Top-Down Task Goals Induce the Retrieval State.

Engaging the retrieval state (Tulving, 1983) impacts processing and behavior (Long and Kuhl, 2019, 2021; Smith et al., 2022), but the extent to which top-down factors-explicit instructions and goals-versus bottom-up factors-stimulus properties such as repetition and similarity-jointly or independently induce the retrieval state is unclear. Identifying the impact of bottom-up and top-down factors on retrieval state engagement is critical for understanding how control of task-relevant versus task-irrelevant brain states influence cognition. We conducted between-subjects recognition memory tasks on male and female human participants in which we varied test phase goals. We recorded scalp electroencephalography and used an independently validated mnemonic state classifier (Long, 2023) to measure retrieval state engagement as a function of top-down task goals (recognize old vs detect new items) and bottom-up stimulus repetition (hits vs correct rejections (CRs)). We find that whereas the retrieval state is engaged for hits regardless of top-down goals, the retrieval state is only engaged during CRs when the top-down goal is to recognize old items. Furthermore, retrieval state engagement is greater for low compared to high confidence hits when the task goal is to recognize old items. Together, these results suggest that top-down demands to recognize old items induce the retrieval state independent from bottom-up factors, potentially reflecting the recruitment of internal attention to enable access of a stored representation.

Variation in encoding context benefits item recognition.

The current study assesses whether varying the encoding context of a repeated event is a potential strategy to improve recognition memory across retrieval contexts. Context variability, also known as encoding variability, has historically been investigated primarily using recall and cued recall tasks, with the consensus being that encoding variability is not necessarily beneficial for episodic retrieval. However, recent studies (see text) suggest that test type may determine the strategy's effectiveness. Aligned with these recent findings, we found consistent benefits to simple item recognition when a word was studied in more variable contexts compared to less variable contexts across four experiments. This main effect of context variability occurred when crossed with a manipulation of repetition spacing and when crossed with a manipulation of encoding-retrieval context match. Variation in encoding contexts beyond the future retrieval context led to better item recognition than repeated study exposures within the future retrieval context. We argue that the current study and other recent findings indicate a need to re-evaluate the historical consensus on encoding variability as a beneficial strategy for learning.

Temporal Context Modulates Encoding and Retrieval of Overlapping Events.

Overlap between events can lead to interference because of a trade-off between encoding the present event and retrieving the past event. Temporal context information, "when" something occurred, a defining feature of episodic memory, can cue retrieval of a past event. However, the influence of temporal overlap, or proximity in time, on the mechanisms of interference is unclear. Here, by identifying brain states using scalp EEG from male and female human subjects, we show the extent to which temporal overlap promotes interference and induces retrieval. In this experiment, subjects were explicitly directed to either encode the present event or retrieve a past, overlapping event while perceptual input was held constant. We find that the degree of temporal overlap between events leads to selective interference. Specifically, greater temporal overlap between two events leads to impaired memory for the past event selectively when the top-down goal is to encode the present event. Using pattern classification analyses to measure neural evidence for a retrieval state, we find that greater temporal overlap leads to automatic retrieval of a past event, independent of top-down goals. Critically, the retrieval evidence we observe likely reflects a general retrieval mode, rather than retrieval success or effort. Collectively, our findings provide insight into the role of temporal overlap on interference and memory formation.SIGNIFICANCE STATEMENT When a present event overlaps with an event from the past, this leads to a trade-off between the tendency to encode the present event versus retrieve the past event. Here we show that, when two events are experienced nearby in time, the memory system is biased toward a retrieval state and that subsequent memory for the past event is impaired. These findings suggest an influence of bottom-up temporal factors on both interference and the trade-off between memory states.

Spatiotemporal Dynamics of Memory Encoding and Memory Retrieval States.

Memory encoding and memory retrieval are neurally distinct brain states that can be differentiated on the basis of cortical network activity. However, it is unclear whether sustained engagement of one network or fluctuations between multiple networks give rise to these memory states. The spatiotemporal dynamics of memory states may have important implications for memory behavior and cognition; however, measuring temporally resolved signals of cortical networks poses a challenge. Here, we recorded scalp electroencephalography from participants performing a mnemonic state task in which they were biased toward memory encoding or retrieval. We performed a microstate analysis to measure the temporal dynamics of cortical networks throughout this mnemonic state task. We find that Microstate E, a putative analog of the default mode network, shows temporally sustained dissociations between memory encoding and retrieval, with greater engagement during retrieve compared with encode trials. We further show that decreased engagement of Microstate E is a general property of encoding, rather than a reflection of retrieval suppression. Thus, memory success, as well as cognition more broadly, may be influenced by the ability to engage or disengage Microstate E in a goal-dependent manner.

Top-down task goals induce the retrieval state.

Engaging the retrieval state (Tulving, 1983) impacts processing and behavior (Long & Kuhl, 2019, 2021; Smith, Moore, & Long, 2022), but the extent to which top-down factors - explicit instructions and goals - vs. bottom-up factors - stimulus properties such as repetition and similarity - jointly or independently induce the retrieval state is unclear. Identifying the impact of bottom-up and top-down factors on retrieval state engagement is critical for understanding how control of task-relevant vs. task-irrelevant brain states influence cognition. We conducted between-subjects recognition memory tasks on male and female human participants in which we varied test phase goals. We recorded scalp electroencephalography and used an independently validated mnemonic state classifier (Long, 2023) to measure retrieval state engagement as a function of top-down task goals (recognize old vs. detect new items) and bottom-up stimulus repetition (hits vs. correct rejections). We find that whereas the retrieval state is engaged for hits regardless of top-down goals, the retrieval state is only engaged during correct rejections when the top-down goal is to recognize old items. Furthermore, retrieval state engagement is greater for low compared to high confidence hits when the task goal is to recognize old items. Together, these results suggest that top-down demands to recognize old items induce the retrieval state independent from bottom-up factors, potentially reflecting the recruitment of internal attention to enable access of a stored representation. Significance Statement: Both top-down goals and automatic bottom-up influences may lead us into a retrieval brain state - a whole-brain pattern of activity that supports our ability to remember the past. Here we tested the extent to which top-down vs. bottom-up factors independently influence the retrieval state by manipulating participants' goals and stimulus repetition during a memory test. We find that in response to the top-down goal to recognize old items, the retrieval state is engaged for both old and new probes, suggesting that top-down and bottom-up factors independently engage the retrieval state. Our interpretation is that top-down demands recruit internal attention in service of the attempt to access a stored representation.

Successful retrieval is its own reward.

The ability to successfully remember past events is critical to our daily lives, yet the neural mechanisms underlying the motivation to retrieve is unclear. Although reward-system activity and feedback-related signals have been observed during memory retrieval, whether this signal reflects intrinsic reward or goal-attainment is unknown. Adjudicating between these two alternatives is crucial for understanding how individuals are motivated to engage in retrieval and how retrieval supports later remembering. To test these two accounts, we conducted between-subjects recognition memory tasks on human participants undergoing scalp electroencephalography and varied test-phase goals (recognize old vs. detect new items). We used an independently validated feedback classifier to measure positive feedback evidence. We find positive feedback following successful retrieval regardless of task goals. Together, these results suggest that successful retrieval is intrinsically rewarding. Such a feedback signal may promote future retrieval attempts as well as bolster later memory for the successfully retrieved events.

Response-locked theta dissociations reveal potential feedback signal following successful retrieval.

Successful memory retrieval relies on memory processes to access an internal representation and decision processes to evaluate and respond to the accessed representation, both of which are supported by fluctuations in theta (4-8Hz) activity. However, the extent to which decision making processes are engaged following a memory response is unclear. Here, we recorded scalp electroencephalography (EEG) while human participants performed a recognition memory task. We focused on response-locked data, allowing us to investigate the processes that occur prior to and following a memory response. We replicate previous work and find that prior to a memory response theta power is greater for identification of previously studied items (hits) relative to rejection of novel lures (correct rejections; CRs). Following the memory response, the theta power dissociation 'flips' whereby theta power is greater for CRs relative to hits. We find that the post-response 'flip' is more robust for hits that are committed quickly, potentially reflecting a positive feedback signal for strongly remembered experiences. Our findings suggest that there are potentially distinct processes occurring before and after a memory response that are modulated by successful memory retrieval.

Mnemonic brain state engagement is diminished in healthy aging.

Healthy older adults typically show impaired episodic memory - memory for when and where an event oc-curred - but intact semantic memory - knowledge for general information and facts. As older adults also have difficulty inhibiting the retrieval of prior knowledge from memory, their selective decline in episodic memory may be due to a tendency to over engage the retrieval state, a brain state in which attention is focused internally in an attempt to access prior knowledge. The retrieval state trades off with the encoding state, a brain state which supports the formation of new memories. Therefore, episodic memory declines in older adults may be the result of differential engagement in mnemonic brain states. Our hypothesis is that older adults are biased toward a retrieval state. We recorded scalp electroencephalography while young, middle-aged and older adults performed a memory task in which they were explicitly directed to either encode the currently presented object stimulus or retrieve a previously presented, categorically-related object stimulus. We used multivariate pattern analysis of spectral activity to decode engagement in the retrieval vs. encoding state. We find that all three age groups can follow top-down instructions to selectively engage in encoding or retrieval and that we can decode mnemonic states for all age groups. However, we find that mnemonic brain state engagement is diminished for older adults relative to middle-aged adults. Our interpretation is that a combination of executive control deficits and a modest bias to retrieve modulates older adults' mnemonic state engagement. Together, these findings suggest that dif-ferential mnemonic state engagement may underlie age-related memory changes.

Engineering the next generation of cell-based therapeutics.

Cell-based therapeutics are an emerging modality with the potential to treat many currently intractable diseases through uniquely powerful modes of action. Despite notable recent clinical and commercial successes, cell-based therapies continue to face numerous challenges that limit their widespread translation and commercialization, including identification of the appropriate cell source, generation of a sufficiently viable, potent and safe product that meets patient- and disease-specific needs, and the development of scalable manufacturing processes. These hurdles are being addressed through the use of cutting-edge basic research driven by next-generation engineering approaches, including genome and epigenome editing, synthetic biology and the use of biomaterials.

Targeted Stimulation of Human Orbitofrontal Networks Disrupts Outcome-Guided Behavior.

Outcome-guided behavior requires knowledge about the current value of expected outcomes. Such behavior can be isolated in the reinforcer devaluation task, which assesses the ability to infer the current value of specific rewards after devaluation. Animal lesion studies demonstrate that orbitofrontal cortex (OFC) is necessary for normal behavior in this task, but a causal role for human OFC in outcome-guided behavior has not been established. Here, we used sham-controlled, non-invasive, continuous theta-burst stimulation (cTBS) to temporarily disrupt human OFC network activity by stimulating a site in the lateral prefrontal cortex that is strongly connected to OFC prior to devaluation of food odor rewards. Subjects in the sham group appropriately avoided Pavlovian cues associated with devalued food odors. However, subjects in the stimulation group persistently chose those cues, even though devaluation of food odors themselves was unaffected by cTBS. This behavioral impairment was mirrored in changes in resting-state functional magnetic resonance imaging (rs-fMRI) activity such that subjects in the stimulation group exhibited reduced OFC network connectivity after cTBS, and the magnitude of this reduction was correlated with choices after devaluation. These findings demonstrate the feasibility of indirectly targeting the human OFC with non-invasive cTBS and indicate that OFC is specifically required for inferring the value of expected outcomes.

Evolving Industry Partnerships and Investments in Cell and Gene Therapies.

Cell and gene therapies hold the promise of providing significant and durable health gains to patients in many disease states and have recently elicited significant investor and partner interest. We cover the current state of industry partnerships and investments, highlight what makes a partnership advantageous, and discuss implications for stem cell therapies.

Assessing commercial opportunities for autologous and allogeneic cell-based products.

The two primary cell sources used to produce cell-based therapies are autologous (self-derived) and allogeneic (derived from a donor). This analysis attempts to compare and contrast the two approaches in order to understand whether there is an emerging preference in the market. While the current clinical trials underway are slightly biased to autologous approaches, it is clear that both cell-based approaches are being aggressively pursued. This analysis also breaks down the commercial advantages of each cell-based approach, comparing both cost of goods and the ideal indication type for each. While allogeneic therapies have considerable advantages over autologous therapies, they do have a distinct disadvantage regarding potential immunogenicity. The introduction of the hybrid autologous business model provides the ability for autologous-based therapies to mitigate some of the advantages that allogeneic cell-based therapies enjoy, including cost of goods. Finally, two case studies are presented that demonstrate that there is sufficient space for both autologous and allogeneic cell-based therapies within a single disease area.

Commercialization challenges associated with induced pluripotent stem cell-based products.

Induced pluripotent stem (iPS) cells have generated excitement in the regenerative medicine industry. Products derived from iPS cells could be used in a range of drug discovery and development processes. These nontherapeutic products will continue to be launched over the next 5 years, and provide income and knowledge to drive the therapeutic use of iPS cells forward. While the commercial opportunity for iPS cell-based therapies is potentially large, the looming technical and scientific hurdles must be overcome and, thus, the launch of a therapy based on iPS cells is unlikely to occur until the 2020s. While the launch of a therapeutic is many years away, the business models for commercialization should be well understood and proven based on experience with other non-iPS cell-based therapies (both autologous and allogeneic) that will already be on the market.

Pharma's developing interest in stem cells.

Human stem cell biology is driving the promise of novel regenerative therapies into clinical trials. Although the pharmaceutical industry has embraced stem cells as tools in drug discovery, few companies have taken the risk to deliver stem cell-based medicines. Here, we evaluate the various cell-based opportunities and corporate strategies.