Precise timing of ERK phosphorylation/dephosphorylation determines the outcome of trial repetition during long-term memory formation.

Two-trial learning in Aplysia reveals nonlinear interactions between training trials: A single trial has no effect, but two precisely spaced trials induce long-term memory. Extracellularly regulated kinase (ERK) activity is essential for intertrial interactions, but the mechanism remains unresolved. A combination of immunochemical and optogenetic tools reveals unexpected complexity of ERK signaling during the induction of long-term synaptic facilitation by two spaced pulses of serotonin (5-hydroxytryptamine, 5HT). Specifically, dual ERK phosphorylation at its activating TxY motif is accompanied by dephosphorylation at the pT position, leading to a buildup of inactive, singly phosphorylated pY-ERK. Phosphorylation and dephosphorylation occur concurrently but scale differently with varying 5HT concentrations, predicting that mixed two-trial protocols involving both "strong" and "weak" 5HT pulses should be sensitive to the precise order and timing of trials. Indeed, long-term synaptic facilitation is induced only when weak pulses precede strong, not vice versa. This may represent a physiological mechanism to prioritize memory of escalating threats.

Induced oscillatory brain responses under virtual reality conditions in the context of repetition priming.

In the human electroencephalogram (EEG), induced oscillatory responses in various frequency bands are regarded as valuable indices to examine the neural mechanisms underlying human memory. While the advent of virtual reality (VR) drives the investigation of mnemonic processing under more lifelike settings, the joint application of VR and EEG methods is still in its infancy (e.g., due to technical limitations impeding the signal acquisition). The objective of the present EEG study was twofold. First, we examined whether the investigation of induced oscillations under VR conditions yields equivalent results compared to standard paradigms. Second, we aimed at obtaining further insights into basic memory-related brain mechanisms in VR. To these ends, we relied on a standard implicit memory design, namely repetition priming, for which the to-be-expected effects are well-documented for conventional studies. Congruently, we replicated a suppression of the evoked potential after stimulus onset. Regarding the induced responses, we observed a modulation of induced alphaband in response to a repeated stimulus. Importantly, our results revealed a repetition-related suppression of the high-frequency induced gammaband response (>30 Hz), indicating the sharpening of a cortical object representation fostering behavioral priming effects. Noteworthy, the analysis of the induced gammaband responses required a number of measures to minimize the influence of external and internal sources of artefacts (i.e., the electrical shielding of the technical equipment and the control for miniature eye movements). In conclusion, joint VR-EEG studies with a particular focus on induced oscillatory responses offer a promising advanced understanding of mnemonic processing under lifelike conditions.

Prime-induced illusion of control: The influence of unconscious priming on self-initiated actions and the role of regression to the mean.

To what degree human cognition is influenced by subliminal stimuli is a controversial empirical question. One striking example was reported by Linser and Goschke (2007): participants overestimated how much control they had over objectively uncontrollable stimuli when masked congruent primes were presented immediately before the action. Critically, however, unawareness of the masked primes was established by post hoc data selection. In our preregistered study we sought to explore these findings while adjusting prime visibility based on individual thresholds, so that each participant underwent both visible and non-visible conditions. In experiment 1, N = 39 participants engaged in a control judgement task: following the presentation of a semantic prime, they freely selected between two keys, which triggered the appearance of a colored circle. The color of the circles, however, was independent of the key-press. Subsequently, participants assessed their perceived control over the circle's color, based on their key-presses, via a rating scale that ranged from 0 % (no control) to 100 % (complete control). Contrary to Linser and Goschke (2007)'s findings, this experiment demonstrated that predictive information influenced the experience of agency only when primes were consciously processed. In experiment 2, utilizing symbolic (arrow) primes, N = 35 participants had to rate their feeling of control over the effect-stimulus' identity during a two-choice identification paradigm (i.e., they were instructed to press a key corresponding to a target stimulus; with a contingency between target and effect stimulus of 75 %/25 %). The results revealed no significant influence of subliminal priming on agency perceptions. In summary, this study implies that unconscious stimuli may not exert a substantial influence on the conscious experience of agency, underscoring the need for careful consideration of methodological aspects and experimental design's impact on observed phenomena.

Conflicts between priming and episodic retrieval: a question of fluency?

Human memory consists of different underlying processes whose interaction can result in counterintuitive findings. One phenomenon that relies on various types of mnemonic processes is the repetition priming effect for unfamiliar target faces in familiarity decisions, which is highly variable and may even reverse. Here, we tested the hypothesis that this reversed priming effect may be due to a conflict between target fluency signals and episodic retrieval processes. After replicating the reverse priming effect, three different manipulations were effective in diminishing it. We suggest that each of these manipulations diminished the ambiguity regarding the source of priming-induced fluency of target processing. Our findings argue against a strictly independent view of different types of memory.

Separating the role of perceptual and conceptual fluency on masked word priming using event-related potentials.

Masked word repetition increases "old" responses on an episodic recognition test (Jacoby & Whitehouse, 1989). This effect is commonly attributed to perceptual fluency; that is, unconscious perception of the prime speeds reading of the target and this fluency leads to elevated familiarity. Two experiments directly tested the claim that perceptual fluency is responsible for word priming effects. Experiment 1 held prime-target meaning constant and altered the physical characteristics of match primes (e.g., "RIGHT" primes "RIGHT") by including both lowercase (e.g, "right") and mixed case primes (e.g., "rIgHt"). If word priming effects are due to perceptual fluency, then lowering the perceptual overlap between the prime and target should decrease or eliminate word priming effects. Instead, all three conditions showed robust priming effects in the behavioral and ERP (i.e., N400) measures. Experiment 2 equated the prime-target perceptual features and lowered the conceptual overlap by using orthographically similar nonwords as primes (e.g., "JIGHT" primes "RIGHT"). Removing prime-target conceptual overlap eliminated behavioral evidence of priming and N400 ERP differences correlated with priming. The evidence suggests that word priming effects on episodic recognition memory are more likely a product of conceptual fluency than perceptual fluency.

Instructing item-specific switch probability: expectations modulate stimulus-action priming.

Both active response execution and passive listening to verbal codes (a form of instruction) in single prime trials lead to item-specific repetition priming effects when stimuli re-occur in single probe trials. This holds for task-specific classification (stimulus-classification, SC priming, e.g., apple-small) and action (stimulus-action, SA priming, e.g., apple-right key press). To address the influence of expectation on item-specific SC and SA associations, we tested if item-specific SC and SA priming effects were modulated by the instructed probability of re-encountering individual SC or SA mappings (25% vs. 75% instructed switch probability). Importantly, the experienced item-specific switch probability was always 50%. In Experiment 1 (N = 78), item-specific SA/SC switch  expectations affected SA, but not SC priming effects exclusively following active response execution. Experiment 2 (N = 40) was designed to emphasize SA priming by only including item-specific SC repetitions. This yielded stronger SA priming for 25% vs. 75% expected switch probability, both following response execution as in Experiment 1 and also following verbally coded SA associations. Together, these results suggest that SA priming effects, that is, the encoding and retrieval of SA associations, is modulated by item-specific switch expectation. Importantly, this expectation effect cannot be explained by item-specific associative learning mechanisms, as stimuli were primed and probed only once and participants experienced item-specific repetitions/switches equally often across stimuli independent of instructed switch probabilities. This corroborates and extends previous results by showing that SA priming effects are modulated by  expectation not only based on experienced item-specific switch probabilities, but also on mere instruction.

Comprehension exposures to words in sentence contexts impact spoken word production.

Comprehension or production of isolated words and production of words embedded in sentence contexts facilitated later production in previous research. The present study examined the extent to which contextualized comprehension exposures would impact later production. Two repetition priming experiments were conducted with Spanish-English bilingual participants. In Experiment 1 (N = 112), all encoding stimuli were presented visually, and in Experiment 2 (N = 112), all encoding stimuli were presented auditorily. After reading/listening or translating isolated words or words embedded in sentences at encoding, pictures corresponding to each target word were named aloud. Repetition priming relative to new items was measured in RT and accuracy. Relative to isolated encoding, sentence encoding reduced RT priming but not accuracy priming. In reading/listening encoding conditions, both isolated and embedded words elicited accuracy priming in picture naming, but only isolated words elicited RT priming. In translation encoding conditions, repetition priming effects in RT (but not accuracy) were stronger for lower-frequency words and with lower proficiency in the picture-naming response language. RT priming was strongest when the translation response at encoding was produced in the same language as final picture naming. In contrast, accuracy priming was strongest when the translation stimulus at encoding was comprehended in the same language as final picture naming. Thus, comprehension at encoding increased the rate of successful retrieval, whereas production at encoding speeded later production. Practice of comprehension may serve to gradually move less well-learned words from receptive to productive vocabulary.

Cross-Modal Somatosensory Repetition Priming and Speech Processing.

BACKGROUND: Motor speech treatment approaches have been applied in both adults with aphasia and apraxia of speech and children with speech-sound disorders. Identifying links between motor speech intervention techniques and the modes of action (MoA) targeted would improve our understanding of how and why motor speech interventions achieve their effects, along with identifying its effective components. The current study focuses on identifying potential MoAs for a specific motor speech intervention technique. OBJECTIVES: We aim to demonstrate that somatosensory inputs can influence lexical processing, thus providing further evidence that linguistic information stored in the brain and accessed as part of speech perception processes encodes information related to speech production. METHODS: In a cross-modal repetition priming paradigm, we examined whether the processing of external somatosensory priming cues was modulated by both word-level (lexical frequency, low- or high-frequency) and speech sound articulatory features. The study participants were divided into two groups. The first group consisted of twenty-three native English speakers who received somatosensory priming stimulation to their oro-facial structures (either to labial corners or under the jaw). The second group consisted of ten native English speakers who participated in a control study where somatosensory priming stimulation was applied to their right or left forehead as a control condition. RESULTS: The results showed significant somatosensory priming effects for the low-frequency words, where the congruent somatosensory condition yielded significantly shorter reaction times and numerically higher phoneme accuracy scores when compared to the incongruent somatosensory condition. Data from the control study did not reveal any systematic priming effects from forehead stimulation (non-speech related site), other than a general (and expected) tendency for longer reaction times with low-frequency words. CONCLUSIONS: These findings provide further support for the notion that speech production information is represented in the mental lexicon and can be accessed through exogenous Speech-Language Pathologist driven somatosensory inputs related to place of articulation.

Network Degeneracy and the Dynamics of Task Switching in the Feeding Circuit in Aplysia.

The characteristics of a network are determined by parameters that describe the intrinsic properties of the component neurons and their synapses. Degeneracy occurs when more than one set of parameters produces the same (or very similar) output. It is not clear whether network degeneracy impacts network function or is simply a reflection of the fact that, although it is important for a network to be able to generate a particular output, it is not important how this is achieved. We address this issue in the feeding network of the mollusc Aplysia In this system, there are two stimulation paradigms that generate egestive motor programs: repetition priming and positive biasing. We demonstrate that circuit parameters differ in the 2 cases (e.g., egestive repetition priming requires activity in an interneuron, B20, which is not essential for positive biasing). We show that degeneracy has consequences for task switching. If egestive repetition priming is immediately followed by stimulation of an ingestive input to the feeding central pattern generator, the first few cycles of activity are egestive (not ingestive). In this situation, there is a task switch cost. This "cost" is in part due to the potentiating effect of egestive repetition priming on B20. In contrast, there is no switch cost after positive biasing. Stimulation of the ingestive central pattern generator input immediately triggers ingestive activity. Our results indicate that the mechanisms used to pattern activity can impact network function in that they can determine how readily a network can switch from one configuration to another.SIGNIFICANCE STATEMENT A particular pattern of neural activity can be generated by more than one set of circuit parameters. How or whether this impacts network function is unclear. We address this issue in the feeding network of Aplysia and demonstrate that degeneracy in network function can have consequences for task switching. Namely, we show that, when egestive activity is generated via one set of circuit modifications, an immediate switch to ingestive activity is not possible. In contrast, rapid transitions to ingestive activity are possible if egestive activity is generated via a different set of circuit modifications.

Performance Monitoring during Visual Priming.

Repetitive performance of single-feature (efficient or pop-out) visual search improves RTs and accuracy. This phenomenon, known as priming of pop-out, has been demonstrated in both humans and macaque monkeys. We investigated the relationship between performance monitoring and priming of pop-out. Neuronal activity in the supplementary eye field (SEF) contributes to performance monitoring and to the generation of performance monitoring signals in the EEG. To determine whether priming depends on performance monitoring, we investigated spiking activity in SEF as well as the concurrent EEG of two monkeys performing a priming of pop-out task. We found that SEF spiking did not modulate with priming. Surprisingly, concurrent EEG did covary with priming. Together, these results suggest that performance monitoring contributes to priming of pop-out. However, this performance monitoring seems not mediated by SEF. This dissociation suggests that EEG indices of performance monitoring arise from multiple, functionally distinct neural generators.

Prior stress followed by a novel stress challenge results in sex-specific deficits in behavioral flexibility and changes in gene expression in rat medial prefrontal cortex.

Chronic stress leads to sex-specific changes in the structure and function of rat medial prefrontal cortex (mPFC). Little is known about whether these effects persist following the cessation of chronic stress, or how these initial effects may impact responses to future stressors. Here we examined attentional set-shifting in male and female rats following chronic restraint stress, a post-chronic stress rest period, and an acute novel stress challenge. Chronic stress resulted in a reversible impairment in extradimensional set-shifting in males, but had no effect on attentional set-shifting in females. Surprisingly, chronically stressed female, but not male, rats had impaired extradimensional set-shifting following a novel stress challenge. Alterations in the balance of excitation and inhibition of mPFC have been implicated in behavioral deficits following chronic stress. Thus, in a separate group of rats, we examined changes in the expression of genes related to glutamatergic (NR1, NR2A, NR2B, GluR1) and GABAergic (Gad67, parvalbumin, somatostatin) neurotransmission in mPFC after acute and chronic stress, rest, and their combination. Stress significantly altered the expression of NR1, GluR1, Gad67, and parvalbumin. Notably, the pattern of stress effects on NR1, Gad67, and parvalbumin expression differed between males and females. In males, these genes were upregulated following the post-chronic stress rest period, while minimal changes were found in females. In contrast, both males and females had greater GluR1 expression following a rest period. These findings suggest that chronic stress leads to sex-specific stress adaptation mechanisms that may contribute to sex differences in response to subsequent stress exposure.

David and Goliath-size does matter: size modulates feature-response binding of irrelevant features.

Stimulus and response features are integrated together in episodic traces. A repetition of any of the features results in the retrieval of the entire episodic trace, including the response features. Such S-R bindings have been suggested to account for different priming effects like repetition priming, negative priming and so on. Previous studies on repetition priming have found priming effects to be size invariant. The present study examines whether the size invariance in previous priming studies was due to the absence of size-response binding. In two experiments, size was varied orthogonally to the response, either without varying any other stimulus features (Experiment 1) or while varying another stimulus feature (Experiment 2). A significant size-response binding effect was observed in Experiment 1 but not in Experiment 2. The results suggest that size is involved in feature-response binding and can retrieve the response upon repetition. However, this retrieval is extinguished if another stimulus feature is varied simultaneously. The results are discussed against the background of S-R binding as the mechanism underlying repetition priming.

A single system account of enhanced recognition memory in synaesthesia.

Researchers often adjudicate between models of memory according to the models' ability to explain impaired patterns of performance (e.g., in amnesia). In contrast, evidence from special groups with enhanced memory is very rarely considered. Here, we explored how people with unusual perceptual experiences (synaesthesia) perform on various measures of memory and test how computational models of memory may account for their enhanced performance. We contrasted direct and indirect measures of memory (i.e., recognition memory, repetition priming, and fluency) in grapheme-colour synaesthetes and controls using a continuous identification with recognition (CID-R) paradigm. Synaesthetes outperformed controls on recognition memory and showed a different reaction-time pattern for identification. The data were most parsimoniously accounted for by a single-system computational model of the relationship between recognition and identification. Overall, the findings speak in favour of enhanced processing as an explanation for the memory advantage in synaesthesia. In general, our results show how synaesthesia can be used as an effective tool to study how individual differences in perception affect cognitive functions.

Pupillometry correlates of visual priming, and their dependency on autistic traits.

In paradigms of visual search where the search feature (say color) can change from trial to trials, responses are faster for trials where the search color is repeated than when it changes. This is a clear example of "priming" of attention. Here we test whether the priming effects can be revealed by pupillometry, and also whether they are related to autistic-like personality traits, as measured by the Autism-Spectrum Quotient (AQ). We repeated Maljkovic and Nakayama's (1994) classic priming experiment, asking subjects to identify rapidly the shape of a singleton target defined by color. As expected, reaction times were faster when target color repeated, and the effect accumulated over several trials; but the magnitude of the effect did not correlate with AQ. Reaction times were also faster when target position was repeated, again independent of AQ. Presentation of stimuli caused the pupil to dilate, and the magnitude of dilation was greater for switched than repeated trials. This effect did not accumulate over trials, and did not correlate with the reaction times difference, suggesting that the two indexes measure independent aspects of the priming phenomenon. Importantly, the amplitude of pupil modulation correlated negatively with AQ, and was significant only for those participants with low AQ. The results confirm that pupillometry can track perceptual and attentional processes, and furnish useful information unobtainable from standard psychophysics, including interesting dependencies on personality traits.

The neural mechanism of fluency-based memory illusions: the role of fluency context.

Recognition memory judgments can be influenced by a variety of signals including fluency. Here, we investigated whether the neural correlates of memory illusions (i.e., misattribution of fluency to prior study) can be modulated by fluency context. Using a masked priming/recognition memory paradigm, we found memory illusions for low confidence decisions. When fluency varied randomly across trials, we found reductions in perirhinal cortex (PrC) activity for primed trials, as well as a (pre)cuneus-PrC (BA 35) connectivity. When the fluency context was unchanging, there was increased PrC activity for primed trials, with the (pre)cuneus showing greater connectivity with PrC (BA 36). Thus, our results tentatively suggest two neural mechanisms via which fluency can lead to memory illusions.

Cellular Effects of Repetition Priming in the Aplysia Feeding Network Are Suppressed during a Task-Switch But Persist and Facilitate a Return to the Primed State.

Many neural networks are multitasking and receive modulatory input, which configures activity. As a result, these networks can enter a relatively persistent state in which they are biased to generate one type of output as opposed to another. A question we address is as follows: what happens to this type of state when the network is forced to task-switch? We address this question in the feeding system of the mollusc Aplysia This network generates ingestive and egestive motor programs. We focus on an identified neuron that is selectively active when programs are ingestive. Previous work has established that the increase in firing frequency observed during ingestive programs is at least partially mediated by an excitability increase. Here we identify the underlying cellular mechanism as the induction of a cAMP-dependent inward current. We ask how this current is impacted by the subsequent induction of egestive activity. Interestingly, we demonstrate that this task-switch does not eliminate the inward current but instead activates an outward current. The induction of the outward current obviously reduces the net inward current in the cell. This produces the decrease in excitability and firing frequency required for the task-switch. Importantly, however, the persistence of the inward current is not impacted. It remains present and coexists with the outward current. Consequently, when effects of egestive priming and the outward current dissipate, firing frequency and excitability remain above baseline levels. This presumably has important functional implications in that it will facilitate a return to ingestive activity.SIGNIFICANCE STATEMENT Under physiological conditions, an animal generating a particular type of motor activity can be forced to at least briefly task-switch. In some circumstances, this involves the temporary induction of an "antagonistic" or incompatible motor program. For example, ingestion can be interrupted by a brief period of egestive activity. In this type of situation, it is often desirable for behavioral switching to occur rapidly and efficiently. In this report, we focus on a particular aspect of this type of task-switch. We determine how the priming that occurs when a multitasking network repeatedly generates one type of motor activity can be retained during the execution of an incompatible motor program.

Semantic and perceptual priming activate partially overlapping brain networks as revealed by direct cortical recordings in humans.

Facilitation of object processing in the brain due to a related context (priming) can be influenced by both semantic connections and perceptual similarity. It is thus important to discern these two when evaluating the spatio-temporal dynamics of primed object processing. The repetition-priming paradigm frequently used to study perceptual priming is, however, unable to differentiate between the mentioned priming effects, possibly leading to confounded results. In the current study, we recorded brain signals from the scalp and cerebral convexity of nine patients with refractory epilepsy in response to related and unrelated image-pairs, all of which shared perceptual features while only related ones had a semantic connection. While previous studies employing a repetition-priming paradigm observed largely overlapping networks between semantic and perceptual priming effects, our results suggest that this overlap is only partial (both temporally and spatially). These findings stress the importance of controlling for perceptual features when studying semantic priming.

Repetition priming effects for famous faces through dynamic causal modelling of latency-corrected event-related brain potentials.

Repetition priming, that is, the repeated processing of a stimulus, facilitates performance. However, the neural underpinnings of repetition priming for famous faces in terms of effective connectivity are not known. Here we investigated this problem using dynamic causal modelling of latency-corrected event-related brain potentials (RERPs). Source waveforms of RERP-derived sources in the Occipital Lobe, Fusiform Gyrus, Mediotemporal Lobe, Prefrontal Cortex and Anterotemporal Lobe of each hemisphere entered into models with only forward (F) or also with backward (FB) connections. Based on the framework of predictive coding formulated for repetition suppression, modulations of F and FB connections were expected for sources that displayed priming effects in their source waveforms. Hence, neural sources in each hemisphere were fitted with either F or FB connections. Inter-hemispheric connections were considered between homologous areas and were allowed to be modulated in an incremental manner resulting in a model space that comprised of 24 models. Bayesian model averaging across models revealed effective bidirectional connectivity between the Fusiform Gyrus (face perception) and Prefrontal Cortex (decision-making) in both hemispheres to be modulated by priming. In the left hemisphere, there is also a substantial involvement from the Mediotemporal Lobe, indicating the facilitation of automatic retrieval of the famous person's name. Furthermore, there is evidence that the priming is supported by connections from the right to the left Fusiform Gyri possibly in the service of inter-hemispheric cooperation. Altogether, the study indicates that along with top-down modulations, efficient processing within and across the two hemispheres is crucial for famous face priming.

An Opponent Process Cerebellar Asymmetry for Regulating Word Association Priming.

A consensus has emerged that the cerebellum makes important contributions to a spectrum of linguistic processes, but that the psychobiology of these contributions remains enigmatic (Mariën et al., Cerebellum 13(3):386-410, 2014). One aspect of this enigma arises from the fact that, although the language-dominant left cerebral hemisphere is connected to the right cerebellum, distinctive contributions of the left cerebellar hemisphere have been documented (Murdoch and Whelan, Folia Phoniatr Logop 59:184-9, 2007), but remain poorly understood. Here, we report that neurodisruption of the left and right cerebellar hemispheres have opposite effects on associative word priming in a lexical decision task. Reaction time was measured for decisions on whether a target letter string constituted a word (e.g. bread) or, with equal probability, a pronounceable non-word (e.g. dreab). A prime word was presented for 150 ms before the target and could either, and with equal probability, be related (e.g. BUTTER) or unrelated (TRACTOR). Associative word priming was computed as the reduction in lexical decision RT on trials with related primes. Left cerebellar hemisphere continuous theta-burst transcranial magnetic stimulation (TMS) decreased, and right hemisphere stimulation increased, priming. The results suggest that the cerebellum contributes to predictive sequential processing, in this case language, through an opponent process mechanism coordinated by both cerebellar hemispheres.

Negative priming is diminished under high blood pressure in healthy subjects.

The ability to ignore distracting objects is a core mechanism in selective attention and has been analyzed particularly with respect to its clinical implications (e.g., depression, schizophrenia, or unhealthy life-style). Here, we investigated the correlation between an established experimental task to measure distractor-processing and participants' blood pressure. We used the negative priming (NP) task in which participants show worse performance to target stimuli that were distractors in the previous trial. Notably, our participants were all healthy, young subjects but nevertheless we observed a correlation between blood pressure levels and NP effects, the higher the blood pressure the less NP was shown by participants. Our results suggest that processes modulated by higher blood pressure diminish the ability to successful ignore distracting objects not only at hypertension levels.