Stimulus Change Research Articles

Optogenetic Manipulation of Covert Attention in the Nonhuman Primate

Abstract Optogenetics affords new opportunities to interrogate neuronal circuits that control behavior. In primates, the usefulness of optogenetics in studying cognitive functions remains a challenge. The technique has been successfully wielded, but behavioral effects have been demonstrated primarily for sensorimotor processes. Here, we tested whether brief optogenetic suppression of primate superior colliculus can change performance in a covert attention task, in addition to previously reported optogenetic effects on saccadic eye movements. We used an attention task that required the monkey to detect and report a stimulus change at a cued location via joystick release, while ignoring changes at an uncued location. When the cued location was positioned in the response fields of transduced neurons in the superior colliculus, transient light delivery coincident with the stimulus change disrupted the monkey's detection performance, significantly lowering hit rates. When the cued location was elsewhere, hit rates were unaltered, indicating that the effect was spatially specific and not a motor deficit. Hit rates for trials with only one stimulus were also unaltered, indicating that the effect depended on selection among distractors rather than a low-level visual impairment. Psychophysical analysis revealed that optogenetic suppression increased perceptual threshold, but only for locations matching the transduced site. These data show that optogenetic manipulations can cause brief and spatially specific deficits in covert attention, independent of sensorimotor functions. This dissociation of effect, and the temporal precision provided by the technique, demonstrates the utility of optogenetics in interrogating neuronal circuits that mediate cognitive functions in the primate.

Cellular-resolution optogenetics reveals attenuation-by-suppression in visual cortical neurons

The relationship between neurons' input and spiking output is central to brain computation. Studies in vitro and in anesthetized animals suggest that nonlinearities emerge in cells' input-output (IO; activation) functions as network activity increases, yet how neurons transform inputs in vivo has been unclear. Here, we characterize cortical principal neurons' activation functions in awake mice using two-photon optogenetics. We deliver fixed inputs at the soma while neurons' activity varies with sensory stimuli. We find that responses to fixed optogenetic input are nearly unchanged as neurons are excited, reflecting a linear response regime above neurons' resting point. In contrast, responses are dramatically attenuated by suppression. This attenuation is a powerful means to filter inputs arriving to suppressed cells, privileging other inputs arriving to excited neurons. These results have two major implications. First, somatic neural activation functions in vivo accord with the activation functions used in recent machine learning systems. Second, neurons' IO functions can filter sensory inputs-not only do sensory stimuli change neurons' spiking outputs, but these changes also affect responses to input, attenuating responses to some inputs while leaving others unchanged.

How the Structure of Signaling Regulation Evolves: Insights from an Evolutionary Model.

To remain responsive to environmental changes, signaling pathways attenuate their activity with negative feedback loops (NFLs), where proteins produced upon stimulation downregulate the response. NFLs function both upstream of signaling to reduce input and downstream to reduce output. Unlike upstream NFLs, downstream NFLs directly regulate gene expression without the involvement of intermediate proteins. Thus, we hypothesized that downstream NFLs evolve under more stringent selection than upstream NFLs. Indeed, genes encoding downstream NFLs exhibit a slower evolutionary rate than upstream genes. Such differences in selective pressures could result in the robust evolution of downstream NFLs while making the evolution of upstream NFLs more sensitive to changes in signaling proteins and stimuli. Here, we test these assumptions within the context of immune signaling. Our minimal model of immune signaling predicts robust evolution of downstream NFLs to changes in model parameters. This is consistent with their critical role in regulating signaling and the conservative rate of evolution. Furthermore, we show that the number of signaling steps needed to activate a downstream NFL is influenced by the cost of signaling. Our model predicts that upstream NFLs are more likely to evolve under a shorter half-life of signaling proteins, absence of host-pathogen co-evolution, and a high infection rate. Although it has been proposed that NFLs evolve to reduce the cost of signaling, we show that a high cost does not necessarily predict the evolution of upstream NFLs. The insights from our model have broad implications for understanding the evolution of regulatory mechanisms across signaling pathways.

The Ramp protocol: Uncovering individual differences in walking to an auditory beat using TeensyStep

Intentionally walking to the beat of an auditory stimulus seems effortless for most humans. However, studies have revealed significant individual differences in the spontaneous tendency to synchronize. Some individuals tend to adapt their walking pace to the beat, while others show little or no adjustment. To fill this gap we introduce the Ramp protocol, which measures spontaneous adaptation to a change in an auditory rhythmic stimulus in a gait task. First, participants walk at their preferred cadence without stimulation. After several steps, a metronome is presented, timed to match the participant’s heel-strike. Then, the metronome tempo progressively departs from the participant’s cadence by either accelerating or decelerating. The implementation of the Ramp protocol required real-time detection of heel-strike and auditory stimuli aligned with participants’ preferred cadence. To achieve this, we developed the TeensyStep device, which we validated compared to a gold standard for step detection. We also demonstrated the sensitivity of the Ramp protocol to individual differences in the spontaneous response to a tempo-changing rhythmic stimulus by introducing a new measure: the Response Score. This new method and quantification of spontaneous response to rhythmic stimuli holds promise for highlighting and distinguishing different profiles of adaptation in a gait task.

Mechanism of sensory perception unveiled by simultaneous measurement of membrane voltage and intracellular calcium

Measuring neuronal activity is important for understanding neuronal function. Ca2+ imaging by genetically encoded calcium indicators (GECIs) is a powerful way to measure neuronal activity. Although it revealed important aspects of neuronal function, measuring the neuronal membrane voltage is important to understand neuronal function as it triggers neuronal activation. Recent progress of genetically encoded voltage indicators (GEVIs) enabled us fast and precise measurements of neuronal membrane voltage. To clarify the relation of the membrane voltage and intracellular Ca2+, we analyzed neuronal activities of olfactory neuron AWA in Caenorhabditis elegans by GCaMP6f (GECI) and paQuasAr3 (GEVI) responding to odorants. We found that the membrane voltage encodes the stimuli change by the timing and the duration by the weak semi-stable depolarization. However, the change of the intracellular Ca2+ encodes the strength of the stimuli. Furthermore, ODR-3, a G-protein alpha subunit, was shown to be important for stabilizing the membrane voltage. These results suggest that the combination of calcium and voltage imaging provides a deeper understanding of the information in neural circuits.

Effective Connectivity Network of Aberrant Prediction Error Processing in Auditory Phantom Perception.

Introduction: Prediction error (PE) is key to perception in the predictive coding framework. However, previous studies indicated the varied neural activities evoked by PE in tinnitus patients. Here, we aimed to reconcile the conflict by (1) a more nuanced view of PE, which could be driven by changing stimulus (stimulus-driven PE [sPE]) and violation of current context (context-driven PE [cPE]) and (2) investigating the aberrant connectivity networks that are engaged in the processing of the two types of PEs in tinnitus patients. Methods: Ten tinnitus patients with normal hearing and healthy controls were recruited, and a local-global auditory oddball paradigm was applied to measure the electroencephalographic difference between the two groups during sPE and cPE conditions. Results: Overall, the sPE condition engaged bottom-up and top-down connections, whereas the cPE condition engaged mostly top-down connections. The tinnitus group showed decreased sensitivity to the sPE and increased sensitivity to the cPE condition. Particularly, the auditory cortex and posterior cingulate cortex were the hubs for processing cPE in the control and tinnitus groups, respectively, showing the orientation to an internal state in tinnitus. Furthermore, tinnitus patients showed stronger connectivity to the parahippocampus and pregenual anterior cingulate cortex for the establishment of the prediction during the cPE condition. Conclusion: These results begin to dissect the role of changes in stimulus characteristics versus changes in the context of processing the same stimulus in mechanisms of tinnitus generation.

Crosstalk between PKA and PIAS3 regulates cardiac Kv4 channel SUMOylation

Post-translational SUMOylation of nuclear and cytosolic proteins maintains homeostasis in eukaryotic cells and orchestrates programmed responses to changes in metabolic demand or extracellular stimuli. In excitable cells, SUMOylation tunes the biophysical properties and trafficking of ion channels. Ion channel SUMOylation status is determined by the opposing enzyme activities of SUMO ligases and deconjugases. Phosphorylation also plays a permissive role in SUMOylation. SUMO deconjugases have been identified for several ion channels, but their corresponding E3 ligases remain unknown. This study shows PIAS3, a.k.a. KChAP, is a bona fide SUMO E3 ligase for Kv4.2 and HCN2 channels in HEK cells, and endogenous Kv4.2 and Kv4.3 channels in cardiomyocytes. PIAS3-mediated SUMOylation at Kv4.2-K579 increases channel surface expression through a rab11a-dependent recycling mechanism. PKA phosphorylation at Kv4.2-S552 reduces the current mediated by Kv4 channels in HEK293 cells, cardiomyocytes, and neurons. This study shows PKA mediated phosphorylation blocks Kv4.2-K579 SUMOylation in HEK cells and cardiomyocytes. Together, these data identify PIAS3 as a key downstream mediator in signaling cascades that control ion channel surface expression.

Naturalistic approach to investigate the neural correlates of a laundry cycle with and without fragrance.

Advancements in brain imaging technologies have facilitated the development of "real-world" experimental scenarios. In this study, participants engaged in a household chore - completing a laundry cycle - while their frontal lobe brain activity was monitored using fNIRS. Participants completed this twice using both fragranced and unfragranced detergent, to explore if fNIRS is able to identify any differences in brain activity in response to subtle changes in stimuli. Analysis was conducted using Automatic IDentification of functional Events (AIDE) software and fNIRS correlation-based signal improvement (CBSI). Results indicated that brain activity, particularly in the right frontopolar and occasionally the left dorsolateral prefrontal cortex, was more pronounced and frequent with the unfragranced detergent than the fragranced. This suggests that completing tasks in an environment where a pleasant and relaxing fragrance is present might be less effortful compared to an odourless environment.

The interplay of multiple unconditioned stimuli in evaluative conditioning: A weighted averaging framework for attitude formation via stimulus co-occurrences.

Evaluative conditioning (EC) is a key effect in attitude formation, leading to changes in the liking of neutral attitude objects due to their pairing with positive or negative stimuli. Despite EC's significance, current theories and most empirical findings are limited to stimulus pairings with a single affective stimulus at a time. In contrast, social environments often involve more complex combinations of affective stimuli. In this article, we introduce a novel framework grounded in information integration research to understand how conditioned attitudes develop in the presence of multiple affective stimuli. Through 10 experiments with different designs, measures, materials, and pairing procedures, we find that individuals' conditioned attitudes follow the average valence of all affective stimuli present with a stronger weighting of negative stimuli. This weighted averaging rule bears two implications for EC in more complex stimulus combinations. First, EC effects are nonmonotonous, such that additional stimuli of the same valence do not produce incremental EC effects. Second, EC effects are interdependent, such that the impact of one stimulus is weakest when accompanied by another negative stimulus and strongest when no other affective stimulus is present. We examine different cognitive processes underlying this weighted averaging rule, including potential differences in pairing memory or changes in the affective stimuli's valence when other stimuli are present. Our findings present a novel theoretical perspective on EC and offer valuable insights into attitude change from stimulus co-occurrences in stimulus-rich environments. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Stimuli‐Responsive Bio‐Based Surfactant‐Polymer Gels

Rheological structuring and tunability of surfactant solutions is a vital aspect of product formulation for pharmaceutical, cosmetic and consumer product applications. Sulfate-free anionic surfactants (amino acid-based or bio-based surfactants) do not tend to build adequate structure and exhibit slow response in the presence of zwitterionics and salts unlike their sulfate-based counterparts which are able to respond quickly to external stimuli (change in pH and electrolyte concentration) via the formation of worm-like micelles. We explored an alternate structuring approach to establishing stimuli responsiveness in a mixed sodium laurylglucosides hydroxypropyl sulfonate (SLHS)-based surfactant system, through engineered surfactant-polymer interactions. We report in this work that the interplay of hydrophobic and electrostatic interactions between the mixed system of SLHS and Cocamidopropyl Betaine (CAPB) with Carrageenan produces a synergistic increase from ∼103 to ∼106 mPa.s in viscosity of the overall system, giving rise to a structuring mechanism which is tunable and responsive to external stimuli- such as variation in pH or electrolyte levels. This finding may prove helpful to formulators in related fields for the development of sulfate-free formulations which impart a novel and differentiated consumer experience.

Frequency synaptic behavior of ZnO/HfZrO memristor with pulsed stimuli

The synaptic response of ZnO/HfZrO memristor devices to electrical stimuli was studied. It was found that the frequency of the stimuli affects the rate of current increase, which can be explained by the cluster state of oxygen vacancies at the interface of ZnO/HfZrO. This variation in the synaptic response due to stimulus frequency was consistent with the dynamic adjustment of tolerance thresholds observed in the human brain's response to environmental stimuli. The rate of change in current, representing the sensitivity to stimuli, mirrors the biological nervous system's reaction to environmental changes, such as Ebbinghaus forgetting behavior. Additionally, frequent irregular changes in stimuli lead to a reduced lifespan of the devices, highly resembling the biological lifetime-injure on frequent environmental fluctuations. These findings highlight the memristors' significant similarity to biological nerves in response to stimuli, confirming their tremendous potential in bionic synaptic simulation applications.

Smart Multi-Responsive Biomaterials and Their Applications for 4D Bioprinting.

The emergence of 4D printing has become a pivotal tool to produce complex structures in biomedical applications such as tissue engineering and regenerative medicine. This chapter provides a concise overview of the current state of the field and its immense potential to better understand the involved technologies to build sophisticated 4D-printed structures. These structures have the capability to sense and respond to a diverse range of stimuli, which include changes in temperature, humidity, or electricity/magnetics. First, we describe 4D printing technologies, which include extrusion-based inkjet printing, and light-based and droplet-based methods including selective laser sintering (SLS). Several types of biomaterials for 4D printing, which can undergo structural changes in various external stimuli over time were also presented. These structures hold the promise of revolutionizing fields that require adaptable and intelligent materials. Moreover, biomedical applications of 4D-printed smart structures were highlighted, spanning a wide spectrum of intended applications from drug delivery to regenerative medicine. Finally, we address a number of challenges associated with current technologies, touching upon ethical and regulatory aspects of the technologies, along with the need for standardized protocols in both in vitro as well as in vivo testing of 4D-printed structures, which are crucial steps toward eventual clinical realization.

Habituation of Central and Electrodermal Responses to an Auditory Two-Stimulus Oddball Paradigm.

The orienting reaction (OR) towards a new stimulus is subject to habituation, i.e., progressively attenuates with stimulus repetition. The skin conductance responses (SCRs) are known to represent a reliable measure of OR at the peripheral level. Yet, it is still a matter of debate which of the P3 subcomponents is the most likely to represent the central counterpart of the OR. The aim of the present work was to study habituation, recovery, and dishabituation phenomena intrinsic to a two-stimulus auditory oddball paradigm, one of the most-used paradigms both in research and clinic, by simultaneously recording SCRs and P3 in twenty healthy volunteers. Our findings show that the target stimulus was capable of triggering a more marked OR, as indexed by both SCRs and P3, compared to the standard stimulus, that could be due to its affective saliency and relevance for task completion; the application of temporal principal components analysis (PCA) to the P3 complex allowed us to identify several subcomponents including both early and late P3a (eP3a; lP3a), P3b, novelty P3 (nP3), and both a positive and a negative Slow Wave (+SW; -SW). Particularly, lP3a and P3b subcomponents showed a similar behavior to that observed for SCRs , suggesting them as central counterparts of OR. Finally, the P3 evoked by the first standard stimulus after the target showed a significant dishabituation phenomenon which could represent a sign of the local stimulus change. However, it did not reach a sufficient level to trigger an SCR/OR since it did not represent a salient event in the context of the task.

Stimulus invariant aspects of the retinal code drive discriminability of natural scenes.

Everything that the brain sees must first be encoded by the retina, which maintains a reliable representation of the visual world in many different, complex natural scenes while also adapting to stimulus changes. This study quantifies whether and how the brain selectively encodes stimulus features about scene identity in complex naturalistic environments. While a wealth of previous work has dug into the static and dynamic features of the population code in retinal ganglion cells, less is known about how populations form both flexible and reliable encoding in natural moving scenes. We record from the larval salamander retina responding to five different natural movies, over many repeats, and use these data to characterize the population code in terms of single-cell fluctuations in rate and pairwise couplings between cells. Decomposing the population code into independent and cell-cell interactions reveals how broad scene structure is encoded in the retinal output. while the single-cell activity adapts to different stimuli, the population structure captured in the sparse, strong couplings is consistent across natural movies as well as synthetic stimuli. We show that these interactions contribute to encoding scene identity. We also demonstrate that this structure likely arises in part from shared bipolar cell input as well as from gap junctions between retinal ganglion cells and amacrine cells.

Consciousness: A Tangled Hierarchy

Consciousness is one of the greatest unsolved mysteries of the brain. The simple and yet fundamental question, “How do we have subjective experience?” remains a matter of great debate among neuroscientists. These debates have generated some challenges for consciousness research, namely the hard problem—do normal scientific approaches work for consciousness— and the binding problem—how are sensory inputs experienced in a unified manner? Historically, consciousness has been studied by searching for the neural correlates of consciousness which are defined as the minimal brain areas jointly necessary for conscious experience. One of the most popular experimental paradigms used to investigate the neural correlates of consciousness is binocular rivalry. In binocular rivalry, separate images are simultaneously presented to each eye and perception vacillates between them, providing a way of determining which neural changes are due to shifts in perceptual consciousness rather than changes in stimuli. As the research progressed, however, scientists realized that finding correlates of consciousness was insufficient and that explanatory theories of consciousness were needed to make further progress. This review article aims to introduce the field of consciousness research by presenting some of the core challenges to the field: tracing the search for the neural correlates of consciousness through the lens of binocular rivalry, and exploring four popular theories of consciousness. These are higher-order theory, global neuronal workspace theory, integrated information theory, and predictive processing. It concludes with a glance at the future directions of research that aim to resolve the beguiling phenomenon of consciousness.

Possible effect of exercise with anti-fatigue nutrition on ROS-induced depression and suicide risk: a review.

Epidemiological evidence shows that physical activity, including continuous stimulus changes and appropriate exercise programs, improves brain degeneration in the hippocampus, prefrontal cortex (PFC), and anterior cingulate cortex (ACC). Therefore, we investigated the possible synergistic effects of physical activity and nutrition in controlling chronic fatigue and reducing oxidative stress in patients at risk for depression and suicide. We systematically reviewed the literature on various systemic factors related to the effects of 1) suppressing oxidative stress and 2) improving depression through exercise and nutrition. To conduct this review, we searched the PubMed database for papers published until May 1, 2024, using the terms "physical activity OR exercise" and "fatigue" OR "anti-fatigue," "oxidative stress" and "depression" and "suicide." We then reviewed the resulting list of articles related to antioxidant mechanisms. Appropriate physical activity and natural product intake can substantially change whole-body homeostasis and provide a way to overcome the threat of depression and suicide by regulating metabolites, scavenging free radicals, and neurotransmitters. Suicide and depression prevention play crucial roles in improving patients' quality of life. Our review provides evidence supporting the idea that exercise and antioxidant nutrition diminish oxidative stress and fatigue by improving the degeneration of the hippocampus, PFC, and ACC.

The social neuroscience of persuasion approach to the religious intercultural communication: A conceptual evidence from Sidhwa’s novel ‘An American Brat’

The study aims to understand the influence of religio-cultural right-wing persuasion in intercultural communication, as exhibited in a novel representing Pakistani national culture and Parsee minority culture. The methodology involves directed qualitative content analysis of Bapsi Sidhwa’s novel “An American Brat,” using a conceptual model/framework adapting/extracting coding protocol from Morin and Renvoisé’s model to analyze communication within a social neuroscience context. The research delves into the curated message of cultural diversity. Furthermore, it explains the insight of the situation into cultural and religio-cultural persuasion by the writer, which she represented in the context of three cultures, American, Pakistani, and Parsee. The characters’ communication seemed dominant, reflecting the communication regarding Pakistani Islamic cultural values due to its impact and dominance, specifically on personal and contrastive stimuli of the characters’ intuitive knowledge. Likewise, the other persuasive elements from the conceptual model/framework of Morin and Renvoisé are also reflected in the characters’ communication, which interprets any communication in a social neuroscience context. The innovative understudy of intercultural communication shows how social neuro-persuasion succeeds in reconnecting characters to their subconscious fundamental brain-rooted cognitive, cultural, and social identity. Hence, cognitive changes in stimuli often would not change or get easily influenced at teenage on conceptual, theoretical, or biological levels. According to the researchers’ conceptual arguments, future studies may utilize the present model within the textual quotations from the novel’s original text, as the present research was only delimited to qualitative content analysis. However, the theoretical/conceptual framework of the neuroscience of persuasion needs to be verified.

A unified framework for perceived magnitude and discriminability of sensory stimuli

The perception of sensory attributes is often quantified through measurements of sensitivity (the ability to detect small stimulus changes), as well as through direct judgments of appearance or intensity. Despite their ubiquity, the relationship between these two measurements remains controversial and unresolved. Here, we propose a framework in which they arise from different aspects of a common representation. Specifically, we assume that judgments of stimulus intensity (e.g., as measured through rating scales) reflect the mean value of an internal representation, and sensitivity reflects a combination of mean value and noise properties, as quantified by the statistical measure of Fisher information. Unique identification of these internal representation properties can be achieved by combining measurements of sensitivity and judgments of intensity. As a central example, we show that Weber’s law of perceptual sensitivity can coexist with Stevens’ power-law scaling of intensity ratings (for all exponents), when the noise amplitude increases in proportion to the representational mean. We then extend this result beyond the Weber’s law range by incorporating a more general and physiology-inspired form of noise and show that the combination of noise properties and sensitivity measurements accurately predicts intensity ratings across a variety of sensory modalities and attributes. Our framework unifies two primary perceptual measurements—thresholds for sensitivity and rating scales for intensity—and provides a neural interpretation for the underlying representation.

Socioeconomic Inequalities Affect Brain Responses of Infants Growing Up in Germany.

Developmental changes in functional neural networks are sensitive to environmental influences. This EEG study investigated how infant brain responses relate to the social context that their families live in. Event-related potentials of 255 healthy, awake infants between six and fourteen months were measured during a passive auditory oddball paradigm. Infants were presented with 200 standard tones and 48 randomly distributed deviants. All infants are part of a longitudinal study focusing on families with socioeconomic and/or cultural challenges (Bremen Initiative to Foster Early Childhood Development; BRISE; Germany). As part of their familial socioeconomic status (SES), parental level of education and infant's migration background were assessed with questionnaires. For 30.6% of the infants both parents had a low level of education (≤10 years of schooling) and for 43.1% of the infants at least one parent was born abroad. The N2-P3a complex is associated with unintentional directing of attention to deviant stimuli and was analysed in frontocentral brain regions. Age was utilised as a control variable. Our results show that tone deviations in infants trigger an immature N2-P3a complex. Contrary to studies with older children or adults, the N2 amplitude was more positive for deviants than for standards. This may be related to an immature superposition of the N2 with the P3a. For infants whose parents had no high-school degree and were born abroad, this tendency was increased, indicating that facing multiple challenges as a young family impacts on the infant's early neural development. As such, attending to unexpected stimulus changes may be important for early learning processes. Variations of the infant N2-P3a complex may, thus, relate to early changes in attentional capacity and learning experiences due to familial challenges. This points towards the importance of early prevention programs.

Single-cell optogenetics reveals attenuation-by-suppression in visual cortical neurons.

The relationship between neurons' input and spiking output is central to brain computation. Studies in vitro and in anesthetized animals suggest nonlinearities emerge in cells' input-output (activation) functions as network activity increases, yet how neurons transform inputs in vivo has been unclear. Here, we characterize cortical principal neurons' activation functions in awake mice using two-photon optogenetics. We deliver fixed inputs at the soma while neurons' activity varies with sensory stimuli. We find responses to fixed optogenetic input are nearly unchanged as neurons are excited, reflecting a linear response regime above neurons' resting point. In contrast, responses are dramatically attenuated by suppression. This attenuation is a powerful means to filter inputs arriving to suppressed cells, privileging other inputs arriving to excited neurons. These results have two major implications. First, somatic neural activation functions in vivo accord with the activation functions used in recent machine learning systems. Second, neurons' IO functions can filter sensory inputs - not only do sensory stimuli change neurons' spiking outputs, but these changes also affect responses to input, attenuating responses to some inputs while leaving others unchanged.