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Exposure to psychosocial deprivation is associated with elevations in numerous forms of impairment throughout the life-course. Disruptions in associative learning may be a key mechanism through which adversity, particularly psychosocial deprivation, increases risk for impairment. Existing data consistent with this claim come entirely from correlational studies. Here, we present the first experimental evidence relating psychosocial deprivation and disruptions in multiple forms of associative learning. Using data from the Bucharest Early Intervention Project, we demonstrate that randomized placement into a family caregiving environment during the infant/toddler period as compared to prolonged institutional care normalizes two forms of associative learning in early adolescence: reward responsivity and implicit motor learning. These forms of associative learning significantly mediate the effect of institutional rearing on depressive symptoms and peer relationships. In sum, we provide evidence for a novel pathway linking early experience to psychopathology and peer relationships through basic associative learning mechanisms. Early childhood deprivation such as institutionalization can greatly affect early development. Here, the authors study children who were raised in institutions but later randomly placed in foster care vs. not, to understand how early-life deprivation affects associative learning in adolescence.

Transcranial alternating current stimulation (tACS) has been reported to improve associative memory (AM) by modulating the frequency of neural oscillations in the brain; however, whether gamma-frequency (> 30 Hz) tACS in the left posterior parietal lobe (PPC) can enhance memory retention in AM remains unclear. This study aimed to investigate whether memory retention in AM could be improved after gamma-frequency tACS of the left PPC. We used a randomly assigned, double-blind, repeated-measures, sham-control design, in which 28 healthy adult participants were assigned to receive a single 20-min session of gamma-frequency (60 Hz) tACS or sham stimulation. The memory learning task consisted of studying and testing 50 unrelated word pairs three times on day 1. The number of correct responses in the cued recall task was measured at three time points: days 1, 7, and 28. The results revealed a significant difference in the number of correct responses between the interventions on day 7 and day 28. These data suggest that gamma-frequency tACS stimulation of the left PPC enhances the long-term retention of AM in healthy adults.

The complementary learning systems account of declarative memory suggests two distinct memory networks, a fast-mapping, episodic system involving the hippocampus, and a slower semantic memory system distributed across the neocortex in which new information is gradually integrated with existing representations. In this study, we investigated the extent to which these two networks are involved in the integration of novel words into the lexicon after extensive learning, and how the involvement of these networks changes after 24h. In particular, we explored whether having richer information at encoding influences the lexicalization trajectory. We trained participants with two sets of novel words, one where exposure was only to the words' phonological forms (the form-only condition), and one where pictures of unfamiliar objects were associated with the words' phonological forms (the picture-associated condition). A behavioral measure of lexical competition (indexing lexicalization) indicated stronger competition effects for the form-only words. Imaging (fMRI) results revealed greater involvement of phonological lexical processing areas immediately after training in the form-only condition, suggesting that tight connections were formed between novel words and existing lexical entries already at encoding. Retrieval of picture-associated novel words involved the episodic/hippocampal memory system more extensively. Although lexicalization was weaker in the picture-associated condition, overall memory strength was greater when tested after a 24hour delay, probably due to the availability of both episodic and lexical memory networks to aid retrieval. It appears that, during lexicalization of a novel word, the relative involvement of different memory networks differs according to the richness of the information about that word available at encoding. •Novel words are better remembered if associated with pictorial information.•Novel words with pictures involved the hippocampal memory system at retrieval.•Neocortical activation for novel words with pictures increased with consolidation.•Novel words without pictures showed increased lexical competition after 24h.•Novel words without pictures involved more phonological processing.

Navigating the physical world requires learning probabilistic associations between sensory events and their change in time (volatility). Bayesian accounts of this learning process rest on hierarchical prediction errors (PEs) that are weighted by estimates of uncertainty (or its inverse, precision). In a previous fMRI study we found that low-level precision-weighted PEs about visual outcomes (that update beliefs about associations) activated the putative dopaminergic midbrain; by contrast, precision-weighted PEs about cue-outcome associations (that update beliefs about volatility) activated the cholinergic basal forebrain. These findings suggested selective dopaminergic and cholinergic influences on precision-weighted PEs at different hierarchical levels. Here, we tested this hypothesis, repeating our fMRI study under pharmacological manipulations in healthy participants. Specifically, we performed two pharmacological fMRI studies with a between-subject double-blind placebo-controlled design: study 1 used antagonists of dopaminergic (amisulpride) and muscarinic (biperiden) receptors, study 2 used enhancing drugs of dopaminergic (levodopa) and cholinergic (galantamine) modulation. Pooled across all pharmacological conditions of study 1 and study 2, respectively, we found that low-level precision-weighted PEs activated the midbrain and high-level precision-weighted PEs the basal forebrain as in our previous study. However, we found pharmacological effects on brain activity associated with these computational quantities only when splitting the precision-weighted PEs into their PE and precision components: in a brainstem region putatively containing cholinergic (pedunculopontine and laterodorsal tegmental) nuclei, biperiden (compared to placebo) enhanced low-level PE responses and attenuated high-level PE activity, while amisulpride reduced high-level PE responses. Additionally, in the putative dopaminergic midbrain, galantamine compared to placebo enhanced low-level PE responses (in a body-weight dependent manner) and amisulpride enhanced high-level precision activity. Task behaviour was not affected by any of the drugs. These results do not support our hypothesis of a clear-cut dichotomy between different hierarchical inference levels and neurotransmitter systems, but suggest a more complex interaction between these neuromodulatory systems and hierarchical Bayesian quantities. However, our present results may have been affected by confounds inherent to pharmacological fMRI. We discuss these confounds and outline improved experimental tests for the future.

The renewal effect describes the recovery of extinguished responses that may occur after a change in context and indicates that extinction memory retrieval is sometimes prone to failure. Stress hormones have been implicated to modulate extinction processes, with mostly impairing effects on extinction retrieval. However, the neurobiological mechanisms mediating stress effects on extinction memory remain elusive. In this functional magnetic resonance imaging study, we investigated the effects of cortisol administration on the neural correlates of extinction memory retrieval in a predictive learning task. In this task, participants were required to predict whether certain food stimuli were associated with stomach trouble when presented in two different contexts. A two-day renewal paradigm was applied in which an association was acquired in context A and subsequently extinguished in context B. On the following day, participants received either cortisol or placebo 40min before extinction memory retrieval was tested in both contexts. Behaviorally, cortisol impaired the retrieval of extinguished associations when presented in the extinction context. On the neural level, this effect was characterized by a reduced context differentiation for the extinguished stimulus in the ventromedial prefrontal cortex, but only in men. In the placebo group, ventromedial prefrontal cortex was functionally connected to the left cerebellum, the anterior cingulate and the right anterior parahippocampal gyrus to express extinction memory. This functional crosstalk was reduced under cortisol. These findings illustrate that the stress hormone cortisol disrupts ventromedial prefrontal cortex functioning and its communication with other brain regions implicated in extinction memory. •Extinction retrieval was studied using a predictive learning task.•The stress hormone cortisol impaired extinction retrieval.•Cortisol reduced differential neural activity in the vm PFC.•Cortisol disrupted the functional connectivity of the vmPFC.

Conditioned pain-related fear may contribute to hyperalgesia and central sensitization, but this has not been tested for interoceptive, visceral pain. The underlying ability to accurately predict pain is based on predictive cue properties and may alter the sensory processing and cognitive–emotional modulation of pain thus exacerbating the subjective pain experience. In this functional magnetic resonance imaging study using painful rectal distensions as unconditioned stimuli (US), we addressed changes in the neural processing of pain during the acquisition of pain-related fear and subsequently tested if conditioned stimuli (CS) contribute to hyperalgesia and increased neural responses in pain-encoding regions. N=49 healthy volunteers were assigned to one of two groups and underwent 3T fMRI during acquisition of either differential fear conditioning (predictable) or non-contingent presentation of CS and US (unpredictable). During a subsequent test phase, pain stimuli signaled randomly by the CSs were delivered. For the acquisition, results confirmed differential conditioning in the predictable but not the unpredictable group. With regard to activation in response to painful stimuli, the unpredictable compared to the predictable group revealed greater activation in pain-encoding (somatosensory cortex, insula) and pain-modulatory (prefrontal and cingulate cortices, periaqueductal grey, parahippocampus) regions. In the test phase, no evidence of hyperalgesia or central sensitization was found, but the predictable group demonstrated enhanced caudate nucleus activation in response to CS−-signaled pain. These findings support that during fear conditioning, the ability to predict pain affects neural processing of visceral pain and alters the associative learning processes underlying the acquisition of predictive properties of cues signaling pain, but conditioned pain-related fear does not result in visceral hyperalgesia or central sensitization. •We addressed the impact of fear on visceral hyperalgesia and central sensitization.•Pain-related fear was assessed through two groups of different predictability.•Pain predictability affected neural pain processes and altered associative learning.•During aversive learning, unpredictability amplified pain encoding, and modulation.•Pain-related fear does not promote visceral hyperalgesia or central sensitization.

Impaired cognitive flexibility represents a widespread symptom in psychiatric disorders, including major depressive disorder (MDD), a disease, characterized by an imbalance of neurotransmitter concentrations. While memory formation is mostly associated with glutamate, also gamma-Aminobutyric acid (GABA) and serotonin show attributions in a complex interplay between neurotransmitter systems. Treatment with selective serotonin reuptake inhibitors (SSRIs) does not solely affect the serotonergic system but shows downstream effects on GABA- and glutamatergic neurotransmission, potentially helping to restore cognitive function via neuroplastic effects. Hence, this study aims to elaborate the effects of associative relearning and SSRI treatment on GABAergic and glutamatergic function within and between five brain regions using magnetic resonance spectroscopy imaging (MRSI). In this study, healthy subjects were randomized into four groups which underwent three weeks of an associative relearning paradigm, with or without emotional connotation, under SSRI (10mg escitalopram) or placebo administration. MRSI measurements, using a spiral-encoded, 3D-GABA-edited MEGA-LASER sequence at 3T, were performed on the first and last day of relearning. Mean GABA+/tCr (GABA+ = GABA + macromolecules; tCr = total creatine) and Glx/tCr (Glx = glutamate + glutamine) ratios were quantified in a ROI-based approach for the hippocampus, insula, putamen, pallidum and thalamus, using LCModel. A total of 66 subjects ((37 female, mean age ± SD = 25.4±4.7) for Glx/tCr and 58 subjects (32 female, mean age ± SD = 25.1±4.7) for GABA+/tCr were included in the final analysis. A significant measurement by region and treatment (SSRI vs placebo) interaction on Glx/tCr ratios was found (pcor=0.017), with post hoc tests confirming differential effects on hippocampus and thalamus (pcor=0.046). Moreover, treatment by time comparison, for each ROI independently, showed a reduction of hippocampal Glx/tCr ratios after SSRI treatment (puncor=0.033). No significant treatment effects on GABA+/tCr ratios or effects of relearning condition on any neurotransmitter ratio could be found. Here, we showed a significant SSRI- and relearning-driven interaction effect of hippocampal and thalamic Glx/tCr levels, suggesting differential behavior based on different serotonin transporter and receptor densities. Moreover, an indication for Glx/tCr adaptions in the hippocampus after three weeks of SSRI treatment could be revealed. Our findings are in line with animal studies reporting glutamate adaptions in the hippocampus following chronic SSRI intake. Due to the complex interplay of serotonin and hippocampal function, involving multiple serotonin receptor subtypes on glutamatergic cells and GABAergic interneurons, the interpretation of underlying neurobiological actions remains challenging.

Rationale Sleep-dependent memory consolidation depends on the concerted reactivation of memories in the hippocampo-neocortical system. The communication of reactivated information from the hippocampus to the neocortex is assumed to be enabled by low levels of acetylcholine, particularly during slow-wave sleep (SWS). Recent studies suggest that the reactivation of memories does not only occur spontaneously but can also be externally triggered by re-presenting learning-associated cues during sleep. Objectives Here we investigated whether the beneficial effect of cued memory reactivation during sleep depends on similar mechanisms as spontaneous reactivation, and specifically on low cholinergic tone. Methods In two experimental nights, healthy volunteers learned a visuo-spatial memory task in the presence of an odor before going to sleep for 40 min. In one night, subjects were presented with the odor again during SWS, whereas in the other night they received an odorless vehicle. In half of the subjects, the availability of acetylcholine during sleep was increased by administering the acetylcholine-esterase inhibitor physostigmine. Results Contrary to our hypothesis, increased cholinergic tone during sleep did not abolish the beneficial effect of odor cueing: memory performance was better after odor cueing compared to odorless vehicle, independent of physostigmine or placebo administration. Conclusions This finding challenges the assumption that odor-cued and spontaneous memory reactivation rely on the same neuropharmacological mechanisms.

Learning associations between stimuli and responses is essential to everyday life. Dorsal striatum (DS) has long been implicated in stimulus-response learning, though recent results challenge this contention. We have proposed that discrepant findings arise because stimulus-response learning methodology generally confounds learning and response selection processes. In 19 patients with Parkinson's disease (PD) and 18 age-matched controls, we found that dopaminergic therapy decreased the efficiency of stimulus-response learning, with corresponding attenuation of ventral striatum (VS) activation. In contrast, exogenous dopamine improved response selection accuracy related to enhanced DS BOLD signal. Contrasts between PD patients and controls fully support these within-subject patterns. These double dissociations in terms of behaviour and neural activity related to VS and DS in PD and in response to dopaminergic therapy, strongly refute the view that DS mediates stimulus-response learning through feedback. Our findings integrate with a growing literature favouring a role for DS in decision making rather than learning, and unite two literature that have been evolving independently. •The effect of dopamine and Parkinson’s disease was investigated in SR learning.•We modelled the stimulus-response and feedback phases of each trial separately.•DS activity correlated with response selection and was improved by dopamine.•VS activity correlated with learning and was impaired by dopamine.•Suggest DS mediates decision making processes and not SR learning.

Although we live in a multisensory world, children’s memory has been usually studied concentrating on only one sensory modality at a time. In this study, we investigated how audiovisual encoding affects recognition memory. Children ( n  = 114) from three age groups (8, 10 and 12 years) memorized auditory or visual stimuli presented with a semantically congruent, incongruent or non-semantic stimulus in the other modality during encoding. Subsequent recognition memory performance was better for auditory or visual stimuli initially presented together with a semantically congruent stimulus in the other modality than for stimuli accompanied by a non-semantic stimulus in the other modality. This congruency effect was observed for pictures presented with sounds, for sounds presented with pictures, for spoken words presented with pictures and for written words presented with spoken words. The present results show that semantically congruent multisensory experiences during encoding can improve memory performance in school-aged children.