Converging neural and behavioral evidence for a rapid, generalized response to threat-related facial expressions in 3-year-old children.

Electrophysiological studies on adults suggest that humans are efficient at detecting threat from facial information and tend to grant these signals a priority in access to attention, awareness, and action. The developmental origins of this bias are poorly understood, partly because few studies have examined the emergence of a generalized neural and behavioral response to distinct categories of threat in early childhood. We used event-related potential (ERP) and eye-tracking measures to examine children's early visual responses and overt attentional biases towards multiple exemplars of angry and fearful vs. other (e.g., happy and neutral) faces. A large group of children was assessed longitudinally in infancy (5, 7, or 12 months) and at 3 years of age. The final ERP dataset included 148 infants and 132 3-year-old children; and the final eye-tracking dataset included 272 infants and 334 3-year-olds. We demonstrate that 1) neural and behavioral responses to facial expressions converge on an enhanced response to fearful and angry faces at 3 years of age, with no differentiation between or bias towards one or the other of these expressions, and 2) a support vector machine learning model using data on the early-stage neural responses to threat reliably predicts the duration of overt attentional dwell time for threat-related faces at 3 years. However, we found little within-subject correlation between threat-bias attention in infancy and at 3 years of age. These results provide unique evidence for the early development of a rapid, unified response to two distinct categories of facial expressions with different physical characteristics, but shared threat-related meaning.

Generalizing to generalize: Humans flexibly switch between compositional and conjunctive structures during reinforcement learning.

Humans routinely face novel environments in which they have to generalize in order to act adaptively. However, doing so involves the non-trivial challenge of deciding which aspects of a task domain to generalize. While it is sometimes appropriate to simply re-use a learned behavior, often adaptive generalization entails recombining distinct components of knowledge acquired across multiple contexts. Theoretical work has suggested a computational trade-off in which it can be more or less useful to learn and generalize aspects of task structure jointly or compositionally, depending on previous task statistics, but it is unknown whether humans modulate their generalization strategy accordingly. Here we develop a series of navigation tasks that separately manipulate the statistics of goal values ("what to do") and state transitions ("how to do it") across contexts and assess whether human subjects generalize these task components separately or conjunctively. We find that human generalization is sensitive to the statistics of the previously experienced task domain, favoring compositional or conjunctive generalization when the task statistics are indicative of such structures, and a mixture of the two when they are more ambiguous. These results support a normative "meta-generalization" account and suggests that people not only generalize previous task components but also generalize the statistical structure most likely to support generalization.

Stimulus Unpredictability in Time, Magnitude, and Direction on Accommodation.

SIGNIFICANCE: The effect of predictability in changes of time, magnitude, and direction of the accommodation demand on the accommodation response latency and its magnitude are insignificant, which suggests that repetitive accommodative tasks such as the clinical accommodative facility test may not be influenced by potential anticipation effects. PURPOSE: The purpose of this study was to investigate the effect of stimulus' time, magnitude, and direction predictability, as well as their interactions, on accommodation latency and response magnitude. METHODS: Monocular accommodative response and latency were measured in 12 young subjects for nine different conditions where the stimulus accommodative demand changed several times in a steplike fashion for a period of 120 seconds. Each change in accommodative demand could have different time duration (i.e., 1, 2, or 3 seconds), magnitude (1, 2, or 3 diopters), and/or direction (i.e., accommodation or disaccommodation). All conditions were created permuting the factors of time, magnitude, and direction with two levels each: random and not random. The baseline condition was a step signal from 0 to 2 diopters persisting for 2 seconds in both accommodative demands. After each condition, subjects were asked to provide a score from 1 to 5 in their perceived predictability. RESULTS: Friedman test conducted on the perceived predictability of each condition resulted in statistically significant differences between the nine conditions (χ = 56.57, P < .01). However, repeated-measures analysis of variance applied to latency and accommodative response magnitude did not show significant differences (P > .05). In addition, no correlation was found between the perceived predictability scores and both latency and accommodative response magnitudes between the most predictable and the most unpredictable conditions. CONCLUSIONS: Subjects were able to perceptually notice whether the stimulus was predictable or not, although our results indicate no significant effect of stimuli predictability on either the accommodation latency or its magnitude.

The relationship of perceptual discrimination to neural mechanisms of fear generalization.

The generalization of conditioned fear responses has been shown to decrease as a function of perceptual similarity. However, generalization may also extend beyond the perceptual discrimination threshold, ostensibly due to contributions from processes other than perception. Currently the neural mechanisms that mediate perceptual and non-perceptual aspects of fear generalization are unclear. To investigate this question, we conducted a Pavlovian fear conditioning and generalization experiment, collecting functional magnetic resonance imaging (fMRI), skin conductance and explicit shock likelihood ratings, in 37 healthy subjects. Face stimuli were initially paired (CS+) or not paired (CS) with an electrical shock. During the generalization phase, responses were measured to the CS+, CS and a range of CS + -toCS morphs (generalization stimuli), selected for each participant based on that participant's discrimination ability. Across multiple measurements, we found that fear generalization responses were limited to stimuli that could not be distinguished from the CS + stimulus, thus following a gradient closely linked to perceptual discriminability. These measurements, which were correlated with one another, included skin conductance responses, behavioral ratings, and fMRI responses of anterior insula and superior frontal gyrus. In contrast, responses in areas of the default network, including the posterior cingulate gyrus, angular gyrus and hippocampus, showed a negative generalization function extending to stimuli that were more likely to be distinguished from the CS+. In addition, the generalization gradients of the anterior insula and the behavioral ratings showed some evidence for extension beyond perceptual limits. Taken together, these results suggest that distinct brain areas are involved in perceptual and non-perceptual components of fear generalization.

Assessing the generalizability of eye dominance across binocular rivalry, onset rivalry, and continuous flash suppression.

It is commonly assumed that one eye is dominant over the other eye. Eye dominance is most frequently determined by using the hole-in-the-card test. However, it is currently unclear whether eye dominance as determined by the hole-in-the-card test (so-called sighting eye dominance) generalizes to tasks involving interocular conflict (engaging sensory eye dominance). We therefore investigated whether sighting eye dominance is linked to sensory eye dominance in several frequently used paradigms that involve interocular conflict. Eye dominance was measured by the hole-in-the-card test, binocular rivalry, and breaking continuous flash suppression (b-CFS). Relationships between differences in eye dominance were assessed using Bayesian statistics. Strikingly, none of the three interocular conflict tasks yielded a difference in perceptual report between eyes when comparing the dominant eye with the nondominant eye as determined by the hole-in-the-card test. From this, we conclude that sighting eye dominance is different from sensory eye dominance. Interestingly, eye dominance of onset rivalry correlated with that of ongoing rivalry but not with that of b-CFS. Hence, we conclude that b-CFS reflects a different form of eye dominance than onset and ongoing rivalry. In sum, eye dominance seems to be a multifaceted phenomenon, which is differently expressed across interocular conflict paradigms. Finally, we highly discourage using tests measuring sighting eye dominance to determine the dominant eye in a subsequent experiment involving interocular conflict. Rather, we recommend that whenever experimental manipulations require a priori knowledge of eye dominance, eye dominance should be determined using pretrials of the same task that will be used in the main experiment.

Early life stress in rats sex-dependently affects remote endocrine rather than behavioral consequences of adult exposure to contextual fear conditioning.

Exposure to electric foot-shocks can induce in rodents contextual fear conditioning, generalization of fear to other contexts and sensitization of the hypothalamic-pituitary-adrenal (HPA) axis to further stressors. All these aspects are relevant for the study of post-traumatic stress disorder. In the present work we evaluated in rats the sex differences and the role of early life stress (ELS) in fear memories, generalization and sensitization. During the first postnatal days subjects were exposed to restriction of nesting material along with exposure to a "substitute" mother. In the adulthood they were exposed to (i) a contextual fear conditioning to evaluate long-term memory and extinction and (ii) to a novel environment to study cognitive fear generalization and HPA axis heterotypic sensitization. ELS did not alter acquisition, expression or extinction of context fear conditioned behavior (freezing) in either sex, but reduced activity in novel environments only in males. Fear conditioning associated hypoactivity in novel environments (cognitive generalization) was greater in males than females but was not specifically affected by ELS. Although overall females showed greater basal and stress-induced levels of ACTH and corticosterone, an interaction between ELS, shock exposure and sex was found regarding HPA hormones. In males, ELS did not affect ACTH response in any situation, whereas in females, ELS reduced both shock-induced sensitization of ACTH and its conditioned response to the shock context. Also, shock-induced sensitization of corticosterone was only observed in males and ELS specifically reduced corticosterone response to stressors in males but not females. In conclusion, ELS seems to have only a minor impact on shock-induced behavioral conditioning, while affecting the unconditioned and conditioned responses of HPA hormones in a sex-dependent manner.

Do clinicians think that pain can be a classically conditioned response to a non-noxious stimulus?

BACKGROUND: Anecdotally, clinical presentations in which pain seems to be elicited by non-noxious stimuli are often explained using a classical conditioning framework. We were primarily interested in whether (a) clinicians think that pain can be a classically conditioned response to a non-noxious stimulus, and (b) clinicians think that there is evidence to support that idea. METHOD: Practising healthcare clinicians participated anonymously in an online survey. The information collected included descriptive demographics, clinical experience, personal experience of chronic pain, beliefs about pain, and beliefs about classical conditioning and pain. Responses to the pre-requisite question - whether pain can occur without nociception - were compared to a historical data set from 2004. RESULTS: 1090 people from 57 countries and eight distinct types of health profession completed the survey. 86% stated that pain can occur without nociception; 96% of those believed that pain can be a classically conditioned response to a non-noxious stimulus; 98% of those believed that there is evidence to support that statement. The 2004 data showed that 44% of participants distinguished between pain and nociception. CONCLUSIONS: This broad sample overwhelmingly endorsed the ideas that clinicians think that pain can be a classically conditioned response to a non-noxious stimulus and think that there is evidence to support that idea, revealing a discrepancy between beliefs in the clinical community and the scientific evidence. The distinction between nociception and pain has become more accepted by the clinical community over the last 10 years.

Effect of context exposure after fear learning on memory generalization in mice.

BACKGROUND: The conditions under which memory generalization occurs are not well understood. Although it is believed that fear memory generalization is gradually established after learning, it is not clear whether experiences soon after learning affect generalization. RESULTS: Using a contextual fear conditioning paradigm in mice, we found that fear memory generalization occurred when mice were exposed to a familiar, unconditioned context soon after fear learning. CONCLUSIONS: Our results suggest that the familiarity of contexts and the timing of their exposure influences memory generalization, which increases our understanding of the mechanisms of generalization.

Prefrontal NMDA receptors expressed in excitatory neurons control fear discrimination and fear extinction.

N-methyl-D-aspartate receptors (NMDARs) are critically involved in various learning mechanisms including modulation of fear memory, brain development and brain disorders. While NMDARs mediate opposite effects on medial prefrontal cortex (mPFC) interneurons and excitatory neurons, NMDAR antagonists trigger profound cortical activation. The objectives of the present study were to determine the involvement of NMDARs expressed specifically in excitatory neurons in mPFC-dependent adaptive behaviors, specifically fear discrimination and fear extinction. To achieve this, we tested mice with locally deleted Grin1 gene encoding the obligatory NR1 subunit of the NMDAR from prefrontal CamKIIα positive neurons for their ability to distinguish frequency modulated (FM) tones in fear discrimination test. We demonstrated that NMDAR-dependent signaling in the mPFC is critical for effective fear discrimination following initial generalization of conditioned fear. While mice with deficient NMDARs in prefrontal excitatory neurons maintain normal responses to a dangerous fear-conditioned stimulus, they exhibit abnormal generalization decrement. These studies provide evidence that NMDAR-dependent neural signaling in the mPFC is a component of a neural mechanism for disambiguating the meaning of fear signals and supports discriminative fear learning by retaining proper gating information, viz. both dangerous and harmless cues. We also found that selective deletion of NMDARs from excitatory neurons in the mPFC leads to a deficit in fear extinction of auditory conditioned stimuli. These studies suggest that prefrontal NMDARs expressed in excitatory neurons are involved in adaptive behavior.

A visuomotor disorder in the absence of movement: does optic ataxia generalize to learned isometric hand action?

Visuomotor deficits in parietal patients suffering from Optic Ataxia (OA) have been so far studied during natural reaching movements. We aimed at understanding if these disorders are also present when more abstract visuomotor transformations are involved. A patient with unilateral OA was tested during both standard reaches and isometric actions, therefore in the absence of hand displacement. Isometric action was affected similarly to standard reaches, with endpoint errors to visual targets that were found in both central and peripheral vision. The dissociation of perceptual and motor components of errors highlighted the existence of field, hand and hemispace effects, which depended on the type of error investigated. A generalization of the reaching disorder to learned isometric conditions would suggest that lesions of posterior parietal cortex (PPC) affect sensory-motor transformations not only for standard reaches, but also when visual signals need to be aligned with information from hand force receptors, therefore regardless of the specific remapping required to generate the directional motor output. The isometric impairment emerged with high and similar severity regardless of whether targets were in central or peripheral vision. Since under all isometric conditions gaze and hand position were decoupled, the spatial correspondence between the hand and the gaze seems to play a critical role in this syndrome. This indicates that regardless of the action to be performed and the specific remapping required, there exists in PPC an abstract representation of the directional motor output, where the computation of eye-hand alignment by parietal neurons plays a crucial role.

Consolidation and long-term retention of an implanted behavioral memory.

Hypothesized circuitry enabling information storage can be tested by attempting to implant memory directly in the brain in the absence of normal experience. Previously, we found that tone paired with activation of the cholinergic nucleus basalis (NB) does induce behavioral memory that shares cardinal features with natural memory; it is associative, highly specific, rapidly formed, consolidates and shows intermediate retention. Here we determine if implanted memory also exhibits long-term consolidation and retention. Adult male rats were first tested for behavioral responses (disruption of ongoing respiration) to tones (1-15 kHz), yielding pre-training behavioral frequency generalization gradients. They next received 3 days of training with a conditioned stimulus (CS) tone (8.0 kHz, 70 dB, 2s) either paired (n=7) or unpaired (n=6) with moderate electrical stimulation of the nucleus basalis (∼ 65 µA, 100 Hz, 0.2s, co-terminating with CS offset). Testing for long-term retention was performed by obtaining post-training behavioral frequency generalization gradients 24h and 2 weeks after training. At 24h post-training, the Paired group exhibited specific associative behavioral memory, manifested by larger responses to the CS frequency band than the Unpaired group. This memory was retained 2 weeks post-training. Moreover, 2 weeks later, the specificity and magnitude of memory had become greater, indicating that the implanted memory had undergone consolidation. Overall, the results demonstrate the validity of NB-implanted memory for understanding natural memory and that activation of the cholinergic nucleus basalis is sufficient to form natural associative memory.

Gesture imitation in musicians and non-musicians.

Imitation plays a crucial role in the learning of many complex motor skills. Recent behavioral and neuroimaging evidence suggests that the ability to imitate is influenced by past experience, such as musical training. To investigate the impact of musical training on motor imitation, musicians and non-musicians were tested on their ability to imitate videoclips of simple and complex two-handed gestures taken from American Sign Language. Participants viewed a set of 30 gestures, one at a time, and imitated them immediately after presentation. Participants' imitations were videotaped and scored off-line by raters blind to participant group. Imitation performance was assessed by a rating of performance accuracy, where the arm, hand, and finger components of the gestures were rated separately on a 5-point scale (1 = unrecognizable; 5 = exact imitation). A global accuracy score (PAglobal) was calculated by summing the three components. Response duration compared to the model (%MTdiff), and reaction time (RT) were also assessed. Results indicated that musicians were able to imitate more accurately than non-musicians, reflected by significantly higher PAglobal and lower %MTdiff scores. Furthermore, the greatest difference in performance was for the fine-motor (finger) gesture component. These findings support the view that the ability to imitate is influenced by experience. This is consistent with generalist theories of motor imitation, which explain imitation in terms of links between perceptual and motor action representations that become strengthened through experience. It is also likely that musical training contributed to the ability to imitate manual gestures by influencing the personal action repertoire of musicians.

Perceptual learning modifies inversion effects for faces and textures.

We trained subjects to identify either upright or inverted faces in a 10AFC task and measured performance subsequently in four conditions: same- and different-upright faces, and same- and different-inverted faces. Performance improved for both the upright-trained and the inverted-trained groups. The improvements were highly specific to the trained face exemplars, and largely specific to the trained face orientations. This pattern of results yielded an increase in the face-inversion effect after upright-training, and a decrease in the inversion effect after inverted-training, but only for the trained set of faces in both groups. A similar pattern of results was found for phase-scrambled faces in which the configural structure of faces had been removed: although there was no baseline inversion effect for the scrambled stimuli, inversion effects emerged after training. We consider the implications of this pattern of learning for current views on the face-inversion effect, and face-encoding more generally.

Neural activation to babyfaced men matches activation to babies.

Behavioral data supports the commonsense view that babies elicit different responses than adults do. Behavioral research also has supported the babyface overgeneralization hypothesis that the adaptive value of responding appropriately to babies produces a tendency for these responses to be overgeneralized to adults whose facial structure resembles babies. Here we show a neural substrate for responses to babies and babyface overgeneralization in the amygdala and the fusiform face area (FFA). Both regions showed greater percentage BOLD signal change compared with fixation when viewing faces of babies or babyfaced men than maturefaced men. Viewing the first two categories also yielded greater effective connectivity between the two regions. Facial qualities previously shown to elicit strong neural activation could not account for the effects. Babyfaced men were distinguished only by their resemblance to babies. The preparedness to respond to infantile facial qualities generalizes to babyfaced men in perceivers' neural responses just as it does in their behavioral reactions.

Generalization of gait adaptation for fall prevention: from moveable platform to slippery floor.

A person's ability to transfer the acquired improvements in the control of center of mass (COM) state stability to slips induced in everyday conditions can have profound theoretical and practical implications for fall prevention. This study investigated the extent to which such generalization could take place. A training group (n=8) initially experienced 24 right-side slips in blocked-and-random order (from the 1st unannounced, novel slip, S-1 to the last, S-24) resulting from release of a low-friction moveable platform in walking. They then experienced a single unannounced slip while walking on an oil-lubricated vinyl floor surface (V-T). A control group (n=8) received only one unannounced slip on the same slippery floor (V-C). Results demonstrated that the incidence of balance loss and fall on V-T was comparable to that on S-24. In both trials, fall and balance-loss incidence was significantly reduced in comparison with that on S-1 or on V-C, resulting from significant improvements in the COM state stability. The observed generalization indicates that the control of COM stability can be optimally acquired to accommodate alterations in environmental constraints, and it may be broadly coded and easily modifiable within the CNS. Because of such mechanisms, it is possible that the locomotor-balance skills acquired with the aid of low-friction moveable platforms can translate into resisting falls encountered in daily living.

A new way to quantify the fidelity of imitation: preliminary results with gesture sequences.

Imitation is a common and effective way for humans to learn new behaviors. Until now, the study of imitation has been hampered by the challenge of measuring how well an attempted imitation corresponds to its stimulus model. We describe a new method for quantifying the fidelity with which observers imitate complex series of gestures. Wearing a data glove that transduced movements of their digits, subjects viewed and then reproduced a sequence of gestures from memory. The velocity profile of each digit's flexion or extension was used to segment movements made during an imitation into gestures that can be compared against corresponding gestures in the stimulus model. The outcome is a multivariate description of each imitation, including its temporal characteristics, as well as spatial errors (in individual gestures and in the ordering of those gestures). As a demonstration, we applied this method to data from an imitation learning experiment with gesture sequences. With repetition, overall fidelity of imitation improved, with various aspects of the imitation improving at different rates. Confirming the approach's usefulness, when we varied the complexity associated with imitation, that variation was robustly reflected in our measures of imitation quality. Finally, we describe a simple way to extend our methods to make them useful not only in assessing imitation and imitation learning, but also in various settings in which the detection and characterization of subtle abnormalities in movement production is paramount.

Potentiation, overshadowing, and blocking of spatial learning based on the shape of the environment.

Rats were trained in Experiment 1 to find a submerged platform in 1 corner of either a rectangular or a kite-shaped pool. When the walls creating this corner were a different color than the opposite walls, then learning about the shape of the pool was potentiated in the kite but not in the rectangle. Experiments 2-4 revealed that learning about the rectangle can be overshadowed and blocked when information about the wall color indicates the location of the platform. The results mimic findings that have been obtained with Pavlovian conditioning, and they challenge the claim that learning about the shape of the environment takes places in a dedicated geometric module.

Transfer of spatial behavior between different environments: implications for theories of spatial learning and for the role of the hippocampus in spatial learning.

In 3 experiments, rats were required to find a submerged platform located in 1 corner of an arena that had 2 long and 2 short sides; they were then trained to find the platform in a new arena that also had 2 long and 2 short sides but a different overall shape. The platform in the new arena was easier to find if it was in a corner that was geometrically equivalent, rather than the mirror image, of the corner where it had previously been located. The final experiment revealed that hippocampal lesions impaired rats' ability to find the platform in these arenas. The results suggest that rats did not use the overall shape of the arena to locate the platform but relied on more local cues and that the hippocampus plays a role in navigation based on these cues.

Multiple n = 1 trials in the identification of responders and non-responders to the cognitive effects of Ginkgo biloba.

OBJECTIVE: A pilot study to assess multiple crossover n = 1 trials with verum/placebo discrimination as the outcome measure as a means of identifying responders and non-responders to the acute nootropic effect of Ginkgo biloba (G. biloba) among healthy volunteers. METHOD: Multiple double-blind, placebo-controlled n = 1 trials with 8 treatments in randomized order and separated by minimum washout periods of 7 days. Treatments were acute 120 mg doses of G. biloba extract (GK501) or undistinguishable placebo. The frequency distribution of correct scores for verum-placebo discrimination was compared with the binomial distribution to identify putative responders, who were then tested for consistency of performance over a further 8 treatments. RESULTS: The frequency distribution of scores (n = 11) was bimodal and a discontinuity defined 3 putative responders and 2 putative negative responders for re-test. Two of the putative responders again performed at above chance level and the probability of achieving their scores or better by chance was 0.013 and 0.052. CONCLUSIONS: n = 1 trials with verum/placebo discrimination as outcome are a promising method for exploring response heterogeneity to treatments with a subjective effect. Preliminary evidence suggests that there are responders and non-responders to an acute G. biloba treatment among healthy subjects.

Dissociating hippocampal versus basal ganglia contributions to learning and transfer.

Based on prior animal and computational models, we propose a double dissociation between the associative learning deficits observed in patients with medial temporal (hippocampal) damage versus patients with Parkinson's disease (basal ganglia dysfunction). Specifically, we expect that basal ganglia dysfunction may result in slowed learning, while individuals with hippocampal damage may learn at normal speed. However, when challenged with a transfer task where previously learned information is presented in novel recombinations, we expect that hippocampal damage will impair generalization but basal ganglia dysfunction will not. We tested this prediction in a group of healthy elderly with mild-to-moderate hippocampal atrophy, a group of patients with mild Parkinson's disease, and healthy controls, using an "acquired equivalence" associative learning task. As predicted, Parkinson's patients were slower on the initial learning but then transferred well, while the hippocampal atrophy group showed the opposite pattern: good initial learning with impaired transfer. To our knowledge, this is the first time that a single task has been used to demonstrate a double dissociation between the associative learning impairments caused by hippocampal versus basal ganglia damage/dysfunction. This finding has implications for understanding the distinct contributions of the medial temporal lobe and basal ganglia to learning and memory.