Vagus nerve stimulation promotes extinction generalization across sensory modalities.

Traumatic experiences involve complex sensory information, and individuals with trauma-related psychological disorders, such as posttraumatic stress disorder (PTSD), can exhibit abnormal fear to numerous different stimuli that remind them of the trauma. Vagus nerve stimulation (VNS) enhances extinction of auditory fear conditioning in rat models for PTSD. We recently found that VNS-paired extinction can also promote extinction generalization across different auditory cues. Here we tested whether VNS can enhance extinction of olfactory fear and promote extinction generalization across auditory and olfactory sensory modalities. Male Sprague Dawley rats were implanted with a stimulating cuff on the cervical vagus nerve. Rats then received two days of fear conditioning where olfactory (amyl acetate odor) and auditory (9 kHz tones) stimuli were concomitantly paired with footshock. Twenty-four hours later, rats were given three days of sham or VNS-paired extinction (5 stimulations, 30-sec trains at 0.4 mA) overlapping with presentation of either the olfactory or the auditory stimulus. Two days later, rats were given an extinction retention test where avoidance of the olfactory stimulus or freezing to the auditory stimulus were measured. VNS-paired with exposure to the olfactory stimulus during extinction reduced avoidance of the odor in the retention test. VNS-paired with exposure to the auditory stimulus during extinction also decreased avoidance of the olfactory cue, and VNS paired with exposure to the olfactory stimulus during extinction reduced freezing when the auditory stimulus was presented in the retention test. These results indicate that VNS enhances extinction of olfactory fear and promotes extinction generalization across different sensory modalities. Extinction generalization induced by VNS may therefore improve outcomes of exposure-based therapies.

Avoiding Based on Shades of Gray: Generalization of Pain-Related Avoidance Behavior to Novel Contexts.

Avoidance behavior is protective, yet in the absence of genuine bodily threat, it may become disabling. Therefore, we investigated whether avoidance generalizes to novel safe contexts based on the similarity with the acquisition context. Healthy participants performed arm movements using a robotic arm to reach a target. Three trajectories (T1-3) led to the target. During acquisition, a painful stimulus could be partly/completely prevented by performing more effortful trajectories (ie, longer and more force needed), T2/T3, in the pain-avoidance context (eg, black background); in the yoked context (eg, white background), the same reinforcement schedule was applied irrespective of the chosen trajectories. Generalization of avoidance was tested in 2 novel contexts (eg, shades of gray backgrounds). We assessed self-reported pain-expectancy and pain-related fear for all trajectories, and avoidance behavior (ie, maximal deviation from T1). Results confirm that fear and expectancy ratings reflect the response-outcome contingencies and differential learning selectively generalized to the novel context resembling the original pain-avoidance context. Furthermore, a linear trend in avoidance behavior across contexts emerged, which is indicative of a generalization gradient. Participants avoided more in the context resembling the original pain-avoidance context than in the one resembling the yoked context, but this effect was not statistically significant. PERSPECTIVE: Perspective: We demonstrated acquisition of pain-related avoidance behavior in a within-subjects design, showing modulation of pain-related fear and pain-expectancy by context and providing limited evidence that avoidance selectively generalizes to novel, similar contexts. These results provide insight regarding the underlying mechanisms of the spreading of protective behavior in chronic pain patients.

Distinct Patterns of Neural Habituation and Generalization in Children and Adolescents With Autism With Low and High Sensory Overresponsivity.

OBJECTIVE: Sensory overresponsivity (SOR), an atypical negative reaction to sensory stimuli, is highly prevalent in autism spectrum disorder (ASD). Previous work has related SOR to increased brain response in sensory-limbic regions. This study investigated where these atypical responses fall in three fundamental stages of sensory processing: arousal (i.e., initial response), habituation (i.e., change in response over time), and generalization of response to novel stimuli. Different areas of atypical response would require distinct intervention approaches. METHODS: Functional MRI was used to examine these patterns of neural habituation to two sets of similar mildly aversive auditory and tactile stimuli in 42 high-functioning children and adolescents with ASD (21 with high levels of SOR and 21 with low levels of SOR) and 27 age-matched typically developing youths (ages 8-17). The relationship between SOR and change in amygdala-prefrontal functional connectivity across the sensory stimulation was also examined. RESULTS: Across repeated sensory stimulation, high-SOR participants with ASD showed reduced ability to maintain habituation in the amygdala and relevant sensory cortices and to maintain inhibition of irrelevant sensory cortices. These results indicate that sensory habituation is a dynamic, time-varying process dependent on sustained regulation across time, which is a particular deficit in high-SOR participants with ASD. However, low-SOR participants with ASD also showed distinct, nontypical neural response patterns, including reduced responsiveness to novel but similar stimuli and increases in prefrontal-amygdala regulation across the sensory exposure. CONCLUSIONS: The results suggest that all children with autism have atypical brain responses to sensory stimuli, but whether they express atypical behavioral responses depends on top-down regulatory mechanisms. Results are discussed in terms of targeted intervention approaches.

The effect of transcutaneous vagus nerve stimulation on fear generalization and subsequent fear extinction.

Fear overgeneralization is thought to be one of the cardinal processes underlying anxiety disorders, and a determinant of the onset, maintenance and recurrence of these disorders. Animal studies have shown that stimulating the vagus nerve (VNS) affects neuronal pathways implicated in pattern separation and completion, suggesting it may reduce the generalization of a fear memory to novel situations. In a one-day study, 58 healthy students were subjected to a fear conditioning, fear generalization, and fear extinction paradigm. Participants were randomly assigned to receive either transcutaneous auricular VNS (tVNS; final N = 29) or sham stimulation (final N = 29) during the generalization and extinction phases. tVNS did not affect fear generalization, as reflected by US expectancy ratings and fear potentiated startle responses. However, participants who received tVNS reported lower US expectancy ratings to the CS+ during the extinction phase, possibly reflecting a stronger declarative extinction of fear. No effects of tVNS on fear potentiated startle responses during extinction were found. The pattern of findings regarding extinction of declarative fear suggest a facilitating effect of tVNS.

Learning-Dependent and -Independent Enhancement of Mitral/Tufted Cell Glomerular Odor Responses Following Olfactory Fear Conditioning in Awake Mice.

Associative fear learning produces fear toward the conditioned stimulus (CS) and often generalization, the expansion of fear from the CS to similar, unlearned stimuli. However, how fear learning affects early sensory processing of learned and unlearned stimuli in relation to behavioral fear responses to these stimuli remains unclear. We subjected male and female mice expressing the fluorescent calcium indicator GCaMP3 in olfactory bulb mitral and tufted cells to a classical olfactory fear conditioning paradigm. We then used awake, in vivo calcium imaging to quantify learning-induced changes in glomerular odor responses, which constitute the first site of olfactory processing in the brain. The results demonstrate that odor-shock pairing nonspecifically enhances glomerular odor representations in a learning-dependent manner and increases representational similarity between the CS and nonconditioned odors, potentially priming the system toward generalization of learned fear. Additionally, CS-specific glomerular enhancements remain even when associative learning is blocked, suggesting two separate mechanisms lead to enhanced glomerular responses following odor-shock pairings.SIGNIFICANCE STATEMENT In the olfactory bulb (OB), odors are uniquely coded in a spatial map that represents odor identity, making the OB a unique model system for investigating how learned fear alters sensory processing. Classical fear conditioning causes fear of the conditioned stimulus (CS) and of neutral stimuli, known as generalization. Combining fear conditioning with fluorescent calcium imaging of OB glomeruli, we found enhanced glomerular responses of the CS as well as neutral stimuli in awake mice, which mirrors fear generalization. We report that CS and neutral stimuli enhancements are, respectively, learning-independent and learning-dependent. Together, these results reveal distinct mechanisms leading to enhanced OB processing of fear-inducing stimuli and provide important implications for altered sensory processing in fear generalization.

Effects of context preexposure and delay until anxiety retrieval on generalization of contextual anxiety.

Animal studies suggest that time delay between acquisition and retrieval of contextual anxiety increases generalization. Moreover, such generalization is prevented by preexposure to the context (CTX), presumably due to an improved representation of such context. We investigated whether preexposure and time-passing modulate generalization of contextual anxiety, in humans. On Day 1, 42 participants (preexposure group) explored two virtual offices, while 41 participants (no-preexposure group) explored a virtual stadium. On Day 2 (24 h later), all participants learned to associate one office (CTX+) with unpredictable unconditioned stimuli (USs), and another office (CTX-) with safety. On Day 3, either 24 h (recent test) or 2 wk (remote test) later, participants revisited CTX- and CTX+ without USs, as well as a generalization context (G-CTX). Results revealed successfully conditioned anxiety and anxiety generalization for ratings (G-CTX was as aversive as CTX+ was), while safety generalization was found for startle responses (G-CTX elicited startle attenuation as CTX- did). Time between learning and testing enhanced generalization as reflected by comparable startle responses to all three offices in the remote test. Contextual preexposure facilitated extinction of explicit conditioned anxiety assessed with ratings. These results suggest that memory trace of a context degrades with passage of time in humans like in animals and, consequently, anxiety generalization enhances. After context preexposure, high cognitive processes seem to be crucially involved in facilitating extinction (or safety) learning.

The neural bases of the learning and generalization of morphological inflection.

Affixal inflectional morphology has been intensively examined as a model of productive aspects of language. Nevertheless, little is known about the neurocognition of the learning and generalization of affixal inflection, or the influence of certain factors that may affect these processes. In an event-related fMRI study, we examined the neurocognition of the learning and generalization of plural inflections in an artificial language, as well as the influence of both affix type frequency (the proportion of words receiving a given affix) and affix predictability (based on phonological cues in the stem). Adult participants were trained in three sessions, and were scanned after the first and last sessions while inflecting trained and untrained words. Untrained words yielded more activation than trained words in medial frontal (including pre-SMA) and left inferior frontal cortices, which have previously shown activation in compositional grammatical processing. A reliance on phonological cues for untrained word inflection correlated positively with pre-SMA activation, but negatively with activation in the pars triangularis. Thus, pre-SMA may be involved in phonological cue-based composition, while the pars triangularis underlies alternative processes. Inflecting trained items yielded activation in the caudate head bilaterally, only in the first session, consistent with a role for procedural memory in learning grammatical regularities. The medial frontal and left inferior regions activated by untrained items were also activated by trained items, but more weakly than untrained items, with weakest activation for trained-items taking the high-frequency affix. This suggests less involvement of compositional processes for inflecting trained than untrained items, and least of all for trained inflected forms with high-frequency affixes, consistent with the storage of such forms (e.g., in declarative memory). Overall, the findings further elucidate the neural bases of the learning and generalization of affixal morphology, and the roles of affix type frequency and affix phonological predictability in these processes. Moreover, the results support and further specify the declarative/procedural model, in particular in adult language learning.

Generalization of skills between operant control and discrimination of EEG alpha.

While biofeedback is often said to increase self-control of physiological states by increasing awareness of their subjective correlates, relatively few studies have analyzed the relationship between control (standard biofeedback) and awareness (a discrimination paradigm). We hypothesized that the two skills would generalize and facilitate each other for 8-12Hz EEG amplitude (alpha). Participants were given 7 sessions of training to either control or discriminate Pz alpha followed by 3 sessions of the other paradigm. Another group was given 7 sessions with time divided equally between the two types of training. The control-training first group showed significant generalization of skills to the discrimination task. However, the reverse was not true, and the combined task group did no better in either task than the other two groups. These results provide ambivalent support for the role of awareness in biofeedback, and suggest possible improvements in the discrimination paradigm.

Generalisation, decision making, and embodiment effects in mental rotation: A neurorobotic architecture tested with a humanoid robot.

Mental rotation, a classic experimental paradigm of cognitive psychology, tests the capacity of humans to mentally rotate a seen object to decide if it matches a target object. In recent years, mental rotation has been investigated with brain imaging techniques to identify the brain areas involved. Mental rotation has also been investigated through the development of neural-network models, used to identify the specific mechanisms that underlie its process, and with neurorobotics models to investigate its embodied nature. Current models, however, have limited capacities to relate to neuro-scientific evidence, to generalise mental rotation to new objects, to suitably represent decision making mechanisms, and to allow the study of the effects of overt gestures on mental rotation. The work presented in this study overcomes these limitations by proposing a novel neurorobotic model that has a macro-architecture constrained by knowledge held on brain, encompasses a rather general mental rotation mechanism, and incorporates a biologically plausible decision making mechanism. The model was tested using the humanoid robot iCub in tasks requiring the robot to mentally rotate 2D geometrical images appearing on a computer screen. The results show that the robot gained an enhanced capacity to generalise mental rotation to new objects and to express the possible effects of overt movements of the wrist on mental rotation. The model also represents a further step in the identification of the embodied neural mechanisms that may underlie mental rotation in humans and might also give hints to enhance robots' planning capabilities.

Retention of perceptual generalization of fear extinction.

Fear reduction obtained during a fear extinction procedure can generalize from the extinction stimulus to other perceptually similar stimuli. Perceptual generalization of fear extinction typically follows a perceptual gradient, with increasing levels of fear reduction the more a stimulus resembles the extinction stimulus. The current study aimed to investigate whether perceptual generalization of fear extinction can be observed also after a retention interval of 24h. Fear was acquired to three geometrical figures of different sizes (CS(+), CS1(+) and CS2(+)) by consistently pairing them with a short-lasting suffocation experience (US). Three other geometrical figures that were never followed by the US served as control stimuli (CS(-), CS1(-), CS2(-)). Next, only the CS(+) was extinguished by presenting it in the absence of the US. One day later, fear responses to all stimuli were assessed without any US-presentation. Outcome measures included startle blink EMG, skin conductance, US expectancy, respiratory rate and tidal volume. On day 2 spontaneous recovery of fear was observed in US expectancy and tidal volume, but not in the other outcomes. Evidence for the retention of fear extinction generalization was present in US expectancy and skin conductance, but a perceptual gradient in the retention of generalized fear extinction could not be observed.

The generalization of prior uncertainty during reaching.

Bayesian statistics defines how new information, given by a likelihood, should be combined with previously acquired information, given by a prior distribution. Many experiments have shown that humans make use of such priors in cognitive, perceptual, and motor tasks, but where do priors come from? As people never experience the same situation twice, they can only construct priors by generalizing from similar past experiences. Here we examine the generalization of priors over stochastic visuomotor perturbations in reaching experiments. In particular, we look into how the first two moments of the prior--the mean and variance (uncertainty)--generalize. We find that uncertainty appears to generalize differently from the mean of the prior, and an interesting asymmetry arises when the mean and the uncertainty are manipulated simultaneously.

Biased generalization of newly learned phonological alternations by 12-month-old infants.

Previous work has suggested that learners are sensitive to phonetic similarity when learning phonological patterns (e.g., Steriade, 2001/2008; White, 2014). We tested 12-month-old infants to see if their willingness to generalize newly learned phonological alternations depended on the phonetic similarity of the sounds involved. Infants were exposed to words in an artificial language whose distributions provided evidence for a phonological alternation between two relatively dissimilar sounds ([p∼v] or [t∼z]). Sounds at one place of articulation (labials or coronals) alternated whereas sounds at the other place of articulation were contrastive. At test, infants generalized the alternation learned during exposure to pairs of sounds that were more similar ([b∼v] or [d∼z]). Infants in a control group instead learned an alternation between similar sounds ([b∼v] or [d∼z]). When tested on dissimilar pairs of sounds ([p∼v] or [t∼z]), the control group did not generalize their learning to the novel sounds. The results are consistent with a learning bias favoring alternations between similar sounds over alternations between dissimilar sounds.

Vocal generalization depends on gesture identity and sequence.

Generalization, the brain's ability to transfer motor learning from one context to another, occurs in a wide range of complex behaviors. However, the rules of generalization in vocal behavior are poorly understood, and it is unknown how vocal learning generalizes across an animal's entire repertoire of natural vocalizations and sequences. Here, we asked whether generalization occurs in a nonhuman vocal learner and quantified its properties. We hypothesized that adaptive error correction of a vocal gesture produced in one sequence would generalize to the same gesture produced in other sequences. To test our hypothesis, we manipulated the fundamental frequency (pitch) of auditory feedback in Bengalese finches (Lonchura striata var. domestica) to create sensory errors during vocal gestures (song syllables) produced in particular sequences. As hypothesized, error-corrective learning on pitch-shifted vocal gestures generalized to the same gestures produced in other sequential contexts. Surprisingly, generalization magnitude depended strongly on sequential distance from the pitch-shifted syllables, with greater adaptation for gestures produced near to the pitch-shifted syllable. A further unexpected result was that nonshifted syllables changed their pitch in the direction opposite from the shifted syllables. This apparently antiadaptive pattern of generalization could not be explained by correlations between generalization and the acoustic similarity to the pitch-shifted syllable. These findings therefore suggest that generalization depends on the type of vocal gesture and its sequential context relative to other gestures and may reflect an advantageous strategy for vocal learning and maintenance.

A history of alternative reinforcement reduces stimulus generalization of ethanol-seeking in a rat recovery model.

BACKGROUND: Longer periods of recovery reduce the likelihood of relapse, which may be due to a reduced ability of various stimuli to occasion alcohol or drug seeking. However, this hypothesis remains largely uninvestigated. METHODS: Here we assessed the ability of intermediate stimuli to occasion responding for ethanol in rats trained to discriminate an 8 kHz tone signaling a food fixed-ratio (FR) of 5 and an ethanol FR5, from a 16 kHz tone signaling a food FR150 and ethanol FR5. In the presence of the 8 kHz tone responding for food predominates, and in the presence of the 16 kHz tone, responding for ethanol predominates. RESULTS: In the context of alternation between these conditions, varying the tone from 8 to 16 kHz produces a graded increase in ethanol (versus food) responding, consistent with a stimulus generalization function. A recent history of responding under food-predominant choice conditions, either during the test session or in the four sessions that precede it shifts the generalization function downwards. Extending this history to nine sessions shifts the curve further downwards. The stimulus generalization function was similar in a separate group, trained with different relative ratios for food and ethanol, but with similar behavioral allocation under each discriminative stimulus. Finally, withholding access to food and ethanol for 4 or 16 sessions did not affect the stimulus generalization gradient. CONCLUSION: These results suggest that longer histories of reinforced alternative behavior might reduce the likelihood of relapse by decreasing the control exerted over alcohol- or drug-seeking by stimuli similar to those that previously occasioned alcohol- or drug-seeking.

Generalization of deferred imitation in 6-, 9-, and 12-month-old infants using visual and auditory contexts.

This study investigated the generalization of deferred imitation in 6-, 9-, and 12-month-old infants across auditory and visual contexts. The task involved testing for the imitation of demonstrated actions on an animal puppet 24h later. There were two independent variables defined by the background music and room of the infant's home on the test day relative to the music and room present on the demonstration day. 6-month-olds generalized imitation only when the music and room on the test day were identical to their learning environment 24h earlier. 9-month-olds were able to generalize deferred imitation across a change in music but not a change in room. 12-month-olds were able to defer imitation across both a change in the room with the same music as well as a change in both the room and music. These results reveal that the similarity between the contextual conditions of encoding and retrieval across multiple contexts determine whether infants generalize and, furthermore, the necessity of such a similarity decreases with age.

Generalization in adaptation to stable and unstable dynamics.

Humans skillfully manipulate objects and tools despite the inherent instability. In order to succeed at these tasks, the sensorimotor control system must build an internal representation of both the force and mechanical impedance. As it is not practical to either learn or store motor commands for every possible future action, the sensorimotor control system generalizes a control strategy for a range of movements based on learning performed over a set of movements. Here, we introduce a computational model for this learning and generalization, which specifies how to learn feedforward muscle activity in a function of the state space. Specifically, by incorporating co-activation as a function of error into the feedback command, we are able to derive an algorithm from a gradient descent minimization of motion error and effort, subject to maintaining a stability margin. This algorithm can be used to learn to coordinate any of a variety of motor primitives such as force fields, muscle synergies, physical models or artificial neural networks. This model for human learning and generalization is able to adapt to both stable and unstable dynamics, and provides a controller for generating efficient adaptive motor behavior in robots. Simulation results exhibit predictions consistent with all experiments on learning of novel dynamics requiring adaptation of force and impedance, and enable us to re-examine some of the previous interpretations of experiments on generalization.

Perceptual and cognitive characteristics of common playing cards.

We examined the perceptual and cognitive characteristics of the playing cards commonly used in the Western world. Specifically, we measured their visibility, memorability, likability, and verbal and visual accessibility. Based on visibility and memorability, four groups of cards were distinguished: the Ace of Spades, other Aces, number cards, and face cards. Within each of these groups, there were few differences due to value or suit. Based on likability and accessibility, three additional groups were distinguished: the Ace of Hearts, Queen of Hearts, and King of Hearts. Several interesting relations were found between how people remember, like, and access cards; some of these were similar to effects found in studies of visual perception, while others seemed entirely new. Our results demonstrate that rigorous examination of real-world stimuli can shed light on the perception of ordinary objects, as well as help us understand why magic works in the mind.

Modality effects in memory for basic stimulus attributes: a temporal and nontemporal comparison.

Previous research suggests that there are significant differences in the operation of reference memory for stimuli of different modalities, with visual temporal entries appearing to be more durable than auditory entries (Ogden, Wearden, & Jones, 2008 , 2010). Ogden et al. ( 2008 , 2010 ) demonstrated that when participants were required to store multiple auditory temporal standards over a period of delay there was significant systematic interference to the representation of the standard characterized by shifts in the location of peak responding. No such performance deterioration was observed when multiple visually presented durations were encoded and maintained. The current article explored whether this apparent modality-based difference in reference memory operation is unique to temporal stimuli or whether similar characteristics are also apparent when nontemporal stimuli are encoded and maintained. The modified temporal generalization method developed in Ogden et al. (2008) was employed; however, standards and comparisons varied by pitch (auditory) and physical line length (visual) rather than duration. Pitch and line length generalization results indicated that increasing memory load led to more variable responding and reduced recognition of the standard; however, there was no systematic shift in the location of peak responding. Comparison of the results of this study with those of Ogden et al. (2008, 2010) suggests that although performance deterioration as a consequence of increases in memory load is common to auditory temporal and nontemporal stimuli and visual nontemporal stimuli, systematic interference is unique to auditory temporal processing.

Multisensory congruency as a mechanism for attentional control over perceptual selection.

The neural mechanisms underlying attentional selection of competing neural signals for awareness remains an unresolved issue. We studied attentional selection, using perceptually ambiguous stimuli in a novel multisensory paradigm that combined competing auditory and competing visual stimuli. We demonstrate that the ability to select, and attentively hold, one of the competing alternatives in either sensory modality is greatly enhanced when there is a matching cross-modal stimulus. Intriguingly, this multimodal enhancement of attentional selection seems to require a conscious act of attention, as passively experiencing the multisensory stimuli did not enhance control over the stimulus. We also demonstrate that congruent auditory or tactile information, and combined auditory-tactile information, aids attentional control over competing visual stimuli and visa versa. Our data suggest a functional role for recently found neurons that combine voluntarily initiated attentional functions across sensory modalities. We argue that these units provide a mechanism for structuring multisensory inputs that are then used to selectively modulate early (unimodal) cortical processing, boosting the gain of task-relevant features for willful control over perceptual awareness.

Learning and generalization of time production in humans: rules of transfer across modalities and interval durations.

This article investigated both the ability of naive human subjects to learn interval production, as well as the properties of learning generalization across modalities and interval durations that varied systematically from the over-trained interval. Human subjects trained on a 450-, 650-, or 850-ms single-interval production task, using auditory stimuli to define the intervals, showed a significant decrease in performance variability with intensive training. This learning generalized to the visual modality and to non-trained durations following a Gaussian transfer pattern. However, the learning carryover followed different rules, depending on the duration of the trained interval as follows: (1) the dispersion of the generalization curve increased as a function of the trained interval, (2) the generalization pattern was tilted to the right in the visual condition, and (3) the transfer magnitude for 650 ms was less prominent than for the other two intervals. These findings suggest the existence of neural circuits that are tuned to specific time lengths and that show different temporal processing properties depending on their preferred interval duration.