Effects of early-life stress on probabilistic reversal learning and response perseverance in young adults.

Early life stress (ELS), including experiences with abuse and neglect, are related to several negative health outcomes in adulthood. One area that has received attention is the increased rate of substance abuse disorder in individuals who had experienced ELS. Given the critical role habitual behavior in the development of substance abuse, ELS may affect the trajectory of neural development such that habitual responding is more dominant than in individuals who did not experience ELS. Here, we examine learning of a probabilistic classification task (the Weather Prediction Task) in healthy young adults who reported significant ELS and those that did not. This task can be learned in a declarative, model-based manner, or in a more habitual, stimulus-response manner. Participants learned to choose the outcome (sun or rain) that was probabilistically associated with each cue combination through reinforcement on each trial. After 100 trials, the probabilities were reversed, and we conceptualized habitual behavior as perseverating responses based on the old probabilities. We also collected information about subjective socio-economic status (sSES), anxiety, depression, and substance use from participants. Using multiple regression, we found that our measure of habitual responding was correlated with reported alcohol use, suggesting that our measure of habit has validity for health behaviors. Furthermore, we found that some forms of early life stress led to greater response perseverance after contingencies were reversed. Overall, the results suggest that childhood adversity may contribute to the development of habit.

Memory and Reward-Based Learning: A Value-Directed Remembering Perspective.

The ability to prioritize valuable information is critical for the efficient use of memory in daily life. When information is important, we engage more effective encoding mechanisms that can better support retrieval. Here, we describe a dual-mechanism framework of value-directed remembering in which both strategic and automatic processes lead to differential encoding of valuable information. Strategic processes rely on metacognitive awareness of effective deep encoding strategies that allow younger and healthy older adults to selectively remember important information. In contrast, some high-value information may also be encoded automatically in the absence of intention to remember, but this may be more impaired in older age. These different mechanisms are subserved by different neural substrates, with left-hemisphere semantic processing regions active during the strategic encoding of high-value items, and automatic enhancement of encoding of high-value items may be supported by activation of midbrain dopaminergic projections to the hippocampal region.

Age-Related Differences in Framing Selective Memory in Terms of Gains and Losses.

We examined whether framing younger and older adults learning goals in terms of maximizing gains or minimizing losses impacts their ability to selectively remember high-value information. Specifically, we presented younger and older adults with lists of words paired with point values and participants were either told that they would receive the value associated with each word if they recalled it on a test or that they would lose the points associated with each word if they failed to recall it on the test. We also asked participants to predict the likelihood of recalling each word to determine if younger and older adults were metacognitively aware of any potential framing effects. Results revealed that older adults expected to be more selective when their goals were framed in terms of losses, but younger adults expected to be more selective when their goals were framed in terms of gains. However, this was not the case as both younger and older adults were more selective for high-value information when their goals were framed in terms of maximizing gains compared with minimizing losses. Thus, the framing of learning goals can impact metacognitive decisions and subsequent memory in both younger and older adults.

Framing effects in value-directed remembering.

Changing how an issue is framed can influence both decision-making and metacognition, but framing a memory task in terms of gains and losses could also impact how learners prioritize information according to its value or importance. We investigated how framing task instructions and feedback in terms of gains and losses influences learners' ability to selectively remember valuable information at the expense of low-value information. Specifically, we presented learners with to-be-remembered words paired with point values and either told participants how many points they scored (the sum of the values of recalled words) or lost (the sum of the values of not-recalled words) on each list, with participants' goal being to maximize their scores or minimize their losses, respectively. Overall, participants were more selective for high-value words when their goals were framed in terms of point gains compared with when their goals were framed in terms of losses, and learners' metacognitive predictions of performance (JOLs) generally mapped onto this trend. Thus, framing in terms of losses for forgetting can reduce memory selectivity, perhaps because even small losses are salient, indicating that framing effects are not limited to decision-making but can influence memory and metacognitive processes as well.

Interleaved practice benefits implicit sequence learning and transfer.

Compared to blocked practice, interleaved practice of different tasks leads to superior long-term retention despite poorer initial acquisition performance. This phenomenon, the contextual interference effect, is well documented in various domains but it is not yet clear if it persists in the absence of explicit knowledge in terms of fine motor sequence learning. Additionally, while there is some evidence that interleaved practice leads to improved transfer of learning to similar actions, transfer of implicit motor sequence learning has not been explored. The present studies used a serial reaction time task where participants practiced three different eight-item sequences that were either interleaved or blocked on Day 1 (training) and Day 2 (testing). In Experiment 1, the retention of the three training sequences was tested on Day 2 and in Experiment 2, three novel sequences were performed on Day 2 to measure transfer. We assessed whether subjects were aware of the sequences to determine whether the benefit of interleaved practice extends to implicitly learned sequences. Even for participants who reported no awareness of the sequences, interleaving led to a benefit for both retention and transfer compared to participants who practiced blocked sequences. Those who trained with blocked sequences were left unprepared for interleaved sequences at test, while those who trained with interleaved sequences were unaffected by testing condition, revealing that learning resulting from blocked practice may be less flexible and more vulnerable to testing conditions. These results indicate that the benefit of interleaved practice extends to implicit motor sequence learning and transfer.

Early-life stress is associated with a preponderance of habitual responding in a novel instrumental avoidance learning paradigm.

There is substantial evidence linking early-life stress (ELS) to negative health outcomes in adulthood, including addiction. However, the neurocognitive and behavioral mechanisms through which ELS increases these risks remain unclear. To address this gap in knowledge, we developed a novel instrumental learning paradigm to explore the effects of ELS on the balance of habitual versus goal-directed learning. Habits efficiently reproduce repetitive behaviors but are inflexible whenreward contingencies related to those behaviors change. Persisting in performing a response after its outcome has been devalued is the hallmark of habitual behavior in instrumental learning. Participants with a history of higher ELS were significantly more likely to make habitual responses in this instrumental avoidance learning paradigm than individuals with a history of lower ELS. Logistic regression analysis showed that ELS is significantly related to habitual responding over and above the effects of retrospective socioeconomic status, trait and state anxiety, depression and recent levels of stress. Analysis of the differential impacts of the type of ELS suggested that these effects are largely driven by experiences of physical neglect.

Contextual interference enhances motor learning through increased resting brain connectivity during memory consolidation.

Increasing contextual interference (CI) during practice benefits learning, making it a desirable difficulty. For example, interleaved practice (IP) of motor sequences is generally more difficult than repetitive practice (RP) during practice but leads to better learning. Here we investigated whether CI in practice modulated resting-state functional connectivity during consolidation. 26 healthy adults (11 men/15 women, age = 23.3 ±â€¯1.3 years) practiced two sets of three sequences in an IP or RP condition over 2 days, followed by a retention test on Day 5 to evaluate learning. On each practice day, functional magnetic resonance imaging (fMRI) data were acquired during practice and also in a resting state immediately after practice. The resting-state fMRI data were processed using independent component analysis (ICA) followed by functional connectivity analysis, showing that IP on Day 1 led to greater resting connectivity than RP between the left premotor cortex and left dorsolateral prefrontal cortex (DLPFC), bilateral posterior cingulate cortices, and bilateral inferior parietal lobules. Moreover, greater resting connectivity after IP than RP on Day 1, between the left premotor cortex and the hippocampus, amygdala, putamen, and thalamus on the right, and the cerebellum, was associated with better learning following IP. Mediation analysis further showed that the association between enhanced resting premotor-hippocampal connectivity on Day 1 and better retention performance following IP was mediated by greater task-related functional activation during IP on Day 2. Our findings suggest that the benefit of CI to motor learning is likely through enhanced resting premotor connectivity during the early phase of consolidation.

Specific responses of human hippocampal neurons are associated with better memory.

A population of human hippocampal neurons has shown responses to individual concepts (e.g., Jennifer Aniston) that generalize to different instances of the concept. However, recordings from the rodent hippocampus suggest an important function of these neurons is their ability to discriminate overlapping representations, or pattern separate, a process that may facilitate discrimination of similar events for successful memory. In the current study, we explored whether human hippocampal neurons can also demonstrate the ability to discriminate between overlapping representations and whether this selectivity could be directly related to memory performance. We show that among medial temporal lobe (MTL) neurons, certain populations of neurons are selective for a previously studied (target) image in that they show a significant decrease in firing rate to very similar (lure) images. We found that a greater proportion of these neurons can be found in the hippocampus compared with other MTL regions, and that memory for individual items is correlated to the degree of selectivity of hippocampal neurons responsive to those items. Moreover, a greater proportion of hippocampal neurons showed selective firing for target images in good compared with poor performers, with overall memory performance correlated with hippocampal selectivity. In contrast, selectivity in other MTL regions was not associated with memory performance. These findings show that a substantial proportion of human hippocampal neurons encode specific memories that support the discrimination of overlapping representations. These results also provide previously unidentified evidence consistent with a unique role of the human hippocampus in orthogonalization of representations in declarative memory.

Effects of aging on value-directed modulation of semantic network activity during verbal learning.

While impairments in memory recall are apparent in aging, older adults show a remarkably preserved ability to selectively remember information deemed valuable. Here, we use fMRI to compare brain activation in healthy older and younger adults during encoding of high and low value words to determine whether there are differences in how older adults achieve value-directed memory selectivity. We find that memory selectivity in older adults is associated with value-related changes in activation during word presentation in left hemisphere regions that are involved in semantic processing, similar to young adults. However, highly selective young adults show a relatively greater increase in semantic network activity during encoding of high-value items, whereas highly selective older adults show relatively diminished activity during encoding of low-value items. Additionally, only younger adults showed value-related increases in activity in semantic and reward processing regions during presentation of the value cue preceding each to-be-remembered word. Young adults therefore respond to cue value more proactively than do older adults, yet the magnitude of value-related differences in cue period brain activity did not predict individual differences in memory selectivity. Thus, our data also show that age-related reductions in prestimulus activity do not always lead to inefficient performance.

Putting the brakes on the brakes: negative emotion disrupts cognitive control network functioning and alters subsequent stopping ability.

The ability to inhibit unwanted responses is critical for effective control of behavior, and inhibition failures can have disastrous consequences in real-world situations. Here, we examined how prior exposure to negative emotional stimuli affects the response-stopping network. Participants performed the stop-signal task, which relies on inhibitory control processes, after they viewed blocks of either negatively emotional or neutral images. In Experiment 1, we found that neural activity was reduced following negative image viewing. When participants were required to inhibit responding after neutral image viewing, we observed activation consistent with previous studies using the stop-signal task. However, when participants were required to inhibit responding after negative image viewing, we observed reductions in the activation of ventrolateral prefrontal cortex, dorsolateral prefrontal cortex, medial frontal cortex, and parietal cortex. Furthermore, analysis of neural connectivity during stop-signal task blocks indicated that across participants, emotion-induced changes in behavioral performance were associated with changes in functional connectivity, such that greater behavioral impairment after negative image viewing was associated with greater weakening of connectivity. In Experiment 2, we collected behavioral data from a larger sample of participants and found that stopping performance was impaired after negative image viewing, as seen in longer stop-signal reaction times. The present results demonstrate that negative emotional events can prospectively disrupt the neural network supporting response inhibition.

High-resolution 7T fMRI of Human Hippocampal Subfields during Associative Learning.

Examining the function of individual human hippocampal subfields remains challenging because of their small sizes and convoluted structures. Previous human fMRI studies at 3 T have successfully detected differences in activation between hippocampal cornu ammonis (CA) field CA1, combined CA2, CA3, and dentate gyrus (DG) region (CA23DG), and the subiculum during associative memory tasks. In this study, we investigated hippocampal subfield activity in healthy participants using an associative memory paradigm during high-resolution fMRI scanning at 7 T. We were able to localize fMRI activity to anterior CA2 and CA3 during learning and to the posterior CA2 field, the CA1, and the posterior subiculum during retrieval of novel associations. These results provide insight into more specific human hippocampal subfield functions underlying learning and memory and a unique opportunity for future investigations of hippocampal subfield function in healthy individuals as well as those suffering from neurodegenerative diseases.

Memory enhancement and deep-brain stimulation of the entorhinal area.

BACKGROUND: The medial temporal structures, including the hippocampus and the entorhinal cortex, are critical for the ability to transform daily experience into lasting memories. We tested the hypothesis that deep-brain stimulation of the hippocampus or entorhinal cortex alters memory performance. METHODS: We implanted intracranial depth electrodes in seven subjects to identify seizure-onset zones for subsequent epilepsy surgery. The subjects completed a spatial learning task during which they learned destinations within virtual environments. During half the learning trials, focal electrical stimulation was given below the threshold that elicits an afterdischarge (i.e., a neuronal discharge that occurs after termination of the stimulus). RESULTS: Entorhinal stimulation applied while the subjects learned locations of landmarks enhanced their subsequent memory of these locations: the subjects reached these landmarks more quickly and by shorter routes, as compared with locations learned without stimulation. Entorhinal stimulation also resulted in a resetting of the phase of the theta rhythm, as shown on the hippocampal electroencephalogram. Direct hippocampal stimulation was not effective. In this small series, no adverse events associated with the procedure were observed. CONCLUSIONS: Stimulation of the entorhinal region enhanced memory of spatial information when applied during learning. (Funded by the National Institutes of Health and the Dana Foundation.).

Value-based modulation of memory encoding involves strategic engagement of fronto-temporal semantic processing regions.

A number of prior fMRI studies have focused on the ways in which the midbrain dopaminergic reward system coactivates with hippocampus to potentiate memory for valuable items. However, another means by which people could selectively remember more valuable to-be-remembered items is to be selective in their use of effective but effortful encoding strategies. To broadly examine the neural mechanisms of value on subsequent memory, we used fMRI to assess how differences in brain activity at encoding as a function of value relate to subsequent free recall for words. Each word was preceded by an arbitrarily assigned point value, and participants went through multiple study-test cycles with feedback on their point total at the end of each list, allowing for sculpting of cognitive strategies. We examined the correlation between value-related modulation of brain activity and participants' selectivity index, which measures how close participants were to their optimal point total, given the number of items recalled. Greater selectivity scores were associated with greater differences in the activation of semantic processing regions, including left inferior frontal gyrus and left posterior lateral temporal cortex, during the encoding of high-value words relative to low-value words. Although we also observed value-related modulation within midbrain and ventral striatal reward regions, our fronto-temporal findings suggest that strategic engagement of deep semantic processing may be an important mechanism for selectively encoding valuable items.

The role of visual imagery in autobiographical memory.

Visual imagery plays a fundamental role in autobiographical memory, but several aspects of this role remain unclear. We conducted three experiments to explore this relationship. In the first experiment, we examined the relation between the phenomenological properties of autobiographical memory and several measures of visual-imagery ability. We found no significant positive relation between imagery ability and autobiographical memory, except on a measure of cognitive style. In a second experiment, we examined the autobiographical memories of people with different cognitive styles-namely, visualizers and verbalizers. We found that, for both kinds of participant, visual imagery was correlated with the feeling that they were reliving their memories, but auditory imagery played a greater role in verbalizers. In a third experiment, we examined the memories of individuals who had a congenital absence of visual imagery. We found that they had a deficit of auditory imagery, as well; moreover, they were much less likely than controls to feel as though they were reliving their memories. The results support the idea that visual imagery plays a vital and irreplaceable role in autobiographical recall.

Memory and automatic processing of valuable information in younger and older adults.

People often engage in the selective remembering of valuable or important information, whether strategic and/or automatic. We examined potential age-related differences in the automatic processing of value during encoding on later remembering by presenting participants with words paired with point values (range: 1-10 twice or 1-20) to remember for a later test. On the first three lists, participants were told that they would receive the points associated with each word if they recalled it on the test (their goal was to maximize their score). On the last three lists, we told participants that all words were worth the same number of points if recalled on the tests, thus making the point value paired with each word meaningless. Results revealed that selective memory may be impaired in older adults using procedures with larger value ranges. Additionally, we demonstrated that the automatic effects of value may have a greater effect on younger adults relative to older adults, but there may be instances where older adults also exhibit these automatic effects. Finally, strategic and automatic processes may not be related within each learner, suggesting that these processes may rely on different cognitive mechanisms. This indicates that these processes could be underpinned by distinct cognitive mechanisms: strategic processes might engage higher-level cognitive operations like imagery, while automatic processes appear to be more perceptually driven.

The effect of early-life stress on memory systems supporting instrumental behavior.

People experiencing early-life stress (ELS) exhibit increased incidence of behaviors that lead to addiction and obesity as adults. Many of these behaviors may be viewed as resulting from an overreliance on habits as opposed to goal-directed instrumental behavior. This increased habitization may result from alterations in the interactions between dorsolateral striatum-dependent and hippocampus-dependent learning systems. As an initial examination of this idea, we investigated the effect of ELS on instrumental learning and extinction. In Experiment 1, we examined the effect of ELS in two groups of people, one trained on a continuous reinforcement schedule and one trained on a partial reinforcement schedule. We found that people who experienced ELS had a diminished effect of the partial reinforcement schedule on extinction. In Experiment 2, we again manipulated reinforcement schedule and also challenged declarative memory by requiring subjects to perform a concurrent task. We found that the declarative challenge did not affect extinction responding in the non-ELS group. In a moderate-ELS group, we observed a diminished sensitivity to the reinforcement schedule during extinction only under divided attention. In the high-ELS group, we observed a reduced sensitivity to reinforcement schedule even in the absence of the declarative memory challenge, consistent with Experiment 1. Our results suggest that ELS reduces the tendency to use declarative, hippocampus-dependent memory in instrumental tasks in favor of habits. ELS may affect hippocampal development, thus altering the interaction between memory systems and potentially contributing to poor health outcomes.

Interleaved practice enhances skill learning and the functional connectivity of fronto-parietal networks.

Practice of tasks in an interleaved order generally induces superior learning compared with practicing in a repetitive order, a phenomenon known as the contextual-interference (CI) effect. Increased neural activity during interleaved over repetitive practice has been associated with the beneficial effects of CI. Here, we used psychophysiological interaction (PPI) analysis to investigate whether the neural connectivity of the dorsal premotor (PM) and the dorsolateral prefrontal (DLPFC) cortices changes when motor sequences are acquired through interleaved practice. Sixteen adults practiced a serial reaction time task where a set of three 4-element sequences were arranged in a repetitive or in an interleaved order on 2 successive days. On Day 5, participants were tested with practiced sequences to evaluate retention. A within-subjects design was used so that participants practiced sequences in the other condition (repetitive or interleaved) 2-4 weeks later. Functional magnetic resonance images were acquired during practice and retention. On Day 2 of practice, there was greater inter-regional functional connectivity in the interleaved compared with the repetitive condition for both PM-seeded and DLPFC-seeded connectivity. The increased functional connectivity between both seeded regions and sensorimotor cortical areas correlated with the benefit of interleaved practice during later retention. During retention, a significant PPI effect was found in DLPFC-seeded connectivity, with increased DLPFC-supplementary motor area connectivity correlated with the benefits of interleaved practice. These data suggest that interleaved practice benefits learning by enhancing coordination of sensorimotor cortical regions, and superior performance of sequences learned under CI is characterized by increased functional connectivity in frontal cortex.

Goal-directed remembering in older adults.

Compared to younger adults, older adults show a reduced difference in memory between items they are directed to remember and items they are directed to forget. This effect may result from increased processing of goal-irrelevant information in aging. In contrast, healthy older adults are often able to selectively remember valuable information, suggesting preservation of goal-directed encoding in aging. Here, we examined how value may differentially affect directed-forgetting and memory for irrelevant details for younger and older adults in a value-directed remembering task. In Experiment 1, participants studied words paired with a directed-forgetting cue and a point-value they earned for later recognition. Participants' memory was then tested, either after an 8-min or 24-hr retention interval. In Experiment 2 words were presented in two colors and the recognition test assessed whether the participant could retrieve the incidentally-presented point value and the color of each recognized words. In both experiments, older and younger adults displayed a comparable ability to selectively encode valuable items. However, older adults showed a reduced directed-forgetting effect compared to younger adults that was maintained across the 24-hr retention interval. In Experiment 2, older adults showed both intact directed-forgetting and similar incidental detail retrieval compared to younger adults. These findings suggest that older adults maintained selectivity to value, demonstrating that aging does not impact the differential encoding of valuable information. Furthermore, younger and older adults may be similarly goal-directed in terms of item features to encode, but that instructions to forget presented items are less effective in older adults.

Establishing a causal role for left ventrolateral prefrontal cortex in value-directed memory encoding with high-definition transcranial direct current stimulation.

One critical approach for promoting the efficiency of memory is to adopt selective encoding strategies to prioritize more valuable information. Past neuroimaging studies have shown that value-directed modulation of verbal memory depends heavily on the engagement of left-lateralized semantic processing regions, particularly in the ventrolateral prefrontal cortex (VLPFC). In the present study, we used high-definition transcranial direct current stimulation (HD-tDCS) to seek evidence for a causal role of left VLPFC in supporting the memory advantage for high-value items. Three groups of healthy young adult participants were presented with lists of words to remember, with each word accompanied by an arbitrarily assigned point value. During the first session, all participants received sham stimulation as they encoded five lists of 30 words each. Two of these lists were immediately tested with free recall, with feedback given to allow participants to develop metacognitive insight and strategies to maximize their point total. The second session had the exact same structure as the first, but the groups differed in whether they received continued sham stimulation (N = 22) or anodal stimulation of the left VLPFC (N = 21) or right VLPFC (N = 20). Those lists not tested with immediate recall were tested with recognition judgments after a one-day delay. Since no brain stimulation was applied during this Day 2 test, any performance differences can be attributed to the effects of stimulation on Day 1 encoding processes. Anodal stimulation of left VLPFC significantly boosted participants' memory encoding selectivity. In comparison, no such effect was seen in participants who received right VLPFC or sham stimulation. Estimates of recollection- and familiarity-based responding revealed that left VLPFC stimulation specifically amplified the effects of item value on recollection. These results demonstrate a causal role for left VLPFC in the implementation of selective value-directed encoding strategies, putatively by boosting deep semantic processing of high-value words. Our findings also provide further evidence on the hemispheric lateralization of value-directed verbal memory encoding.

Dynamic neural representations of memory and space during human ambulatory navigation.

Our ability to recall memories of personal experiences is an essential part of daily life. These episodic memories often involve movement through space and thus require continuous encoding of one's position relative to the surrounding environment. The medial temporal lobe (MTL) is thought to be critically involved, based on studies in freely moving rodents and stationary humans. However, it remains unclear if and how the MTL represents both space and memory especially during physical navigation, given challenges associated with deep brain recordings in humans during movement. We recorded intracranial electroencephalographic (iEEG) activity while participants completed an ambulatory spatial memory task within an immersive virtual reality environment. MTL theta activity was modulated by successful memory retrieval or spatial positions within the environment, depending on dynamically changing behavioral goals. Altogether, these results demonstrate how human MTL oscillations can represent both memory and space in a temporally flexible manner during freely moving navigation.