who did not find any significant associations between grey matter and hearing loss. Finally, it is notable that the measurement of hearing loss in the studies reported above varies. For example, one study compared pure tone and speech thresholds and found that speech detection threshold was strongly correlated with the best pure tone threshold (Ristovska et al., 2021). These are both measures we are interested in and although not much research has been carried out comparing the methods, generally, it appears they are both getting at broadly the same underlying phenomenon, though unclear how far the brain correlates of hearing loss measured in those two ways compare. That is of course partly confounded by heterogeneity in neuroimaging and other modalities across studies. Brain correlates of tinnitus Tinnitus (the perception of sound without an external source) is another age-related auditory issue whose exact aetiology remains unclear. The acoustic radiation (AR) is the largest white matter tract of the central auditory system and connects the auditory thalamus (or MGN) to the auditory cortex, and intermingles with the fibres of the IC in its posterior portion (Maffei et al., 2019). As such, it is a primary candidate for cerebral correlates of age-related hearing loss and tinnitus; alongside other major white matter tracts, its microstructural properties show decline with age (Koops et al., 2021; Cox et al., 2016). Tinnitus is associated with both a lower cross-sectional size and higher MD in the left acoustic radiation, although the effect size was not substantially different to the contralateral pathway (Koops et al., 2021). This was interpreted as a decrease in myelination of the auditory pathways, potentially reflecting pre-existing markers of tinnitus vulnerability (Koops et al., 2021). ). Though it is worth observing that MD is sensitive to numerous structural differences in the brain’s microstructural environment beyond myelination (Jones et al., 2013). Notably, Koops et al. (2021) also interpreted their finding that age was negatively correlated with axonal density in bilateral acoustic radiation to indicate that this loss of fibre may contribute to the poorer speech understanding and slower auditory processing seen in older adults. However, it is unclear whether this association is confounded by the fact that all white matter (WM) microstructural properties show common ageing patterns to some degree. Thus, the magnitude of unique association between the AR and tinnitus requires further empirical testing. It also appears that the extent, loci and laterality of reported tinnitus-brain correlates is heterogeneous and may also be partially distinct from hearing loss. For example, Tarabichi et al., (2018) systematic review investigated white matter changes associated with tinnitus vs hearing loss – participants without tinnitus had a greater reduction in FA (in the IC, trapezoid body, lateral lemniscus (LL), superior olivary nucleus, MGN, Heschl’s gyrus, AR, and the STG) compared to those with tinnitus (Tarabichi et al., 2018). The fibre connectivity to the auditory cortex from the IC and amygdala was found to be weaker in right hemisphere in participants with tinnitus compared to normal hearing controls. They suggested that tinnitus is a hyperplastic process (disinhibition of the central auditory nuclei) driven by depravation of auditory input. Summary and Hypotheses Whereas there are several reports indicating brain structural differences as a function of hearing loss and tinnitus, the precise loci and nature of those associations are not consistently replicated across studies. Reasons for this include i) relatively small sample sizes (typically N

Psychotic experiences are usually associated with major psychiatric disorders, but they also occur in about 5 % of the general healthy population. Because healthy people who have psychotic-like experiences (PLE) are at heightened risk of developing mental disorders, it is important to understand the cause of these symptoms. The present study aims to find support for the framework that abnormalities in connections of the brain (white matter) cause cognitive deficits, which in turn cause a proneness to PLE. To this end, we will look at the mediating quality of general intelligence and processing speed on the relationship between white matter and PLE (research question 1). The second goal of this study is to find out whether any specific white matter abnormalities are associated with PLE (research question 2). To investigate these questions, we will analyse the structural connectomes of 8185 participants sampled by the UK biobank using a cross-sectional design.