Tinnitus and auditory cortex; Using adapted functional near- infrared- spectroscopy to expand brain imaging in humans

ObjectivesPhantom sound perception (tinnitus) may arise from altered brain activity within auditory cortex. Auditory cortex neurons in tinnitus animal models show increased spontaneous firing rates. This may be a core characteristic of tinnitus. Functional near- infrared spectroscopy (fNIRS) has shown similar findings in human auditory cortex. Current fNIRS approaches with cap recordings are limited to - ¼3- cm depth of signal penetration due to the skull thickness. To address this limitation, we present an innovative fNIRS approach via probes adapted to the external auditory canal. The adapted probes were placed deeper and closer to temporal lobe of the brain to bypass confining skull bone and improve neural recordings.MethodsTwenty adults with tinnitus and 20 nontinnitus controls listened to periods of silence and broadband noise (BBN) during standard cap and adapted ear canal fNIRS neuroimaging. The evaluators were not blinded, but the protocol and postprocessing for the two groups were identical.ResultsStandard fNIRS measurements in participants with tinnitus revealed increased auditory cortex activity during silence that was suppressed during auditory stimulation with BBN. Conversely, controls displayed increased activation with noise but not during silence. Importantly, adapted ear canal fNIRs probes showed similar hemodynamic responses seen with cap probes in both tinnitus and controls.ConclusionsIn this proof of concept study, we have successfully fabricated, adapted, and utilized a novel fNIRS technology that replicates established findings from traditional cap fNIRS probes. This exciting new innovation, validated by replicating previous and current cap findings in auditory cortex, may have applications to future studies to investigate brain changes not only in tinnitus but in other pathologic states that may involve the temporal lobe and surrounding brain regions.Level of EvidenceNA.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/166400/1/lio2510_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/166400/2/lio2510.pd

Identification of Human Islet Amyloid Polypeptide as a BACE2 Substrate.

Pancreatic amyloid formation by islet amyloid polypeptide (IAPP) is a hallmark pathological feature of type 2 diabetes. IAPP is stored in the secretory granules of pancreatic beta-cells and co-secreted with insulin to maintain glucose homeostasis. IAPP is innocuous under homeostatic conditions but imbalances in production or processing of IAPP may result in homodimer formation leading to the rapid production of cytotoxic oligomers and amyloid fibrils. The consequence is beta-cell dysfunction and the accumulation of proteinaceous plaques in and around pancreatic islets. Beta-site APP-cleaving enzyme 2, BACE2, is an aspartyl protease commonly associated with BACE1, a related homolog responsible for amyloid processing in the brain and strongly implicated in Alzheimer's disease. Herein, we identify two distinct sites of the mature human IAPP sequence that are susceptible to BACE2-mediated proteolytic activity. The result of proteolysis is modulation of human IAPP fibrillation and human IAPP protein degradation. These results suggest a potential therapeutic role for BACE2 in type 2 diabetes-associated hyperamylinaemia

BACE2 modulates human IAPP protein levels HEK293 cells.

<p>(A) RNAseq FPKM values for basal expression of human <i>IAPP</i>, <i>BACE2</i>, <i>BACE1</i>, <i>PCSK1</i>, <i>PCSK2</i> and <i>APP</i> in HEK293 cells. (B) HEK293 cells co-transfected with, or without, hIAPP plasmid DNA (1μg) and varying concentrations of hBACE2 plasmid DNA, hBACE1 plasmid DNA, or empty pCMV DNA, the latter to normalize DNA concentrations across conditions. A commercial source of Myc-DDK tagged hIAPP lysate (5 μg, last lane) was used to confirm identification of the hIAPP bands. The relative intensity of the top hIAPP band (C) and bottom hIAPP band (D) for each condition, as detected by anti-DDK and normalized to β-actin. Results are averaged from two separate experiments and the standard deviation is shown. (E) HEK293 cells co-transfected with hAPP, hBACE2, hBACE1 or empty pCMV DNA.</p

Morphometric analysis of pancreas tissue from the chronic dosing study.

<p>Morphometric analysis of pancreas tissue from the chronic dosing study.</p