Effects of transcutaneous auricular vagus nerve stimulation on reversal learning, tonic pupil size, salivary alpha-amylase, and cortisol.

This study investigated whether transcutaneous auricular vagus nerve stimulation (taVNS) enhances reversal learning and augments noradrenergic biomarkers (i.e., pupil size, cortisol, and salivary alpha-amylase [sAA]). We also explored the effect of taVNS on respiratory rate and cardiac vagal activity (CVA). Seventy-one participants received stimulation of either the cymba concha (taVNS) or the earlobe (sham) of the left ear. After learning a series of cue-outcome associations, the stimulation was applied before and throughout a reversal phase in which cue-outcome associations were changed for some (reversal), but not for other (distractor) cues. Tonic pupil size, salivary cortisol, sAA, respiratory rate, and CVA were assessed at different time points. Contrary to our hypothesis, taVNS was not associated with an overall improvement in performance on the reversal task. Compared to sham, the taVNS group performed worse for distractor than reversal cues. taVNS did not increase tonic pupil size and sAA. Only post hoc analyses indicated that the cortisol decline was steeper in the sham compared to the taVNS group. Exploratory analyses showed that taVNS decreased respiratory rate but did not affect CVA. The weak and unexpected effects found in this study might relate to the lack of parameters optimization for taVNS and invite to further investigate the effect of taVNS on cortisol and respiratory rate.

Rhythmic Modulation of Visual Perception by Continuous Rhythmic Auditory Stimulation.

At any given moment our sensory systems receive multiple, often rhythmic, inputs from the environment. Processing of temporally structured events in one sensory modality can guide both behavioral and neural processing of events in other sensory modalities, but whether this occurs remains unclear. Here, we used human electroencephalography (EEG) to test the cross-modal influences of a continuous auditory frequency-modulated (FM) sound on visual perception and visual cortical activity. We report systematic fluctuations in perceptual discrimination of brief visual stimuli in line with the phase of the FM-sound. We further show that this rhythmic modulation in visual perception is related to an accompanying rhythmic modulation of neural activity recorded over visual areas. Importantly, in our task, perceptual and neural visual modulations occurred without any abrupt and salient onsets in the energy of the auditory stimulation and without any rhythmic structure in the visual stimulus. As such, the results provide a critical validation for the existence and functional role of cross-modal entrainment and demonstrates its utility for organizing the perception of multisensory stimulation in the natural environment.SIGNIFICANCE STATEMENT Our sensory environment is filled with rhythmic structures that are often multi-sensory in nature. Here, we show that the alignment of neural activity to the phase of an auditory frequency-modulated (FM) sound has cross-modal consequences for vision: yielding systematic fluctuations in perceptual discrimination of brief visual stimuli that are mediated by accompanying rhythmic modulation of neural activity recorded over visual areas. These cross-modal effects on visual neural activity and perception occurred without any abrupt and salient onsets in the energy of the auditory stimulation and without any rhythmic structure in the visual stimulus. The current work shows that continuous auditory fluctuations in the natural environment can provide a pacing signal for neural activity and perception across the senses.

No benefit of auditory closed-loop stimulation on memory for semantically-incongruent associations.

Auditory closed-loop stimulation has gained traction in recent years as a means of enhancing slow oscillatory activity and, consequently, sleep-associated memory consolidation. Previous studies on this topic have primarily focused on the consolidation of semantically-congruent associations. In this study, we investigated the effect of auditory closed-loop stimulation on the overnight retention of semantically-incongruent associations. Twelve healthy males (age: M = 20.06, SD = 2.02 years) participated in two experimental conditions (simulation and sham). In the stimulation condition, clicks were delivered in phase with slow oscillation up-states, whereas in the sham condition no auditory stimuli were applied. Corroborating earlier work, stimulation (vs. sham) enhanced the slow oscillation rhythm, phase-coupled spindle activity and slow oscillation power. However, there was no benefit of stimulation on overnight memory retention. These findings suggest that closed-loop stimulation does not benefit semantically-incongruent associations.

Pivotal mental states.

This paper introduces a new construct, the 'pivotal mental state', which is defined as a hyper-plastic state aiding rapid and deep learning that can mediate psychological transformation. We believe this new construct bears relevance to a broad range of psychological and psychiatric phenomena. We argue that pivotal mental states serve an important evolutionary function, that is, to aid psychological transformation when actual or perceived environmental pressures demand this. We cite evidence that chronic stress and neurotic traits are primers for a pivotal mental state, whereas acute stress can be a trigger. Inspired by research with serotonin 2A receptor agonist psychedelics, we highlight how activity at this particular receptor can robustly and reliably induce pivotal mental states, but we argue that the capacity for pivotal mental states is an inherent property of the human brain itself. Moreover, we hypothesize that serotonergic psychedelics hijack a system that has evolved to mediate rapid and deep learning when its need is sensed. We cite a breadth of evidences linking stress via a variety of inducers, with an upregulated serotonin 2A receptor system (e.g. upregulated availability of and/or binding to the receptor) and acute stress with 5-HT release, which we argue can activate this primed system to induce a pivotal mental state. The pivotal mental state model is multi-level, linking a specific molecular gateway (increased serotonin 2A receptor signaling) with the inception of a hyper-plastic brain and mind state, enhanced rate of associative learning and the potential mediation of a psychological transformation.

A thalamocortical top-down circuit for associative memory.

The sensory neocortex is a critical substrate for memory. Despite its strong connection with the thalamus, the role of direct thalamocortical communication in memory remains elusive. We performed chronic in vivo two-photon calcium imaging of thalamic synapses in mouse auditory cortex layer 1, a major locus of cortical associations. Combined with optogenetics, viral tracing, whole-cell recording, and computational modeling, we find that the higher-order thalamus is required for associative learning and transmits memory-related information that closely correlates with acquired behavioral relevance. In turn, these signals are tightly and dynamically controlled by local presynaptic inhibition. Our results not only identify the higher-order thalamus as a highly plastic source of cortical top-down information but also reveal a level of computational flexibility in layer 1 that goes far beyond hard-wired connectivity.

The different effects of concept definition and interactive imagery encoding on associative recognition for word and picture stimuli.

Traditional view holds that associative recognition require recollection while familiarity can't support associative recognition. However, recent research indicate that familiarity can also contribute to associative recognition when the stimuli are unitized in encoding. Here, we investigated the electrophysiological correlates of retrieval of word and picture stimuli in three encoding conditions. Semantically unrelated word pairs or picture pairs were encoded in concept definition, interactive imagery, and item comparison conditions, separately. In test, the participants were required to discriminate between old pairs that appeared in the same pairing as in study, rearranged pairs that appeared in different pairings in study, or completely new pairs. The behavioral results revealed that higher associative recognition was observed in interactive imagery condition than in concept definition condition, with item comparison condition eliciting the worst recognition, regardless of word or picture stimuli. ERP results of word stimuli revealed that the FN400 old/new effect was solely elicited in concept definition and interactive imagery conditions, but not in item comparison condition. However, ERP results of picture stimuli revealed that the late FN400 old/new effect was observed in three encoding conditions and that larger magnitude of old/new effect was elicited in item comparison condition than in interactive imagery condition. There may be different neural mechanisms of unitization on associative recognition for word and picture stimuli. These findings suggested that the pattern of engagement of familiarity during successful retrieval was dependent on the stimulating properties and the encoding conditions. We will discuss the possibility that top-down unitization which manipulates two unrelated stimuli through instructions may lead to the engagement of specific forms of familiarity-association familiarity and item familiarity.

Neurocognitive mechanisms of guided item and associative encoding in young and older adults.

A hallmark of aging is a decline in episodic memory that is especially pronounced for memory for associations. To examine the neurocognitive mechanisms, young and older adults completed an item encoding task involving a semantic judgment on individual objects and an associative encoding task involving a judgment whether one of two objects could fit into the other, while their EEG was recorded. Item and associative recognition were equally reduced in older adults, unexpectedly yielding no disproportionate age-related associative deficit. A behavioral follow-up experiment did reveal an associative deficit when item and associative memory were both tested for the stimuli encoded in an easier version of the associative task, although this effect tended to be smaller than the deficit in an interactive imagery task. The behavioral and ERP results together suggest that in the item task, older adults failed to bind together perceptual object features, leading to low item memory performance. In the association task, both age groups engaged shallow, perceptual encoding processes, which appeared to be less efficient in older adults. These results suggest that the age-related associative deficit is modulated by the extent to which both item and associative memory depend on low-level feature binding and higher-level strategic processes.

Rapid changes in brain activity during learning of grapheme-phoneme associations in adults.

Learning to associate written letters with speech sounds is crucial for the initial phase of acquiring reading skills. However, little is known about the cortical reorganization for supporting letter-speech sound learning, particularly the brain dynamics during the learning of grapheme-phoneme associations. In the present study, we trained 30 Finnish participants (mean age: 24.33 years, SD: 3.50 years) to associate novel foreign letters with familiar Finnish speech sounds on two consecutive days (first day â€‹~ â€‹50 â€‹min; second day â€‹~ â€‹25 â€‹min), while neural activity was measured using magnetoencephalography (MEG). Two sets of audiovisual stimuli were used for the training in which the grapheme-phoneme association in one set (Learnable) could be learned based on the different learning cues provided, but not in the other set (Control). The learning progress was tracked at a trial-by-trial basis and used to segment different learning stages for the MEG source analysis. The learning-related changes were examined by comparing the brain responses to Learnable and Control uni/multi-sensory stimuli, as well as the brain responses to learning cues at different learning stages over the two days. We found dynamic changes in brain responses related to multi-sensory processing when grapheme-phoneme associations were learned. Further, changes were observed in the brain responses to the novel letters during the learning process. We also found that some of these learning effects were observed only after memory consolidation the following day. Overall, the learning process modulated the activity in a large network of brain regions, including the superior temporal cortex and the dorsal (parietal) pathway. Most interestingly, middle- and inferior-temporal regions were engaged during multi-sensory memory encoding after the cross-modal relationship was extracted from the learning cues. Our findings highlight the brain dynamics and plasticity related to the learning of letter-speech sound associations and provide a more refined model of grapheme-phoneme learning in reading acquisition.

Confidence in Decision-Making during Probabilistic Tactile Learning Related to Distinct Thalamo-Prefrontal Pathways.

The flexibility in adjusting the decision strategy from trial to trial is a prerequisite for learning in a probabilistic environment. Corresponding neural underpinnings remain largely unexplored. In the present study, 28 male humans were engaged in an associative learning task, in which they had to learn the changing probabilistic strengths of tactile sample stimuli. Combining functional magnetic resonance imaging with computational modeling, we show that an unchanged decision strategy over successively presented trials related to weakened functional connectivity between ventralmedial prefrontal cortex (vmPFC) and left secondary somatosensory cortex. The weaker the connection strength, the faster participants indicated their choice. If the decision strategy remained unchanged, participant's decision confidence (i.e., prior belief) was related to functional connectivity between vmPFC and right pulvinar. While adjusting the decision strategy, we instead found confidence-related connections between left orbitofrontal cortex and left thalamic mediodorsal nucleus. The stronger the participant's prior belief, the weaker the connection strengths. Together, these findings suggest that distinct thalamo-prefrontal pathways encode the confidence in keeping or changing the decision strategy during probabilistic learning. Low confidence in the decision strategy demands more thalamo-prefrontal processing resources, which is in-line with the theoretical accounts of the free-energy principle.

Hippocampal GABA levels correlate with retrieval performance in an associative learning paradigm.

Neural plasticity is a complex process dependent on neurochemical underpinnings. Next to the glutamatergic system which contributes to memory formation via long-term potentiation (LTP) and long-term depression (LTD), the main inhibitory neurotransmitter, GABA is crucially involved in neuroplastic processes. Hence, we investigated changes in glutamate and GABA levels in the brain in healthy participants performing an associative learning paradigm. Twenty healthy participants (10 female, 25 ±â€¯5 years) underwent paired multi-voxel magnetic resonance spectroscopy imaging before and after completing 21 days of a facial associative learning paradigm in a longitudinal study design. Changes of GABA and glutamate were compared to retrieval success in the hippocampus, insula and thalamus. No changes in GABA and glutamate concentration were found after 21 days of associative learning. However, baseline hippocampal GABA levels were significantly correlated with initial retrieval success (pcor = 0.013, r = 0.690). In contrast to the thalamus and insula (pcor>0.1), higher baseline GABA levels in the hippocampus were associated with better retrieval performance in an associative learning paradigm. Therefore, our findings support the importance of hippocampal GABA levels in memory formation in the human brain in vivo.

Targeted Memory Reactivation During Sleep Improves Next-Day Problem Solving.

Many people have claimed that sleep has helped them solve a difficult problem, but empirical support for this assertion remains tentative. The current experiment tested whether manipulating information processing during sleep impacts problem incubation and solving. In memory studies, delivering learning-associated sound cues during sleep can reactivate memories. We therefore predicted that reactivating previously unsolved problems could help people solve them. In the evening, we presented 57 participants with puzzles, each arbitrarily associated with a different sound. While participants slept overnight, half of the sounds associated with the puzzles they had not solved were surreptitiously presented. The next morning, participants solved 31.7% of cued puzzles, compared with 20.5% of uncued puzzles (a 55% improvement). Moreover, cued-puzzle solving correlated with cued-puzzle memory. Overall, these results demonstrate that cuing puzzle information during sleep can facilitate solving, thus supporting sleep's role in problem incubation and establishing a new technique to advance understanding of problem solving and sleep cognition.

Mental imagery in animals: Learning, memory, and decision-making in the face of missing information.

When we open our eyes, we see a world filled with objects and events. Yet, due to occlusion of some objects by others, we only have partial perceptual access to the events that transpire around us. I discuss the body of research on mental imagery in animals. I first cover prior studies of mental rotation in pigeons and imagery using working memory procedures first developed for human studies. Next, I discuss the seminal work on a type of learning called mediated conditioning in rats. I then provide more in-depth coverage of work from my lab suggesting that rats can use imagery to fill in missing details of the world that are expected but hidden from perception. We have found that rats make use of an active expectation (i.e., an image) of a hidden visual event. I describe the behavioral and neurobiological studies investigating the use of a mental image, its theoretical basis, and its connections to current human cognitive neuroscience research on episodic memory, imagination, and mental simulations. Collectively, the reviewed literature provides insight into the mechanisms that mediate the flexible use of an image during ambiguous situations. I position this work in the broader scientific and philosophical context surrounding the concept of mental imagery in human and nonhuman animals.

Coffee cues elevate arousal and reduce level of construal.

Coffee and tea are two beverages commonly-consumed around the world. Therefore, there is much research regarding their physiological effects. However, less is known about their psychological meanings. Derived from a predicted lay association between coffee and arousal, we posit that exposure to coffee-related cues should increase arousal, even in the absence of actual ingestion, relative to exposure to tea-related cues. We further suggest that higher arousal levels should facilitate a concrete level of mental construal as conceptualized by Construal Level Theory. In four experiments, we find that coffee cues prompted participants to see temporal distances as shorter and to think in more concrete, precise terms. Both subjective and physiological arousal explain the effects. We situate our work in the literature that connects food and beverage to cognition or decision-making. We also discuss the applied relevance of our results as coffee and tea are among the most prevalent beverages globally.

Punishment-Predictive Cues Guide Avoidance through Potentiation of Hypothalamus-to-Habenula Synapses.

Throughout life, individuals learn to predict a punishment via its association with sensory stimuli. This process ultimately prompts goal-directed actions to prevent the danger, a behavior defined as avoidance. Neurons in the lateral habenula (LHb) respond to aversive events as well as to environmental cues predicting them, supporting LHb contribution to cue-punishment association. However, whether synaptic adaptations at discrete habenular circuits underlie such associative learning to instruct avoidance remains elusive. Here, we find that, in mice, contingent association of an auditory cue (tone) with a punishment (foot shock) progressively causes cue-driven LHb neuronal excitation during avoidance learning. This process is concomitant with the strengthening of LHb AMPA receptor-mediated neurotransmission. Such a phenomenon occludes long-term potentiation and occurs specifically at hypothalamus-to-habenula synapses. Silencing hypothalamic-to-habenulainputs or optically inactivating postsynaptic AMPA receptors within the LHb disrupts avoidance learning. Altogether, synaptic strengthening at a discrete habenular circuit transforms neutral stimuli into salient punishment-predictive cues to guide avoidance.

Coffee time: Low caffeine dose promotes attention and focus in zebrafish.

In this study we investigated the ability of zebrafish to discriminate visual signs and associate them with a reward in an associative-learning protocol including distractors. Moreover, we studied the effects of caffeine on animal performance in the task. After being trained to associate a specific image pattern with a reward (food) in the presence of other, distractor images, the fish were challenged to locate the exact cue associated with the reward. The distractors were same-colored pattern images similar to the target. Both the target and distractors were continually moved around the tank. Fish were exposed to three caffeine concentrations for 14 days: 0 mg/L (control, n = 12), 10 mg/L (n = 14), and 50 mg/L (n = 14). Zebrafish spent most of the time close to the target (where the reward was offered) under the effects of 0 and 10 mg/L caffeine, and the shortest latency to reach the target was observed for the 10-mg/L caffeine group. Both caffeine treatments (10 and 50 mg/L) increased the average speed and distance traveled when compared to the control group. This study confirms previous results showing that zebrafish demonstrate conditioned learning ability; however, low-dose caffeine exposure seems to favor visual cue discrimination and to increase zebrafish performance in a multicue discrimination task, in which primarily focus and attention are required in order to obtain the reward.

A hybrid model of source monitoring in paired-associates learning.

Three source-monitoring models were tested using the data of Bellezza, Elek, and Zhang (2016), who presented word pairs with each word in 1 of 4 locations. Given 1 word as a cue, participants had to remember the other word as well as the 2 corresponding locations. Results included (a) locations of the cue and target words were identified equally well; (b) source identification of unrecalled words was above chance; (c) the correct identification of the cue word was positively correlated with that of the target word; and (d) the location of the cue word was frequently confused with the location of the target. Three multinomial processing-tree models were tested to explain these results: a word-code model, an event-code model, and a hybrid model. The hybrid model was able to fit the data from the 5 experimental conditions of Bellezza et al. data. The model also fit data both from an experiment using four background colors as the source attributes and from a validation experiment manipulating visual-imagery instructions. The parameter values of the hybrid model suggested that source performance using locations was based predominantly on a memory code labeled an event code that included a source axis describing the locations of the 2 words, whereas performance using color relied more on word codes that associated each word with its color. It appears that different source attributes draw upon different combinations of cognitive processes, but each process occurs within the framework of the hybrid model. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

From learning to action: the integration of dorsal striatal input and output pathways in instrumental conditioning.

Considerable evidence suggests that the learning and performance of instrumental actions depend on activity in basal ganglia circuitry; however, these two functions have generally been considered independently. Whereas research investigating the associative mechanisms underlying instrumental conditioning has identified critical cortical and limbic input pathways to the dorsal striatum, the performance of instrumental actions has largely been attributed to activity in the dorsal striatal output pathways, with direct and indirect pathway projection neurons mediating action initiation, perseveration and cessation. Here, we discuss evidence that the dorsal striatal input and basal ganglia output pathways mediate the learning and performance of instrumental actions, respectively, with the dorsal striatum functioning as a transition point. From this perspective, the issue of how multiple striatal inputs are integrated at the level of the dorsal striatum and converted into relatively restricted outputs becomes one of critical significance for understanding how learning is translated into action. So too does the question of how learning signals are modulated by recent experience. We propose that this occurs through recurrent corticostriatothalamic feedback circuits that serve to integrate performance signals by updating ongoing action-related learning.

Neurobehavioral and oxidative stress alterations following methylmercury and retinyl palmitate co-administration in pregnant and lactating rats and their offspring.

Fish consumption and ubiquitous methylmercury (MeHg) exposure represent a public health problem globally. Micronutrients presented in fish affects MeHg uptake/distribution. Vitamin A (VitA), another fish micronutrient is used in nutritional supplementation, especially during pregnancy. However, there is no information about the health effects arising from their combined exposure. The present study aimed to examine the effects of both MeHg and retinyl palmitate administered to pregnant and lactating rats. Thirty Wistar female rats were orally supplemented with MeHg (0,5 mg/Kg/day) and retinyl palmitate (7500 µg RAE1/Kg/day), either individually or in combination from the gestational day 0 to weaning. In dams, maternal behavior was scored. In neonatal and infant offspring, associative learning and neurodevelopment were evaluated. Further periadolescent male and female pups were assessed for open field, habituation and object recognition using episodic-like memory paradigm. Maternal and offspring redox parameters were evaluated. Our results showed no effects of MeHg-VitA co-administration in the quality of maternal care but showed subtle alterations in the pro-oxidant response of the hippocampus. In offspring, MeHg-VitA co-exposure affected early associative learning in neonatal pups, with no further modifications in neurodevelopment, and no locomotor or exploratory alterations in later developmental stages. Habituation was altered in a sex-dependent manner, but no overall memory disturbances were encountered. Finally, MeHg-VitA co-administration reduced lipoperoxidation in male offspring hippocampus. In conclusion, VitA co-administration in dams, under our exposure protocol, can counteract the deleterious neurodevelopmental effects solely attributed to low-dose MeHg in a tissue-specific mechanism, suggesting a protective effect of VitA against MeHg-induced oxidative damage in the central nervous system, especially in the offspring. Further work is needed to confirm our findings and elucidate the molecular mechanisms of MeHg-VitA modulation. Pre-clinical assays are necessary to demonstrate the potential therapeutical use of VitA in populations directly or indirectly exposed to MeHg.

Learning unfamiliar pitch intervals: A novel paradigm for demonstrating the learning of statistical associations between musical pitches.

While mastering a musical instrument takes years, becoming familiar with a new music system requires less time and skills. In this study, we examine whether musically untrained Western listeners can incidentally learn an unfamiliar, microtonal musical scale from simply engaging in a timbre discrimination task. The experiment is comprised of an Exposure and a Test phase. During Exposure, 21 non-musicians were instructed to detect a timbre shift (TS) within short microtonal melodies, and we hypothesised that they would incidentally learn about the pitch interval structure of the microtonal scale from attending to the melodies during the task. In a follow-up Test phase, the tone before the TS was either a member (congruent) or a non-member (incongruent) of the scale. Based on our statistical manipulation of the stimuli, incongruent tones would be a better predictor of an incoming TS than the congruent tones. We therefore expect a faster response time to the shift after the participants have heard an incongruent tone. Specifically, a faster response time observed after an incongruent tone would imply participants' ability to differentiate tones from the microtonal and the diatonic scale, and reflect their learning of the microtonal pitch intervals. Results are consistent with our predictions. In investigating the learning of a microtonal scale, our study can offer directions for future research on the perception of computer music and new musical genres.

Replay of Stimulus-specific Temporal Patterns during Associative Memory Formation.

Forming a memory often entails the association of recent experience with present events. This recent experience is usually an information-rich and dynamic representation of the world around us. We here show that associating a static cue with a previously shown dynamic stimulus yields a detectable, dynamic representation of this stimulus. We further implicate this representation in the decrease of low-frequency power (∼4-30 Hz) in the ongoing EEG, which is a well-known correlate of successful memory formation. The reappearance of content-specific patterns in desynchronizing brain oscillations was observed in two sensory domains, that is, in a visual condition and in an auditory condition. Together with previous results, these data suggest a mechanism that generalizes across domains and processes, in which the decrease in oscillatory power allows for the dynamic representation of information in ongoing brain oscillations.