bioRxiv Subject Collection: Neuroscience's Journal
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Saturday, February 10th, 2024
| Time |
Event |
| 12:30a |
Does amplitude compression help or hinder attentional neural speech tracking?
Amplitude compression is an indispensable feature of contemporary audio production and especially relevant in modern hearing aids. The cortical fate of amplitude-compressed speech signals is not well-studied, however, and may yield undesired side effects: We hypothesize that compressing the amplitude envelope of continuous speech reduces neural tracking. Yet, leveraging such compression side effect on unwanted, distracting sounds could potentially support attentive listening if effectively reducing their neural tracking. Here we studied 24 normal-hearing (NH) and 9 hearing-impaired (HI) individuals who were asked to focus on one of two competing talkers while ignoring the other. Envelope compression (1:8 ratio, loudness-matched) was applied to one or both streams containing short speech repeats. Electroencephalography (EEG) allowed us to quantify the cortical response function and degree of speech tracking. With compression applied to the attended target stream, NH and HI participants showed reduced behavioural accuracy, and compressed speech yielded generally lowered metrics of neural tracking. Despite the expected weaker tracking of a compressed distractor stream, however, HI individuals exhibited stronger tracking of the concurrently presented target stream. Our results imply that intelligent compression algorithms, with variable compression ratios applied to separated sources, could help individuals with hearing loss suppress distraction in complex multi-talker environments. | | 12:30a |
Adapting to loss: A normative account of grief
Grief is a reaction to loss that is observed across human cultures and even in other species. While the particular expressions of grief vary significantly, universal aspects include experiences of emotional pain and frequent remembering of what was lost. Despite its prevalence, and its obvious nature, the normative value of grief is puzzling: Why do we grieve? Why is it painful? And why is it sometimes prolonged enough to be clinically impairing? Using the framework of reinforcement learning with memory replay, we offer answers to these questions and suggest that grief may have normative value with respect to reward maximization. | | 2:33a |
Dynamics of White Matter Architecture in Lexical Production among Middle-Aged Adults
This study aimed to elucidate the white matter changes associated with lexical production (LP) difficulties that typically emerge in middle age, resulting in increased naming latencies. To delay the onset of LP decline, middle-aged adults may rely on domain-general (DG) and language-specific (LS) compensatory mechanisms as proposed by the LARA model (Lexical Access and Retrieval in Aging). However, our knowledge of the white matter changes supporting these mechanisms remains incomplete. Based on a sample of 155 middle-aged adults from the CAMCAN cohort, we combined dimensionality reduction techniques with multivariate statistical methods to jointly examine the relationships between diffusion-weighted imaging and LP-related neuropsychological data. Our findings (i) show that midlife constitutes a pivotal period marked by a discontinuity in brain structure within distributed networks within dorsal, ventral, and anterior cortico-subcortical pathways, and (ii) reveal that this discontinuity signals a neurocognitive transition around age 53-54, marking the onset of LP decline. Indeed, our results propose that middle-aged adults may initially adopt a 'semantic strategy' to compensate for initial LP challenges. Still, this strategy may be compromised when late middle-aged adults (age 55-60) lose the ability to exert cognitive control over semantic representations (i.e., reduced semantic control). In summary, our study advances our comprehension of brain structure changes that underpin the neurocognitive profile of LP in middle age. Specifically, we underscore the importance of considering the interplay between DG and LS processes when studying the trajectory of LP performance in healthy aging. Furthermore, these findings offer valuable insights into identifying predictive biomarkers related to the compensatory dynamics observed in midlife, which can help understand language-related neurodegenerative pathologies. | | 2:33a |
Resource or slot model in visual working memory: Are they different?
The slot model and resource model are two well-established theories used to explain working memory (WM) organization. With newer computational models suggesting that WM may not strictly conform to one model, this study aimed to understand the relationship between these models. By implementing correlational assessments of subject performances in two different tasks (analog recall paradigm with sequential bar presentation and delayed match-to-sample task (DMS) with checkerboard stimuli which are representative for resource and slot models, respectively), our study revealed significant correlations between WM performance (measured by DMS tasks) with recall error, precision, and sources of error (measured by sequential paradigm). Overall, the findings emphasize the importance of considering both models in understanding WM processes, shedding light on the debate between slot and resource models by demonstrating overlap in elements of both models. | | 2:33a |
ChineseEEG: A Chinese Linguistic Corpora EEG Dataset for Semantic Alignment and Neural Decoding
An Electroencephalography (EEG) dataset utilizing rich text stimuli can advance the understanding of how the brain encodes semantic information and contribute to semantic decoding in brain-computer interface (BCI). Addressing the scarcity of EEG datasets featuring Chinese linguistic stimuli, we present the ChineseEEG dataset, a high-density EEG dataset complemented by simultaneous eye-tracking recordings. This dataset was compiled while 10 participants silently read approximately 11 hours of Chinese text from two well-known novels. This dataset provides long-duration EEG recordings, along with pre-processed EEG sensor-level data and semantic embeddings of reading materials extracted by a pre-trained natural language processing (NLP) model. As a pilot EEG dataset derived from natural Chinese linguistic stimuli, ChineseEEG can significantly support research across neuroscience, NLP, and linguistics. It establishes a benchmark dataset for Chinese semantic decoding, aids in the development of BCIs, and facilitates the exploration of alignment between large language models and human cognitive processes. It can also aid research into the brain's mechanisms of language processing within the context of the Chinese natural language. | | 2:33a |
Upregulation of the Proto-Oncogene Src Kinase in Alzheimer's Disease: From Molecular Interactions to Therapeutic Potential
Alzheimer's disease (AD) is a progressive neurodegenerative disease, resulting in an irreversible deterioration of multiple brain regions associated with cognitive dysfunction. Phosphorylation of the microtubule-associated protein, Tau, is known to occur decades before symptomatic AD. The Src family of tyrosine kinases are known to phosphorylate select tyrosine sites on Tau and promote microtubule disassembly and subsequent neurofibrillary tangle (NFT) formation. Our data show that the proto-oncogene, non-receptor tyrosine kinase Src colocalizes with a range of late (PHF1) to early (MC1) AD-associated phosphorylated Tau epitopes. The strongest co-occurrence is seen with MC1 (probability of MC1 given Src = 100%), an early AD-specific conformational dependent epitope. Single-cell RNA sequencing data of 101 subjects show that Src is upregulated in both AD inhibitory and excitatory neurons. The most significantly affected, by orders of magnitude, were excitatory neurons which are the most prone to pathological Tau accumulation. We measured Src phosphorylation by mass spectrometry across a cohort of 48 patient neocortical tissues and found that Src has increased phosphorylation on Ser75, Tyr187, and Tyr440 in AD, showing that Src kinase undergoes distinct phosphorylation alterations in AD. Through Brownian dynamics simulations of Src and Tau, we show that as Tau undergoes the transition into disease-associated paired helical filaments, there is a notable seven-fold increase in Src contact with Tau. These results collectively emphasize Src kinase's central role in Tau phosphorylation and its close association with Tau epitopes, presenting a promising target for potential therapeutic intervention. | | 2:33a |
Minimum Effective Dose of Clemastine in a Mouse Model of Preterm White Matter Injury
Background: Preterm white matter injury (PWMI) is the most common cause of brain injury in premature neonates. PWMI involves a differentiation arrest of oligodendrocytes, the myelinating cells of the central nervous system. Clemastine was previously shown to induce oligodendrocyte differentiation and myelination in mouse models of PWMI at a dose of 10 mg/kg/day. The minimum effective dose (MED) of clemastine is unknown. Identification if the MED is essential for maximizing safety and efficacy in neonatal clinical trials. We hypothesized that the MED in neonatal mice is lower than 10 mg/kg/day. Methods: Mouse pups were exposed to normoxia or hypoxia (10% FiO2) from postnatal day 3 (P3) through P10. Vehicle or clemastine fumarate at one of four doses (0.5, 2, 7.5 or 10 mg/kg/day) was given orally to hypoxia-exposed pups. At P14, myelination was assessed by immunohistochemistry and electron microscopy to determine the MED. Clemastine pharmacokinetics were evaluated at steady-state on day 8 of treatment. Results: Clemastine rescued hypoxia-induced hypomyelination with a MED of 7.5 mg/kg/day. Pharmacokinetic analysis of the MED revealed Cmax 44.0 ng/mL, t1/2 4.6 hours, and AUC24 280.1 ng*hr/mL. Conclusion: Based on these results, myelination-promoting exposures should be achievable with oral doses of clemastine in neonates with PWMI. | | 3:47a |
Fine-grained neural coding of bodies and body parts in human visual cortex
The visual image of a human body provides a valuable source of socially relevant information. However, our understanding of the neuronal mechanisms underlying body perception in humans remains limited given the spatiotemporal constraints of functional imaging. Here we recorded multi-unit spiking activity in two neurosurgical patients in or near the extrastriate body area (EBA), a critical region for body perception. Our recordings revealed a strong preference for human bodies over a large range of control stimuli. Notably, this preference was driven by a distinct selectivity for body parts. Moreover, the observed body selectivity generalized to non-photographic depictions of bodies such as silhouettes and stick figures. Overall, our study provides an unprecedented access into the representation of bodies in the human visual cortex to bridge the gap between human neuroimaging and macaque electrophysiology studies, and form a solid basis for computational models of human body processing. | | 3:47a |
Integrative single-cell analysis of neural stem/progenitor cells reveals epigenetically dysregulated interferon response in progressive multiple sclerosis
Progressive multiple sclerosis (PMS) is characterized by a primary smoldering pathological disease process associated with a superimposed inflammatory activity. Cellular and molecular processes sustaining the pathobiology of PMS remain to be identified. We previously discovered senescence signatures in neural stem/progenitor cells (NSCs) from people with PMS. Applying direct reprogramming to generate directly induced NSCs (iNSCs) from somatic fibroblasts, we retain epigenetic information and observe hypomethylation of genes associated with lipid metabolic processes and IFN signaling only in PMS lines. Single-cell/nucleus transcriptomic and epigenetic profiling reveal an inflammatory, senescent-like, IFN-responsive radial glia (RG)-like cell subcluster mainly in PMS iNSCs that is driven by IFN-associated transcription factors. Lastly, we identify a population of senescent, IFN-responsive, disease-associated RG-like cells (DARGs) in the PMS brain that share pseudotime trajectories with iNSCs in vitro. We describe the existence of a non-neurogenic, dysfunctional DARG population that has the potential to fuel smoldering inflammation in PMS. | | 3:47a |
The Memorability of Voices is Predictable and Consistent across Listeners
Memorability, the likelihood that a stimulus is remembered, is an intrinsic stimulus property that is highly consistent across people--participants tend to remember and forget the same faces, objects, and more. However, these consistencies in memory have thus far only been observed for visual stimuli. We provide the first study of auditory memorability, collecting recognition memory scores from over 3000 participants listening to a sequence of different speakers saying the same sentence. We found significant consistency across participants in their memory for voice clips and for speakers across different utterances. Next, we tested regression models incorporating both low-level (e.g., fundamental frequency) and high-level (e.g., dialect) voice properties to predict their memorability. These models were significantly predictive, and cross-validated out-of-sample, supporting an inherent memorability of speakers' voices. These results provide the first evidence that listeners are similar in the voices they remember, which can be reliably predicted by quantifiable voice features. | | 3:47a |
Brain signal complexity and aperiodicity predict human corticospinal excitability
Transcranial magnetic stimulation (TMS) is a frequently used intervention for brain modulation with highly promising scientific and therapeutic applications. Two shortcomings of TMS applications, however, are the high within-subject and between-subjects variability in response to stimulation, which undermine the robustness and reproducibility of results. A possible solution is to optimize individual responses to TMS by exploiting rapidly fluctuating state variables such as the phase and power of neural oscillations. However, there is widespread uncertainty concerning the appropriate frequency and/or phase to target. Here, we evaluate two different approaches which do not require a choice of frequency or phase but instead utilize properties of the broadband EEG signal to predict corticospinal excitability (CSE). Our results suggest that both the spectral exponent (i.e., the steepness of the EEG 1/f background or aperiodic component) and the entropy or "complexity" of the EEG signal are both useful predictors of CSE above and beyond band-limited features, and may be deployed in brain state-dependent TMS applications. | | 3:47a |
Weight illusions explained by efficient coding based on correlated natural statistics
In our everyday experience, the sizes and weights of objects we encounter are strongly correlated. When objects are lifted, visual information about size can be combined with haptic feedback about weight, and a naive application of Bayes rule predicts that the perceived weight of larger objects should be exaggerated and smaller objects underestimated. Instead it is the smaller of two objects of equal weight that is perceived as heavier, a phenomenon termed the Size-Weight Illusion (SWI). Here we provide a normative explanation of the SWI based on principles of efficient coding, which dictate that stimulus properties should be encoded with a fidelity that depends on how frequently those properties are encountered in the natural environment. We show that the precision with which human observers estimate object weight varies as a function of both mass and volume in a manner consistent with the estimated joint distribution of those properties among everyday objects. We further show that participants' seemingly ``anti-Bayesian'' biases (the SWI) are predicted by Bayesian estimation when taking into account the gradient of discriminability induced by efficient encoding. The related Material-Weight Illusion (MWI) can also be accounted for on these principles, with surface material providing a visual cue for object density. This model framework could be used to predict perceptual biases in other properties that are correlated in the natural environment. | | 3:47a |
Low frequency stimulation for seizure suppression: identification of optimal targets in the entorhinal-hippocampal circuit
Mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS) is a common form of drug-resistant focal epilepsy in adults. Treatment for pharmacoresistant patients remains a challenge, with deep brain stimulation (DBS) showing promise for alleviating intractable seizures. This study explores the efficacy of low-frequency stimulation (LFS) on specific neuronal targets within the entorhinal-hippocampal circuit in a mouse model of MTLE. Our previous research demonstrated that LFS of the medial perforant path (MPP) fibers in the sclerotic hippocampus reduced seizures in epileptic mice. Here, we aimed to identify the critical neuronal population responsible for this antiepileptic effect by optogenetically stimulating presynaptic and postsynaptic compartments of the MPP-dentate granule cell (DGC) synapse at 1 Hz. We hypothesize that specific targets for LFS can differentially influence seizure activity depending on the cellular identity and location within or outside the seizure focus. We utilized the intrahippocampal kainate (ihKA) mouse model of MTLE and targeted specific neural populations using Channelrhodopsin2 (ChR2) and stereotactic optic fiber implantation. We recorded intracranial neuronal activity from freely moving chronically epileptic mice with and without optogenetic LFS up to three hours. We found that LFS of MPP fibers in the sclerotic hippocampus effectively suppressed epileptiform activity while stimulating principal cells in the MEC had no impact. Targeting DGCs in the sclerotic septal or non-sclerotic temporal hippocampus with LFS did not reduce seizure numbers but shortened the epileptiform bursts. Presynaptic stimulation of the MPP-DGC synapse within the sclerotic hippocampus is critical for seizure suppression via LFS. | | 4:43a |
Focused ultrasound increases gene delivery to deep brain structure following the administration of a recombinant adeno-associated virus in the cerebrospinal fluid
Gene delivery via adeno-associated viral vectors can provide lasting clinical benefits following a one-time treatment. Delivery throughout the brain is needed for the treatment of neurological disorders with widespread pathology, including Alzheimer and Parkinson diseases, and amyotrophic lateral sclerosis. Most gene vectors have poor diffusion in the brain tissue. Furthermore, it is only at high intravenous doses that gene vectors can overcome the blood-brain barrier. In contrast, relatively lower doses of gene vectors injected in the cerebrospinal fluid enable significant transduction of superficial brain regions. The remaining challenge and unmet need of gene therapy is to deliver gene vectors to deep brain structures using a minimally invasive strategy. Here, we demonstrate that non-invasive focused ultrasound blood-brain barrier modulation can increase the delivery of recombinant adeno-associated virus by 5-fold to deep brain structures following injection in the cisterna magna. Delivery of adeno-associated viral vectors to the central nervous system, via administration in the cerebrospinal fluid, is being evaluated in several clinical trials for treating beta-galactosidase-1 deficiency, Batten disease, Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and spinal muscular atrophy. Our findings suggest that the efficacy of gene therapies delivered in the cerebrospinal fluid can be enhanced by targeting brain areas of interest with focused ultrasound. | | 4:43a |
Global neural encoding of model-free and inference-based strategies in mice
When a simple model-free strategy does not provide sufficient outcomes, an inference-based strategy estimating a hidden task structure becomes essential for optimizing choices. However, the neural circuitry involved in inference-based strategies is still unclear. We developed a tone frequency discrimination task in head-fixed mice in which the tone category of the current trial depended on the category of the previous trial. When the tone category was repeated every trial, the mice continued to use the default model-free strategy, as well as when tone was randomly presented, to bias the choices. In contrast, the default strategy gradually shifted to an inference-based strategy when the tone category was alternated in each trial. Brain-wide electrophysiological recording during the overtrained phase suggested that the neural activity of the frontal and sensory cortices, hippocampus, and striatum was correlated with the reward expectation of both the model-free and inference-based strategies. These results suggest the global encoding of multiple strategies in the brain. | | 9:20p |
Parvalbumin Interneuron Impairment Leads to Synaptic Transmission Deficits and Seizures in SCN8A Epileptic Encephalopathy
SCN8A epileptic encephalopathy (EE) is a severe epilepsy syndrome resulting from de novo mutations in the voltage-gated sodium channel Nav1.6, encoded by the gene SCN8A. Nav1.6 is expressed in both excitatory and inhibitory neurons, yet previous studies have primarily focused on the impact SCN8A mutations have on excitatory neuron function, with limited studies on the importance of inhibitory interneurons to seizure onset and progression. Inhibitory interneurons are critical in balancing network excitability and are known to contribute to the pathophysiology of other epilepsies. Parvalbumin (PV) interneurons are the most prominent inhibitory neuron subtype in the brain, making up about 40% of inhibitory interneurons. Notably, PV interneurons express high levels of Nav1.6. To assess the role of PV interneurons within SCN8A EE, we used two mouse models harboring patient-derived SCN8A gain-of-function mutations, Scn8aD/+, where the SCN8A mutation N1768D is expressed globally, and Scn8aW/+-PV, where the SCN8A mutation R1872W is selectively expressed in PV interneurons. Expression of the R1872W SCN8A mutation selectively in PV interneurons led to the development of spontaneous seizures in Scn8aW/+-PV mice and seizure-induced death, decreasing survival compared to wild-type. Electrophysiology studies showed that PV interneurons in Scn8aD/+ and Scn8aW/+-PV mice were susceptible to depolarization block, a state of action potential failure. Scn8aD/+ and Scn8aW/+-PV interneurons also exhibited increased persistent sodium current, a hallmark of SCN8A gain-of-function mutations that contributes to depolarization block. Evaluation of synaptic connections between PV interneurons and pyramidal cells showed an increase in synaptic transmission failure at high frequencies (80-120Hz) as well as an increase in synaptic latency in Scn8aD/+ and Scn8aW/+-PV interneurons. These data indicate a distinct impairment of synaptic transmission in SCN8A EE, potentially decreasing overall cortical network inhibition. Together, our novel findings indicate that failure of PV interneuron spiking via depolarization block along with frequency-dependent inhibitory synaptic impairment likely elicits an overall reduction in the inhibitory drive in SCN8A EE, leading to unchecked excitation and ultimately resulting in seizures and seizure-induced death. |
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