Biology subjects

Farhadi, A.

Publications and source records attributed to Farhadi, A..

12 recordsLinked to original sources

bioRxiv2026

Ototoxicity-induced inner-hair-cell specific dysfunction degrades neurometric modulation detection in noise without altering peripheral tuning

Sensorineural hearing loss can result from different pathologies, but the primary diagnostic method is a threshold-based audiogram, which is insensitive to some forms of cochlear dysfunction. Individuals may experience difficulty understanding speech in noise despite normal audiometric thresholds. Because most cochlear insults damage both inner (IHCs) and outer hair cells (OHCs), the contribution of IHC dysfunction to auditory-nerve coding has been difficult to isolate. We used the IHC-selective ototoxicity of carboplatin in chinchillas to examine how IHC dysfunction, with preserved OHC function, affects temporal-envelope coding in auditory-nerve fibers (ANFs). Carboplatin produced 10 to 20% IHC loss with stereocilia damage in surviving IHCs, while OHC-dependent measures such as DPOAEs and ANF thresholds were unchanged. Suprathreshold ABR wave 1 was reduced, whereas wave 5 was preserved, suggesting central compensation. Both spontaneous and driven firing rates decreased following exposure. Mean vector strength to amplitude-modulated tones was unchanged, but response variability increased. Neurometric analysis and mutual information showed degraded AM detection in carboplatin-exposed fibers, an effect accounted for by reduced driven rate (i.e., normalizing spike counts across groups removed the group difference). Background noise degraded AM coding similarly in both groups. Pooled-neurometric modeling showed that population redundancy compensated for impaired fibers in quiet, but not in noise, where carboplatin-exposed pools remained worse. These findings indicate that IHC dysfunction degrades envelope coding by reducing neural output rather than by altering temporal synchrony. This study suggests IHC dysfunction is a phenotype consistent with "hidden hearing loss" (but distinct from cochlear synaptopathy), and motivates suprathreshold clinical assays.

neuroscience↗

bioRxiv2025

A computational model of the mammalian auditory periphery with a multichannel, energy-driven, medial olivocochlear reflex

The afferent auditory system, and how its specialized mechanisms and circuits support ecologically relevant auditory computations such as speech recognition, has received considerable attention in decades past. This work has culminated in accurate computational models of early afferent coding alongside a good understanding of how low-level mechanisms (e.g., peripheral tuning) impact auditory perception. In contrast, the auditory efferent system and its role in auditory perception is much less well understood. To address this gap in knowledge, we describe modifications to a model of the auditory periphery to include a medial olivocochlear efferent pathway that dynamically adjusts cochlear gain in response to sound via the classical medial olivocochlear reflex loop. We show that this model can simulate the effects of contralateral elicitors on auditory-nerve responses, including the effect of elicitors that are tonotopically distant from probes. Inclusion of across-frequency efferent effects necessitated a novel multichannel design.

neuroscience↗

bioRxiv2025

Modelling Auditory Enhancement: Efferent Control of Cochlear Gain can Explain Level Dependence and Effects of Hearing Loss

The role of medial olivocochlear (MOC) efferent gain control in auditory enhancement (AE) was investigated using a subcortical auditory model. AE refers to the influence of a precursor on detectability of targets. The absence (or presence) of a precursor component at the target frequency enhances (or suppresses) detection under simultaneous masking conditions. Furthermore, the enhanced target under simultaneous masking acts as a stronger forward masker for a delayed probe tone, known as AE under forward masking. Psychoacoustic studies of AE report findings that challenge conventional expectations, and the underlying mechanisms remain unclear. For instance, listeners with hearing impairment have AE under simultaneous masking but not forward masking (Kreft et al., 2018; Kreft and Oxenham, 2019), whereas listeners with normal hearing have level-dependent AE under forward masking (Kreft and Oxenham, 2019). Our model with MOC efferent gain control successfully replicated these findings. In contrast, a model without efferent gain control failed to capture these effects, supporting the hypothesis that MOC-mediated cochlear gain modulation may play a role in AE and its alteration by hearing loss.

neuroscience↗

bioRxiv2025

Forward masking in the Inferior Colliculus: Dynamics of Discharge-rate Recovery after Narrowband Noise Maskers

In forward masking the detection threshold for a target sound (probe) is elevated due to the presence of a preceding sound (masker). Although many factors are known to influence the probe response following a masker, the current work focused on the temporal separation (delay) between the masker and probe and the inter-trial interval (ITI). Human probe thresholds recover from forward masking within 150-300 ms, similar to neural threshold recovery in the IC within 300 ms after tone maskers. Our study focused on recovery of discharge rate of IC neurons in response to probe tones after narrowband gaussian noise (GN) forward maskers, with varying time delays. Additionally, we examined how prior masker trials influenced IC rates by varying ITI. Our findings showed that previous masker trials impacted probe-evoked discharge rates, with full recovery requiring ITIs over 1.5 s after 70 dB SPL narrowband GN maskers. Neural thresholds in the IC for probes preceded by noise maskers were in the range observed in psychoacoustical studies. Two proposed mechanisms for forward masking, persistence and efferent gain control, were tested using rate analyses or computational modeling. A physiological model with efferent feedback gain control had responses consistent with trends in the physiological recordings.

neuroscience↗

bioRxiv2024

Auditory Forward Masking Explained by a Subcortical Model with Efferent Control of Cochlear Gain

Previous physiological and psychophysical studies have explored whether feedback to the cochlea from the efferent system influences forward masking. The present work proposes that the limited growth-of-masking (GOM) observed in auditory-nerve (AN) fibers may have been misunderstood; namely, that this limitation may be due to the influence of anesthesia on the efferent system. Building on the premise that the unanesthetized AN may exhibit GOM similar to more central nuclei, the present computational modeling study demonstrates that feedback from the medial olivocochlear (MOC) efferents may account for GOM observed physiologically in onset-type neurons in both the cochlear nucleus and inferior colliculus (IC). Additionally, the computational model of MOC efferents used here generates a decrease in masking with longer masker-signal delays similar to that observed in IC physiology and in psychophysical studies. An advantage of this explanation over alternative physiological explanations (e.g., that forward masking requires inhibition from the superior paraolivary nucleus) is that this theory can explain forward masking observed in the brainstem, early in the ascending pathway. For explaining psychoacoustic results, one strength of this model is that it can account for the lack of elevation in thresholds observed when masker level is randomly varied from interval-to-interval, a result that is difficult to explain using the conventional temporal-window model of psychophysical forward masking. Future directions for evaluating the efferent mechanism as a contributing mechanism for psychoacoustical results are discussed. Significance StatementThe simulations presented here demonstrate that a recent computational model of the auditory subcortex including medial-olivocochlear efferents generates forward masking, an increase in detection threshold for a short probe tone following a preceding sound. This model explains results from physiological recordings and suggests potential connections to psychoacoustic experiments. The theory that efferent control of cochlear gain is a contributing mechanism for forward masking has several advantages. This theory can explain the strength of masking exhibited by cochlear nucleus neurons, a phenomenon not explained by current physiological theories in which the strength of forward-masking is not increased relative to the periphery until later in the ascending pathway. Additionally, this theory explains results for a psychoacoustic task with random variation in masker level, results not explained by the theory that persistent masker energy interferes with detection of the probe.

neuroscience↗

bioRxiv2022

Auditory-nerve Model including Efferent Dynamic Gain Control with Inputs from Cochlear Nucleus and Inferior Colliculus

We developed an auditory model with a time-varying, gain-control signal based on the physiology of the efferent system and the sub-cortical neural pathways. The medial olivocochlear (MOC) efferent stage of the model receives excitatory projections from both fluctuation-sensitive model neurons of the inferior colliculus (IC) and wide-dynamic-range model neurons of the cochlear nucleus. The response of the model MOC stage dynamically controls cochlear gain via simulated outer hair cells. In response to amplitude-modulated (AM) noise, firing rates of most IC neurons with band-enhanced modulation transfer functions in awake rabbits increase over a time course consistent with the dynamics of the MOC efferent feedback. These changes in the rates of IC neurons in awake rabbits were employed to adjust the parameters of the efferent stage of the proposed model. Responses of the proposed model to AM noise were able to simulate the increasing IC rate over time, while the model without the efferent system did not show this trend. The proposed model with efferent gain control provides a powerful tool for testing hypotheses, shedding insight on mechanisms in hearing, specifically those involving the efferent system.

neuroscience↗

bioRxiv2022

Representations of fricatives in sub-cortical model responses: comparisons with human perception

Fricatives are obstruent sound contrasts made by airflow constrictions in the vocal tract that produce turbulence across the constriction or at a site downstream from the constriction. Fricatives exhibit significant intra/inter-subject and contextual variability. Yet fricatives are perceived with high accuracy. The current study investigated modeled neural responses to fricatives in the auditory nerve (AN) and inferior colliculus (IC), with the hypothesis that response profiles across populations of neurons provide robust correlates to consonant perception. Stimuli were 270 intervocalic fricatives (10 speakers x 9 fricatives x 3 utterances). Computational model response profiles had characteristic frequencies that were log-spaced from 125 Hz to 8 or 20 kHz, to explore the impact of high-frequency responses. Confusion matrices generated by k-nearest-neighbor subspace classifiers were based on the profiles of average rates across characteristic frequencies as feature vectors. Model confusion matrices were compared them with published behavioral data. The modeled AN and IC neural responses provided better predictions of behavioral accuracy than the stimulus spectra, with IC showing better accuracy than AN. Behavioral fricative accuracy was explained by modeled neural response profiles, whereas confusions were only partially explained. Extended frequencies improved accuracy based on the model IC, corroborating the importance of extended high frequencies in speech perception.

neuroscience↗

bioRxiv2022

Inherent envelope fluctuations in forward masking: Effects of age and hearing loss

Forward masking is generally greater for Gaussian noise (GN) than for low-fluctuation noise maskers, i.e., GN disruption. Because the minimal hearing loss that is associated with older age may affect GN disruption differently than more significant hearing loss, the current study explored the contribution of minimal hearing loss associated with older age to GN disruption. GN disruption was measured using three masker-signal delays (25, 75, and 150 ms) for three adult groups: younger participants with normal hearing, older participants with minimal hearing loss, and older participants with sensorineural hearing loss. The role of underlying mechanisms was tested using a computational model for midbrain neurons. The primary result suggests that older listeners with mild threshold elevations that typically occur with age may be more susceptible to the deleterious effects of masker-envelope fluctuations than younger listeners with normal hearing. Results from the computational model indicate that there may be a larger influence of efferent feedback and saturation of inner hair cells on forward masking and GN disruption than previously thought.

neuroscience↗

bioRxiv2022

SARS-CoV-2 Non-Structural Protein 1(NSP1) Mutation Virulence and Natural Selection: Evolutionary Trends in the Six Continents

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an unsegmented positivesense single-stranded RNA virus that belongs to the {beta}-coronavirus. This virus was the cause of a novel severe acute respiratory syndrome in 2019 (COVID-19) that emerged in Wuhan, China at the early stage of the pandemic and rapidly spread around the world. Rapid transmission and reproduction of SARS-CoV-2 threaten worldwide health with a high mortality rate from the virus. According to the significant role of non-structural protein 1 (NSP1) in inhibiting host mRNA translation, this study focuses on the link between amino acid sequences of NSP1 and alterations of them spreading around the world. The SARS-CoV-2 NSP1 protein sequences were analyzed and FASTA files were processed by Python language programming libraries. Reference sequences compared with each NSP1 sample to identify every mutation and categorize them were based on continents and frequencies. NSP1 mutations rate divided into continents were different. Based on continental studies, E87D in global vision and also in Europe notably increased. The E87D mutation has significantly risen especially in the last months of the study as the first frequent mutation observed. The remarkable mutations, H110Y and R24C, have the second and third frequencies, respectively. Based on this mutational information, despite NSP1 being a conserved sequence occurrence, these mutations change the rate of flexibility and stability of the NSP1 protein, which can eventually affect inhibiting the host translation. IMPORTANCEIn this study, we analyzed 6,510,947 sequences of non-structural protein 1 as a conserved region of SARS-CoV-2. According to the obtained results, 93.4819% of samples had no mutant regions on their amino acid sequences. Heat map data of mutational samples demonstrated high percentages of mutations that occurred in the region of 72 to 126 amino acids indicating a hot spot region of the protein. Increased rates of E87D, H110Y, and R24C mutations in the timeline of our study were reported as significant compared to available mutant samples. Analyzing the details of replacing amino acids in the most frequent E87D mutation reveals the role of this alteration in increasing molecule flexibility and destabilizing the structure of the protein.

bioinformatics↗

bioRxiv2022

The First Geographic Identification by Country of Sustainable Mutations of SARS-COV-2 Sequence Samples: Worldwide Natural Selection Trends

The high mutation rates of RNA viruses, coupled with short generation times and large population sizes, allow viruses to evolve rapidly and adapt to the host environment. The rapidity of viral mutation also causes problems in developing successful vaccines and antiviral drugs. With the spread of SARS-CoV-2 worldwide, thousands of mutations have been identified, some of which have relatively high incidences, but their potential impacts on virus characteristics remain unknown. The present study analyzed mutation patterns, SARS-CoV-2 AASs retrieved from the GISAID database containing 10,500,000 samples. Python 3.8.0 programming language was utilized to pre-process FASTA data, align to the reference sequence, and analyze the sequences. Upon completion, all mutations discovered were categorized based on geographical regions and dates. The most stable mutations were found in nsp1(8% S135R), nsp12(99.3% P323L), nsp16 (1.2% R216C), envelope (30.6% T9I), spike (97.6% D614G), and Orf8 (3.5% S24L), and were identified in the United States on April 3, 2020, and England, Gibraltar, and, New Zealand, on January 1, 2020, respectively. The study of mutations is the key to improving understanding of the function of the SARS-CoV-2, and recent information on mutations helps provide strategic planning for the prevention and treatment of this disease. Viral mutation studies could improve the development of vaccines, antiviral drugs, and diagnostic assays designed with high accuracy, specifically useful during pandemics. This knowledge helps to be one step ahead of new emergence variants. IMPORTANCEMore than two years into the global COVID-19 pandemic, the focus of attention is shifted to the emergence and spread of the SARS-CoV-2 variants that cause the evolutionary trend. Here, we analyzed and compared about 10.5 million sequences of SARS-CoV-2 to extract the stable mutations, frequencies and the substitute amino acid that changed with the wild-type one in the evolutionary trend. Also, developing and designing accurate vaccines could prepare long-term immunization against different local variants. In addition, according to the false negative results of the COVID-19 PCR test report in the diagnosis of new strains, investigating local mutation patterns could help to design local primer and vaccine.

bioinformatics↗

bioRxiv2019

Genetically encoded phase contrast agents for digital holographic microscopy

Quantitative phase imaging and digital holographic microscopy have shown great promise for visualizing the motion, structure and physiology of microorganisms and mammalian cells in three dimensions. However, these imaging techniques currently lack molecular contrast agents analogous to the fluorescent dyes and proteins that have revolutionized fluorescence microscopy. Here we introduce the first genetically encodable phase contrast agents based on gas vesicles, a unique class of air-filled protein nanostructures derived from buoyant microbes. The relatively low index of refraction of the air-filled core of gas vesicles results in optical phase advancement relative to aqueous media, making them a "positive" phase contrast agent easily distinguished from organelles, dyes, or microminerals. We demonstrate this capability by identifying and tracking the motion of gas vesicles and gas vesicle-expressing bacteria using digital holographic microscopy, and by imaging the uptake of engineered gas vesicles by mammalian cells. These results give phase imaging a biomolecular contrast agent, greatly expanding the capabilities of this powerful technology for three-dimensional biological imaging.

bioengineering↗

bioRxiv2019

Ultrasound Imaging of Gene Expression in Mammalian Cells

The study of cellular processes occurring inside intact organisms and the development of cell-based diagnostic and therapeutic agents requires methods to visualize cellular functions such as gene expression in deep tissues. Ultrasound is a widely used biomedical technology enabling deep-tissue imaging with high spatial and temporal resolution. However, no genetically encoded molecular reporters are available to connect ultrasound contrast to gene expression in mammalian cells. To address this limitation, we introduce the first mammalian acoustic reporter genes. Starting with an eleven-gene polycistronic gene cluster derived from bacteria, we engineered a eukaryotic genetic program whose introduction into mammalian cells results in the expression of a unique class of intracellular air-filled protein nanostructures called gas vesicles. The scattering of ultrasound by these nanostructures allows mammalian cells to be visualized at volumetric densities below 0.5%, enables the monitoring of dynamic circuit-driven gene expression, and permits high-resolution imaging of gene expression in living animals. These mammalian acoustic reporter genes enable previously impossible approaches to monitoring the location, viability and function of mammalian cells in vivo.

bioengineering↗