The mechanisms of tinnitus: perspectives from human functional neuroimaging

In this review, we highlight the contribution of advances in human neuroimaging to the current understanding of central mechanisms underpinning tinnitus and explain how interpretations of neuroimaging data have been guided by animal models. The primary motivation for studying the neural substrates of tinnitus in humans has been to demonstrate objectively its representation in the central auditory system and to develop a better understanding of its diverse pathophysiology and of the functional interplay between sensory, cognitive and affective systems. The ultimate goal of neuroimaging is to identify subtypes of tinnitus in order to better inform treatment strategies. The three neural mechanisms considered in this review may provide a basis for TI classification. While human neuroimaging evidence strongly implicates the central auditory system and emotional centres in TI, evidence for the precise contribution from the three mechanisms is unclear because the data are somewhat inconsistent. We consider a number of methodological issues limiting the field of human neuroimaging and recommend approaches to overcome potential inconsistency in results arising from poorly matched participants, lack of appropriate controls and low statistical power

Magnetoencephalography:technical improvements in image co-registration and studies of visual cortical oscillations

The work presented in this thesis is divided into two distinct sections. In the first, the functional neuroimaging technique of Magnetoencephalography (MEG) is described and a new technique is introduced for accurate combination of MEG and MRI co-ordinate systems. In the second part of this thesis, MEG and the analysis technique of SAM are used to investigate responses of the visual system in the context of functional specialisation within the visual cortex. In chapter one, the sources of MEG signals are described, followed by a brief description of the necessary instrumentation for accurate MEG recordings. This chapter is concluded by introducing the forward and inverse problems of MEG, techniques to solve the inverse problem, and a comparison of MEG with other neuroimaging techniques. Chapter two provides an important contribution to the field of research with MEG. Firstly, it is described how MEG and MRI co-ordinate systems are combined for localisation and visualisation of activated brain regions. A previously used co-registration methods is then described, and a new technique is introduced. In a series of experiments, it is demonstrated that using fixed fiducial points provides a considerable improvement in the accuracy and reliability of co-registration. Chapter three introduces the visual system starting from the retina and ending with the higher visual rates. The functions of the magnocellular and the parvocellular pathways are described and it is shown how the parallel visual pathways remain segregated throughout the visual system. The structural and functional organisation of the visual cortex is then described. Chapter four presents strong evidence in favour of the link between conscious experience and synchronised brain activity. The spatiotemporal responses of the visual cortex are measured in response to specific gratings. It is shown that stimuli that induce visual discomfort and visual illusions share their physical properties with those that induce highly synchronised gamma frequency oscillations in the primary visual cortex. Finally chapter five is concerned with localization of colour in the visual cortex. In this first ever use of Synthetic Aperture Magnetometry to investigate colour processing in the visual cortex, it is shown that in response to isoluminant chromatic gratings, the highest magnitude of cortical activity arise from area V2

The hepatitis В virus: general description, physical structure, genetic organization, gene transcripts and genomic regulatory elements

The HBV genome is a circular partially double-stranded DNA molecule. It contains four overlapping open reading frames (ORFs) genes. The S (preS1, preS2) region(s) encodes the major (small), middle and large proteins (HBsAg). The C and pre-C regions encode HBcAg and HBeAg. The X region encodes a polypeptide expressed during HBV infection. The P region codes for a protein with several, functions in replication. Four classes of HBV mRNAs have been identified, in the HBV genome the pre-S1 promoter expresses the large protein. The pre-S2/S promoters produce both major and middle proteins. The X promoter produces 0.7 and 0.9 kb transcripts. The C and pre-C promoters produce the Core, pol(HBcAg), and the HBeAg proteins. Enhancer I and II are key regulatory elements in the transcriptional regulation of HBV. The activity of enhancer II is highly the liwr specific. Enhancer II activates the transcriptional activity of both the pre-S1 and preS2/S promoters. Two HBV enhancers strongly affect the activity of all three major HBV promoters. A box-α in the II-A and box-β in II-B elements of HBV genome, are necessary for the enhancer II function. Either box-α or box-β can regulate the activity of the Core promoter, a, b, f proteins and c, d proteins bind to box-α and box-β, respectively, and mediate the enhancer function.Геном вірусу гепатиту В людини (HBV) існує у вигляді дволанцюгових кільцевих молекул ДНК Він містить чотири фланкуючі відкриті рамки зчитування (ORFs) генів, S (preSl, preS2) регіоні и) кодує головний, середній та великий білки (HBsAg). С і preC регіони кодують HBcAg і HBeAg, X регіон кед у є поліпептид, який експресується за час HBV інфекції Р регіон кодує білок з різноманітними функціями у реплікації. Ідентифіковано чотири класи HBV мРНК. У геномі HBV pre-S1 промотор продукує великий білок, pre-S2/S виробляє головний і середній білки. X промотор кодує 0,7 і 0,9 трагскрипти. С і пре-С промотори кодують Core і pol(HBVcAg) і HBeAg білки. Ключовими регуляторними елементами HBV є енхансери І і II. Активність енхансера II є специфічною для печінки. Він активує транскрипцію обох пре-S1 і пре-S2/S промоторів. Два HBV енхансери активують основні промото­ри HBV. Бокс-α в І 1-А і бокс-β в ІІ-В елементах у геномі HBV необхідні для функції енхансера II. Бокси а і р можуть регулювати активацію промотора Core, білки a, b, f і білки с, d прикріплюються у боксах а і р відповідно і впливають на енхансерну функцію.Геном вируса гепатита В человека (HBV) существует в виде двухцепочных кольцевых молекуул ДНК Он содержит четыре фланкирующие открытые рамки считывания (ORF8) генов. S (преS1, преS2) регион/ы) кодирует главный, средний и боль­шой белки (HBsAg). С и пре-С регионы кодируют HBсAg и HBeAg. X регион кодирует полипептид, экспрессирующийся в течение HBV инфекции. Р регион кодирует белок с разнообраз­ными функциями в репликации. Идентифицированы четыре класса HBV мРНК. В геноме HBV npe-Sl промотор продуци­рует большой белок, пpe-S2/S промотор производит оба (главный и средний) белка. X промотор кодирует 0,7 и 0,9 транскрипты. С и пре-С промоторы кодируют Core и pol(HBcAg) и HBeAg белки. Ключевыми регуляторными эле­ментами в HBV являются энхансеры I и II. Активность энхансера II очень специфична для печени, Энхансер II активи­рует транскрипционную активность пре-S1 и пре-S2/S про­ моторов. Два HBV энхансера активируют основные промото­ры HBV. Вокс-α в НА и бокс-β в П-В элементах в геноме HBV необходимы для функции энхансера II. Воксы α и β могут регулировать активацию Core промотора, белки a, b, f и белки с, d прикрепляются в боксах α и β соответственно и дейст­вуют на энхансерную функцию

Electrical stimulation of the ear, head, cranial nerve, or cortex for the treatment of tinnitus: a scoping review

Tinnitus is defined as the perception of sound in the absence of an external source. It is often associated with hearing loss and is thought to result from abnormal neural activity at some point or points in the auditory pathway, which is incorrectly interpreted by the brain as an actual sound. Neurostimulation therapies therefore, which interfere on some level with that abnormal activity, are a logical approach to treatment. For tinnitus, where the pathological neuronal activity might be associated with auditory and other areas of the brain, interventions using electromagnetic, electrical, or acoustic stimuli separately, or paired electrical and acoustic stimuli, have been proposed as treatments. Neurostimulation therapies should modulate neural activity to deliver a permanent reduction in tinnitus percept by driving the neuroplastic changes necessary to interrupt abnormal levels of oscillatory cortical activity and restore typical levels of activity. This change in activity should alter or interrupt the tinnitus percept (reduction or extinction) making it less bothersome. Here we review developments in therapies involving electrical stimulation of the ear, head, cranial nerve, or cortex in the treatment of tinnitus which demonstrably, or are hypothesised to, interrupt pathological neuronal activity in the cortex associated with tinnitus

Source space estimation of oscillatory power and brain connectivity in tinnitus

Tinnitus is the perception of an internally generated sound that is postulated to emerge as a result of structural and functional changes in the brain. However, the precise pathophysiology of tinnitus remains unknown. Llinas’ thalamocortical dysrhythmia model suggests that neural deafferentation due to hearing loss causes a dysregulation of coherent activity between thalamus and auditory cortex. This leads to a pathological coupling of theta and gamma oscillatory activity in the resting state, localised to the auditory cortex where normally alpha oscillations should occur. Numerous studies also suggest that tinnitus perception relies on the interplay between auditory and non-auditory brain areas. According to the Global Brain Model, a network of global fronto—parietal—cingulate areas is important in the generation and maintenance of the conscious perception of tinnitus. Thus, the distress experienced by many individuals with tinnitus is related to the top—down influence of this global network on auditory areas. In this magnetoencephalographic study, we compare resting-state oscillatory activity of tinnitus participants and normal-hearing controls to examine effects on spectral power as well as functional and effective connectivity. The analysis is based on beamformer source projection and an atlas-based region-of-interest approach. We find increased functional connectivity within the auditory cortices in the alpha band. A significant increase is also found for the effective connectivity from a global brain network to the auditory cortices in the alpha and beta bands. We do not find evidence of effects on spectral power. Overall, our results provide only limited support for the thalamocortical dysrhythmia and Global Brain models of tinnitus

Neuromagnetic indicators of tinnitus and tinnitus masking in patients with and without hearing loss

Tinnitus is an auditory phenomenon characterised by the perception of a sound in the absence of an external auditory stimulus. Chronic subjective tinnitus is almost certainly maintained via central mechanisms, and this is consistent with observed measures of altered spontaneous brain activity. A number of putative central auditory mechanisms for tinnitus have been proposed. The influential thalamocortical dysrhythmia model suggests that tinnitus can be attributed to the disruption of coherent oscillatory activity between thalamus and cortex following hearing loss. However, the extent to which this disruption specifically contributes to tinnitus or is simply a consequence of the hearing loss is unclear because the necessary matched controls have not been tested. Here, we rigorously test several predictions made by this model in four groups of participants (tinnitus with hearing loss, tinnitus with clinically normal hearing, no tinnitus with hearing loss and no tinnitus with clinically normal hearing). Magnetoencephalography was used to measure oscillatory brain activity within different frequency bands in a ‘resting’ state and during presentation of a masking noise. Results revealed that low-frequency activity in the delta band (1–4 Hz) was significantly higher in the ‘tinnitus with hearing loss’ group compared to the ‘no tinnitus with normal hearing’ group. A planned comparison indicated that this effect was unlikely to be driven by the hearing loss alone, but could possibly be a consequence of tinnitus and hearing loss. A further interpretative linkage to tinnitus was given by the result that the delta activity tended to reduce when tinnitus was masked. High-frequency activity in the gamma band (25–80 Hz) was not correlated with tinnitus (or hearing loss). The findings partly support the thalamocortical dysrhythmia model and suggest that slow-wave (delta band) activity may be a more reliable correlate of tinnitus than high-frequency activity

Induced gamma activity in primary visual cortex is related to luminance and not color contrast: an MEG study

Gamma activity in the visual cortex has been reported in numerous EEG studies of coherent and illusory figures. A dominant theme of many such findings has been that temporal synchronization in the gamma band in response to these identifiable percepts is related to perceptual binding of the common features of the stimulus. In two recent studies using magnetoencephalography (MEG) and the beamformer analysis technique, we have shown that the magnitude of induced gamma activity in visual cortex is dependent upon independent stimulus features such as spatial frequency and contrast. In particular, we showed that induced gamma activity is maximal in response to gratings of 3 cycles per degree (3 cpd) of high luminance contrast. In this work, we set out to examine stimulus contrast further by using isoluminant red/green gratings that possess color but not luminance contrast using the same cohort of subjects. We found no induced gamma activity in V1 or visual cortex in response to the isoluminant gratings in these subjects who had previously shown strong induced gamma activity in V1 for luminance contrast gratings

Retinotopic mapping of the primary visual cortex – a challenge for MEG imaging of the human cortex

Magnetoencephalography (MEG) can be used to reconstruct neuronal activity with high spatial and temporal resolution. However, this reconstruction problem is ill-posed, and requires the use of prior constraints in order to produce a unique solution. At present there are a multitude of inversion algorithms, each employing different assumptions, but one major problem when comparing the accuracy of these different approaches is that often the true underlying electrical state of the brain is unknown. In this study, we explore one paradigm, retinotopic mapping in the primary visual cortex (V1), for which the ground truth is known to a reasonable degree of accuracy, enabling the comparison of MEG source reconstructions with the true electrical state of the brain. Specifically, we attempted to localize, using a beanforming method, the induced responses in the visual cortex generated by a high contrast, retinotopically varying stimulus. Although well described in primate studies, it has been an open question whether the induced gamma power in humans due to high contrast gratings derives from V1 rather than the prestriate cortex (V2). We show that the beanformer source estimate in the gamma and theta bands does vary in a manner consistent with the known retinotopy of V1. However, these peak locations, although retinotopically organized, did not accurately localize to the cortical surface. We considered possible causes for this discrepancy and suggest that improved MEG/magnetic resonance imaging co-registration and the use of more accurate source models that take into account the spatial extent and shape of the active cortex may, in future, improve the accuracy of the source reconstructions

Microtesla MRI of the human brain combined with MEG

One of the challenges in functional brain imaging is integration of complementary imaging modalities, such as magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI). MEG, which uses highly sensitive superconducting quantum interference devices (SQUIDs) to directly measure magnetic fields of neuronal currents, cannot be combined with conventional high-field MRI in a single instrument. Indirect matching of MEG and MRI data leads to significant co-registration errors. A recently proposed imaging method - SQUID-based microtesla MRI - can be naturally combined with MEG in the same system to directly provide structural maps for MEG-localized sources. It enables easy and accurate integration of MEG and MRI/fMRI, because microtesla MR images can be precisely matched to structural images provided by high-field MRI and other techniques. Here we report the first images of the human brain by microtesla MRI, together with auditory MEG (functional) data, recorded using the same seven-channel SQUID system during the same imaging session. The images were acquired at 46 microtesla measurement field with pre-polarization at 30 mT. We also estimated transverse relaxation times for different tissues at microtesla fields. Our results demonstrate feasibility and potential of human brain imaging by microtesla MRI. They also show that two new types of imaging equipment - low-cost systems for anatomical MRI of the human brain at microtesla fields, and more advanced instruments for combined functional (MEG) and structural (microtesla MRI) brain imaging - are practical.Comment: 8 pages, 5 figures - accepted by JM

Reductions in cortical alpha activity, enhancements in neural responses and impaired gap detection caused by sodium salicylate in awake guinea pigs

Tinnitus chronically affects between 10–15% of the population but, despite its prevalence, the underlying mechanisms are still not properly understood. One experimental model involves administration of high doses of sodium salicylate, as this is known to reliably induce tinnitus in both humans and animals. Guinea pigs were implanted with chronic electrocorticography (ECoG) electrode arrays, with silver-ball electrodes placed on the dura over left and right auditory cortex. Two more electrodes were positioned over the cerebellum to monitor auditory brainstem responses (ABRs). We recorded resting-state and auditory evoked neural activity from awake animals before and 2 h following salicylate administration (350 mg/kg; i.p.). Large increases in click-evoked responses (> 100%) were evident across the whole auditory cortex, despite significant reductions in wave I ABR amplitudes (in response to 20 kHz tones), which are indicative of auditory nerve activity. In the same animals, significant decreases in 6–10 Hz spontaneous oscillations (alpha waves) were evident over dorsocaudal auditory cortex. We were also able to demonstrate for the first time that cortical evoked potentials can be inhibited by a preceding gap in background noise [gap-induced pre-pulse inhibition (PPI)], in a similar fashion to the gap-induced inhibition of the acoustic startle reflex that is used as a behavioural test for tinnitus. Furthermore, 2 h following salicylate administration, we observed significant deficits in PPI of cortical responses that were closely aligned with significant deficits in behavioural responses to the same stimuli. Together, these data are suggestive of neural correlates of tinnitus and oversensitivity to sound (hyperacusis)