The role of the medial geniculate body of the thalamus in the pathophysiology of tinnitus and implications for treatment

Tinnitus is an auditory sensation in the absence of actual external stimulation. Different clinical interventions are used in tinnitus treatment, but only few patients respond to available options. The lack of successful tinnitus treatment is partly due to the limited knowledge about the mechanisms underlying tinnitus. Recently, the auditory part of the thalamus has gained attention as a central structure in the neuropathophysiology of tinnitus. Increased thalamic spontaneous firing rate, bursting activity and oscillations, alongside an increase of GABAergic tonic inhibition have been shown in the auditory thalamus in animal models of tinnitus. In addition, clinical neuroimaging studies have shown structural and functional thalamic changes with tinnitus. This review provides a systematic overview and discussion of these observations that support a central role of the auditory thalamus in tinnitus. Based on this approach, a neuromodulative treatment option for tinnitus is proposed

Wireless stimulation of the subthalamic nucleus with nanoparticles modulates key monoaminergic systems similar to contemporary deep brain stimulation

BACKGROUND: Deep brain stimulation (DBS) is commonly used to alleviate motor symptoms in several movement disorders. However, the procedure is invasive, and the technology has remained largely stagnant since its inception decades ago. Recently, we have shown that wireless nanoelectrodes may offer an alternative approach to conventional DBS. However, this method is still in its infancy, and more research is required to characterize its potential before it can be considered as an alternative to conventional DBS. OBJECTIVES: Herein, we aimed to investigate the effect of stimulation via magnetoelectric nanoelectrodes on primary neurotransmitter systems that have implications for DBS in movement disorders. METHODS: Mice were injected with either magnetoelectric nanoparticles (MENPs) or magnetostrictive nanoparticles (MSNPs, as a control) in the subthalamic nucleus (STN). Mice then underwent magnetic stimulation, and their motor behavior was assessed in the open field test. In addition, magnetic stimulation was applied before sacrifice and post-mortem brains were processed for immunohistochemistry (IHC) to assess the co-expression of c-Fos with either tyrosine hydroxylase (TH), tryptophan hydroxylase-2 (TPH2) or choline acetyltransferase (ChAT). RESULTS: Stimulated animals covered longer distances in the open field test when compared to controls. Moreover, we found a significant increase in c-Fos expression in the motor cortex (MC) and paraventricular region of the thalamus (PV-thalamus) after magnetoelectric stimulation. Stimulated animals showed fewer TPH2/c-Fos double-labelled cells in the dorsal raphe nucleus (DRN), as well as TH/c-Fos double-labelled cells in the ventral tegmental area (VTA), but not in the substantia nigra pars compacta (SNc). There was no significant difference in the number of ChAT/ c-Fos double-labelled cells in the pedunculopontine nucleus (PPN). CONCLUSIONS: Magnetoelectric DBS in mice enables selective modulation of deep brain areas and animal behavior. The measured behavioral responses are associated with changes in relevant neurotransmitter systems. These changes are somewhat similar to those observed in conventional DBS, suggesting that magnetoelectric DBS might be a suitable alternative

High-frequency stimulation of the subthalamic nucleus induces a sustained inhibition of serotonergic system via loss of cell phenotype

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become a standard treatment for Parkinson's disease (PD). However, in a considerable number of patients debilitating psychiatric side-effects occur. Recent research has revealed that external stimuli can alter the neurotransmitters' homeostasis in neurons, which is known as "neurotransmitter respecification". Herein, we addressed if neurotransmitter respecification could be a mechanism by which DBS suppresses the serotonergic function in the dorsal raphe nucleus (DRN) leading to mood changes. We infused transgenic 5-HT-Cre (ePET-Cre) mice with AAV viruses to achieve targeted expression of eYFP and the genetically encoded calcium indicator GCaMP6s in the DRN prior to methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. Mice received bilateral DBS electrodes in the STN and an optic fiber in the DRN for calcium photometry. MPTP-treated mice demonstrated behavioral and histological PD phenotype, whereas all STN-DBS animals exhibited an increased immobility time in the forced swim test, reduced calcium activity, and loss of tryptophan hydroxylase-2 expression in the DRN. Given the prominent role of calcium transients in mediating neurotransmitter respecification, these results suggest a loss of serotonergic phenotype in the DRN following STN-DBS. These findings indicate that loss of serotonergic cell phenotype may underlie the unwanted depressive symptoms following STN-DBS

The Effect of Noise Trauma and Deep Brain Stimulation of the Medial Geniculate Body on Tissue Activity in the Auditory Pathway

Tinnitus is defined as the phantom perception of sound. To date, there is no curative treatment, and contemporary treatments have failed to show beneficial outcomes. Deep brain stimulation has been suggested as a potential therapy for refractory tinnitus. However, the optimal target and stimulation regimens remain to be defined. Herein, we investigated metabolic and neuronal activity changes using cytochrome C oxidase histochemistry and c-Fos immunohistochemistry in a noise trauma-induced rat model of tinnitus. We also assessed changes in neuronal activity following medial geniculate body (MGB) high-frequency stimulation (HFS). Metabolic activity was reduced in the primary auditory cortex, MGB and CA1 region of the hippocampus in noise-exposed rats. Additionally, c-Fos expression was increased in the primary auditory cortex of those animals. Furthermore, MGB-HFS enhanced c-Fos expression in the thalamic reticular nucleus. We concluded that noise trauma alters tissue activity in multiple brain areas including the auditory and limbic regions. MGB-HFS resulted in higher neuronal activity in the thalamic reticular nucleus. Given the prominent role of the auditory thalamus in tinnitus, these data provide more rationales towards targeting the MGB with HFS as a symptom management tool in tinnitus

Post-Mortem Analysis of Neuropathological Changes in Human Tinnitus

Tinnitus is the phantom perception of a sound, often accompanied by increased anxiety and depressive symptoms. Degenerative or inflammatory processes, as well as changes in monoaminergic systems, have been suggested as potential underlying mechanisms. Herein, we conducted the first post-mortem histopathological assessment to reveal detailed structural changes in tinnitus patients' auditory and non-auditory brain regions. Tissue blocks containing the medial geniculate body (MGB), thalamic reticular nucleus (TRN), central part of the inferior colliculus (CIC), and dorsal and obscurus raphe nuclei (DRN and ROb) were obtained from tinnitus patients and matched controls. Cell density and size were assessed in Nissl-stained sections. Astrocytes and microglia were assessed using immunohistochemistry. The DRN was stained using antibodies raised against phenylalanine hydroxylase-8 (PH8) and tyrosine-hydroxylase (TH) to visualize serotonergic and dopaminergic cells, respectively. Cell density in the MGB and CIC of tinnitus patients was reduced, accompanied by a reduction in the number of astrocytes in the CIC only. Quantification of cell surface size did not reveal any significant difference in any of the investigated brain regions between groups. The number of PH8-positive cells was reduced in the DRN and ROb of tinnitus patients compared to controls, while the number of TH-positive cells remained unchanged in the DRN. These findings suggest that both neurodegenerative and inflammatory processes in the MGB and CIC underlie the neuropathology of tinnitus. Moreover, the reduced number of serotonergic cell bodies in tinnitus cases points toward a potential role of the raphe serotonergic system in tinnitus