In vivo structural connectivity of the reward system along the hippocampal long axis.

Recent work has identified a critical role for the hippocampus in reward-sensitive behaviors, including motivated memory, reinforcement learning, and decision-making. Animal histology and human functional neuroimaging have shown that brain regions involved in reward processing and motivation are more interconnected with the ventral/anterior hippocampus. However, direct evidence examining gradients of structural connectivity between reward regions and the hippocampus in humans is lacking. The present study used diffusion MRI (dMRI) and probabilistic tractography to quantify the structural connectivity of the hippocampus with key reward processing regions in vivo. Using a large sample of subjects (N = 628) from the human connectome dMRI data release, we found that connectivity profiles with the hippocampus varied widely between different regions of the reward circuit. While the dopaminergic midbrain (ventral tegmental area) showed stronger connectivity with the anterior versus posterior hippocampus, the ventromedial prefrontal cortex showed stronger connectivity with the posterior hippocampus. The limbic (ventral) striatum demonstrated a more homogeneous connectivity profile along the hippocampal long axis. This is the first study to generate a probabilistic atlas of the hippocampal structural connectivity with reward-related networks, which is essential to investigating how these circuits contribute to normative adaptive behavior and maladaptive behaviors in psychiatric illness. These findings describe nuanced structural connectivity that sets the foundation to better understand how the hippocampus influences reward-guided behavior in humans.

Awake targeted memory reactivation doesn't work.

Memories are pliable and can be biased by post-encoding information. In targeted memory reactivation (TMR) studies, participants encode information then sleep, during which time sounds or scents that were previously associated with the encoded images are re-presented in an effort to trigger reactivation of the associated memory traces. Upon subsequent testing, memory for reactivated items is often enhanced. Is sleep essential for this process? The literature on awake TMR is small and findings are mixed. Here, we asked English-speaking adults to learn Japanese vocabulary words. During a subsequent active rest phase, participants played Tetris while sound cues associated with the vocabulary words were presented. Results showed that when memories were reactivated, they were either disrupted (Experiment 1) or unaffected (Experiments 2, 3). These findings indicate that awake TMR is not beneficial, and may actually impair subsequent memory. These findings have important implications for research on memory consolidation and reactivation.

Awake Hippocampal-Cortical Co-reactivation Is Associated with Forgetting.

Systems consolidation theories posit that consolidation occurs primarily through a coordinated communication between hippocampus and neocortex [Moscovitch, M., & Gilboa, A. Systems consolidation, transformation and reorganization: Multiple trace theory, trace transformation theory and their competitors. PsyArXiv, 2021; Kumaran, D., Hassabis, D., & McClelland, J. L. What learning systems do intelligent agents need? Complementary learning systems theory updated. Trends in Cognitive Sciences, 20, 512-534, 2016; McClelland, J. L., & O'Reilly, R. C. Why there are complementary learning systems in the hippocampus and neocortex: Insights from the successes and failures of connectionist models of learning and memory. Psychological Review, 102, 419-457, 1995]. Recent sleep studies in rodents have shown that hippocampus and visual cortex replay the same information at temporal proximity ("co-replay"; Lansink, C. S., Goltstein, P. M., Lankelma, J. V., McNaughton, B. L., & Pennartz, C. M. A. Hippocampus leads ventral striatum in replay of place-reward information. PLoS Biology, 7, e1000173, 2009; Peyrache, A., Khamassi, M., Benchenane, K., Wiener, S. I., & Battaglia, F. P. Replay of rule-learning related neural patterns in the prefrontal cortex during sleep. Nature Neuroscience, 12, 919-926, 2009; Wierzynski, C. M., Lubenov, E. V., Gu, M., & Siapas, A. G. State-dependent spike-timing relationships between hippocampal and prefrontal circuits during sleep. Neuron, 61, 587-596, 2009; Ji, D., & Wilson, M. A. Coordinated memory replay in the visual cortex and hippocampus during sleep. Nature Neuroscience, 10, 100-107, 2007). We developed a novel repetition time (TR)-based co-reactivation analysis method to study hippocampal-cortical co-replays in humans using fMRI. Thirty-six young adults completed an image (face or scene) and location paired associate encoding task in the scanner, which were preceded and followed by resting state scans. We identified post-encoding rest TRs (± 1) that showed neural reactivation of each image-location trials in both hippocampus (HPC) and category-selective cortex (fusiform face area [FFA]). This allowed us to characterize temporally proximal coordinated reactivations ("co-reactivations") between HPC and FFA. Moreover, we found that increased HPC-FFA co-reactivations were associated with incorrectly recognized trials after a 1-week delay (p = .004). Finally, we found that these HPC-FFA co-reactivations were also associated with trials that were initially correctly recognized immediately after encoding but were later forgotten in 1-day (p = .043) and 1-week delay period (p = .031). We discuss these results from a trace transformation perspective [Sekeres, M. J., Winocur, G., & Moscovitch, M. The hippocampus and related neocortical structures in memory transformation. Neuroscience Letters, 680, 39-53, 2018; Winocur, G., & Moscovitch, M. Memory transformation and systems consolidation. Journal of the International Neuropsychological Society, 17, 766-780, 2011] and speculate that HPC-FFA co-reactivations may be integrating related events, at the expense of disrupting event-specific details, hence leading to forgetting.

Setting boundaries: Development of neural and behavioral event cognition in early childhood.

The ongoing stream of sensory experience is so complex and ever-changing that we tend to parse this experience at "event boundaries," which structures and strengthens memory. Memory processes undergo profound change across early childhood. Whether young children also divide their ongoing processing along event boundaries, and if those boundaries relate to memory, could provide important insight into the development of memory systems. In Study 1, 4-7-year-old children and adults segmented a cartoon, and we tested their memory. Children's event boundaries were more variable than adults' and differed in location and consistency of agreement. Older children's event segmentation was more adult-like than younger children's, and children who segmented events more like adults had better memory for those events. In Study 2, we asked whether these developmental differences in event segmentation had their roots in distinct neural representations. A separate group of 4-8-year-old children watched the same cartoon while undergoing an fMRI scan. In the right hippocampus, greater pattern dissimilarity across event boundaries compared to within events was evident for both child and adult behavioral boundaries, suggesting children and adults share similar event cognition. However, the boundaries identified by a data-driven Hidden Markov Model found that a different brain region-the left and right angular gyrus-aligned only with event boundaries defined by children. Overall, these data suggest that children's event cognition is reasonably well-developed by age 4 but continues to become more adult-like across early childhood. RESEARCH HIGHLIGHTS: Adults naturally break their experience into events, which structures and strengthens memory, but less is known about children's event perception and memory. Study 1 had adults and children segment and remember events from an animated show, and Study 2 compared those segmentations to other children's fMRI data. Children show better recognition and temporal order memory and more adult-like event segmentation with age, and children who segment more like adults have better memory. Children's and adults' behavioral boundaries mapped onto pattern similarity differences in hippocampus, and children's behavioral boundaries matched a data-driven model's boundaries in angular gyrus.

The Social Cerebellum: A Large-Scale Investigation of Functional and Structural Specificity and Connectivity.

The cerebellum has been traditionally disregarded in relation to nonmotor functions, but recent findings indicate it may be involved in language, affective processing, and social functions. Mentalizing, or Theory of Mind (ToM), is the ability to infer mental states of others and this skill relies on a distributed network of brain regions. Here, we leveraged large-scale multimodal neuroimaging data to elucidate the structural and functional role of the cerebellum in mentalizing. We used functional activations to determine whether the cerebellum has a domain-general or domain-specific functional role, and effective connectivity and probabilistic tractography to map the cerebello-cerebral mentalizing network. We found that the cerebellum is organized in a domain-specific way and that there is a left cerebellar effective and structural lateralization, with more and stronger effective connections from the left cerebellar hemisphere to the right cerebral mentalizing areas, and greater cerebello-thalamo-cortical and cortico-ponto-cerebellar streamline counts from and to the left cerebellum. Our study provides novel insights to the network organization of the cerebellum, an overlooked brain structure, and mentalizing, one of humans' most essential abilities to navigate the social world.

The fornix supports episodic memory during childhood.

Episodic memory relies on the coordination of widespread brain regions that reconstruct spatiotemporal details of an episode. These topologically dispersed brain regions can rapidly communicate through structural pathways. Research in animal and human lesion studies implicate the fornix-the major output pathway of the hippocampus-in supporting various aspects of episodic memory. Because episodic memory undergoes marked changes in early childhood, we tested the link between the fornix and episodic memory in an age window of robust memory development (ages 4-8 years). Children were tested on the stories subtest from the Children's Memory Scale, a temporal order memory task, and a source memory task. Fornix streamlines were reconstructed using probabilistic tractography to estimate fornix microstructure. In addition, we measured fornix macrostructure and computed free water. To assess selectivity of our findings, we also reconstructed the uncinate fasciculus. Findings show that children's memory increases from ages 4 to 8 and that fornix micro- and macrostructure increases between ages 4 and 8. Children's memory performance across nearly every memory task correlated with individual differences in fornix, but not uncinate fasciculus, white matter. These findings suggest that the fornix plays an important role in supporting the development of episodic memory, and potentially semantic memory, in early childhood.

SymCog: An open-source toolkit for assessing human symbolic cognition.

Symbol systems have a profound influence on human behavior, spanning countless modalities such as natural language, clothing styles, monetary systems, and gestural conventions (e.g., handshaking). Selective impairments in understanding and manipulating symbols are collectively known as asymbolia. Here we address open questions about the nature of asymbolia in the context of both historical and contemporary approaches to human symbolic cognition. We describe a tripartite perspective on symbolic cognition premised upon (1) mental representation of a concept, (2) a stored pool of symbols segregated from their respective referents, and (3) fast and accurate mapping between concepts and symbols. We present an open-source toolkit for assessing symbolic knowledge premised upon matching animated video depictions of abstract concepts to their corresponding verbal and nonverbal symbols. Animations include simple geometric shapes (e.g., filled circles, squares) moving in semantically meaningful ways. For example, a rectangle bending under the implied weight of a large square denotes "heaviness." We report normative data for matching words and images to these target animations. In a second norming study, participants rated target animations across a range of semantic dimensions (e.g., valence, dominance). In a third study, we normed a set of concepts familiar to American English speakers but lacking verbal labels (e.g., the feeling of a Sunday evening). We describe how these tools may be used to assess human symbolic processing and identify asymbolic deficits across the span of human development.

A large-scale structural and functional connectome of social mentalizing.

Humans have a remarkable ability to infer the mind of others. This mentalizing skill relies on a distributed network of brain regions but how these regions connect and interact is not well understood. Here we leveraged large-scale multimodal neuroimaging data to elucidate the brain-wide organization and mechanisms of mentalizing processing. Key connectomic features of the mentalizing network (MTN) have been delineated in exquisite detail. We found the structural architecture of MTN is organized by two parallel subsystems and constructed redundantly by local and long-range white matter fibers. We uncovered an intrinsic functional architecture that is synchronized according to the degree of mentalizing, and its hierarchy reflects the inherent information integration order. We also examined the correspondence between the structural and functional connectivity in the network and revealed their differences in network topology, individual variance, spatial specificity, and functional specificity. Finally, we scrutinized the connectome resemblance between the default mode network and MTN and elaborated their inherent differences in dynamic patterns, laterality, and homogeneity. Overall, our study demonstrates that mentalizing processing unfolds across functionally heterogeneous regions with highly structured fiber tracts and unique hierarchical functional architecture, which make it distinguishable from the default mode network and other vicinity brain networks supporting autobiographical memory, semantic memory, self-referential, moral reasoning, and mental time travel.

Understanding relational binding in early childhood: Interacting effects of overlap and delay.

Episodic memories typically share overlapping elements in distinctive combinations, and to be valuable for future behavior they need to withstand delays. There is relatively little work on whether children have special difficulty with overlap or withstanding delay. However, Yim, Dennis, and Sloutsky (Psychological Science, 2013, Vol. 24, pp. 2163-2172) suggested that extensive overlap is more problematic for younger children, and Darby and Sloutsky (Psychological Science, 2015, Vol. 26, pp. 1937-1946) reported that a 48-h delay period actually improves children's memory for overlapping pairs of items. In the current study, we asked how children's episodic memory is affected by stimulus overlap, delay, and age using visual stimuli containing either overlapping or unique item pairs. Children aged 4 and 6 years were tested both immediately and after a 24-h delay. As expected, older children performed better than younger children, and both age groups performed worse on overlapping pairs. Surprisingly, the 24-h delay had only a marginal effect on overall accuracy. Although there were no interactions, when errors were examined, there was evidence that delay buffered memory for overlapping pairs against cross-contextual confusion for younger children.

Pattern separation and pattern completion: Behaviorally separable processes?

Episodic memory capacity requires several processes, including mnemonic discrimination of similar experiences, termed pattern separation, and holistic retrieval of multidimensional experiences given a cue, termed pattern completion. Both computations seem to rely on the hippocampus proper, but they also seem to be instantiated by distinct hippocampal subfields. Thus, we investigated whether individual differences in behavioral expressions of pattern separation and pattern completion were correlated after accounting for general mnemonic ability. Young adult participants learned events comprised of a scene-animal-object triad. In the pattern separation task, we estimated mnemonic discrimination using lure classification for events that contained a similar lure element. In the pattern completion task, we estimated holistic recollection using dependency in retrieval success for different associations from the same event. Although overall accuracies for the two tasks correlated as expected, specific measures of individual variation in holistic retrieval and mnemonic discrimination did not correlate, suggesting that these two processes involve distinguishable properties of episodic memory.

Dynamic neural architecture for social knowledge retrieval.

Social behavior is often shaped by the rich storehouse of biographical information that we hold for other people. In our daily life, we rapidly and flexibly retrieve a host of biographical details about individuals in our social network, which often guide our decisions as we navigate complex social interactions. Even abstract traits associated with an individual, such as their political affiliation, can cue a rich cascade of person-specific knowledge. Here, we asked whether the anterior temporal lobe (ATL) serves as a hub for a distributed neural circuit that represents person knowledge. Fifty participants across two studies learned biographical information about fictitious people in a 2-d training paradigm. On day 3, they retrieved this biographical information while undergoing an fMRI scan. A series of multivariate and connectivity analyses suggest that the ATL stores abstract person identity representations. Moreover, this region coordinates interactions with a distributed network to support the flexible retrieval of person attributes. Together, our results suggest that the ATL is a central hub for representing and retrieving person knowledge.

Development of Holistic Episodic Recollection.

Episodic memory binds the diverse elements of an event into a coherent representation. This coherence allows for the reconstruction of different aspects of an experience when triggered by a cue related to a past event-a process of pattern completion. Previous work has shown that such holistic recollection is evident in young adults, as revealed by dependency in retrieval success for various associations from the same event. In addition, episodic memory shows clear quantitative increases during early childhood. However, the ontogeny of holistic recollection is uncharted. Using dependency analyses, we found here that 4-year-olds (n = 32), 6-year-olds (n = 30), and young adults (n = 31) all retrieved complex events in a holistic manner; specifically, retrieval accuracy for one aspect of an event predicted accuracy for other aspects of the same event. However, the degree of holistic retrieval increased from the age 4 to adulthood. Thus, extended refinement of multiway binding may be one aspect of episodic memory development.

Gain-Loss Framing Enhances Mnemonic Discrimination in Preschoolers.

Episodic memory relies on discriminating among similar elements of episodes. Mnemonic discrimination is relatively poor at age 4, and then improves markedly. We investigated whether motivation to encode items with fine-grain resolution would change this picture of development, using an engaging computer-administered memory task in which a bird ate items that made her healthier (gain frame), sicker (loss frame), or led to no change (control condition). Using gain-loss framing led to enhanced mnemonic discrimination in 4- and 5-year-olds, but did not affect older children or adults. Despite this differential improvement, age-related differences persisted. An additional finding was that loss-framing led to greater mnemonic discrimination than gain-framing across age groups. Motivation only partially accounts for the improvement in mnemonic discrimination.

The ontogeny of relational memory and pattern separation.

Episodic memory relies on memory for the relations among multiple elements of an event and the ability to discriminate among similar elements of episodes. The latter phenomenon, termed pattern separation, has been studied mainly in young and older adults with relatively little research on children. Building on prior work with young children, we created an engaging computer-administered relational memory task assessing what-where relations. We also modified the Mnemonic Similarity Task used to assess pattern discrimination in young and older adults for use with preschool children. Results showed that 4-year-olds performed significantly worse than 6-year-olds and adults on both tasks, whereas 6-year-olds and adults performed comparably, even though there were no ceiling effects. However, performance on the two tasks did not correlate, suggesting that two distinct mnemonic processes with different developmental trajectories may contribute to age-related changes in episodic memory.

Dissociable frontostriatal white matter connectivity underlies reward and motor impulsivity.

Dysfunction of cognitive control often leads to impulsive decision-making in clinical and healthy populations. Some research suggests that a generalized cognitive control mechanism underlies the ability to modulate various types of impulsive behavior, while other evidence suggests different forms of impulsivity are dissociable, and rely on distinct neural circuitry. Past research consistently implicates several brain regions, such as the striatum and portions of the prefrontal cortex, in impulsive behavior. However the ventral and dorsal striatum are distinct in regards to function and connectivity. Nascent evidence points to the importance of frontostriatal white matter connectivity in impulsivity, yet it remains unclear whether particular tracts relate to different control behaviors. Here we used probabilistic tractography of diffusion imaging data to relate ventral and dorsal frontostriatal connectivity to reward and motor impulsivity measures. We found a double dissociation such that individual differences in white matter connectivity between the ventral striatum and the ventromedial prefrontal cortex and dorsolateral prefrontal cortex was associated with reward impulsivity, as measured by delay discounting, whereas connectivity between dorsal striatum and supplementary motor area was associated with motor impulsivity, but not vice versa. Our findings suggest that (a) structural connectivity can is associated with a large amount of behavioral variation; (b) different types of impulsivity are driven by dissociable frontostriatal neural circuitry.

The neural representation of social status in the extended face-processing network.

Social status is a salient cue that shapes our perceptions of other people and ultimately guides our social interactions. Despite the pervasive influence of status on social behavior, how information about the status of others is represented in the brain remains unclear. Here, we tested the hypothesis that social status information is embedded in our neural representations of other individuals. Participants learned to associate faces with names, job titles that varied in associated status, and explicit markers of reputational status (star ratings). Trained stimuli were presented in an functional magnetic resonance imaging experiment where participants performed a target detection task orthogonal to the variable of interest. A network of face-selective brain regions extending from the occipital lobe to the orbitofrontal cortex was localized and served as regions of interest. Using multivoxel pattern analysis, we found that face-selective voxels in the lateral orbitofrontal cortex - a region involved in social and nonsocial valuation, could decode faces based on their status. Similar effects were observed with two different status manipulations - one based on stored semantic knowledge (e.g., different careers) and one based on learned reputation (e.g., star ranking). These data suggest that a face-selective region of the lateral orbitofrontal cortex may contribute to the perception of social status, potentially underlying the preferential attention and favorable biases humans display toward high-status individuals.

Short-Term Memory Depends on Dissociable Medial Temporal Lobe Regions in Amnestic Mild Cognitive Impairment.

Short-term memory (STM) has generally been thought to be independent of the medial temporal lobe (MTL) in contrast to long-term memory (LTM). Prodromal Alzheimer's disease (AD) is a condition in which the MTL is a major early focus of pathology and LTM is thought disproportionately affected relative to STM. However, recent studies have suggested a role for the MTL in STM, particularly hippocampus, when binding of different elements is required. Other work has suggested involvement of extrahippocampal MTL structures, particularly in STM tasks that involve item-level memory. We examined STM for individual objects, locations, and object-location conjunctions in amnestic mild cognitive impairment (MCI), often associated with prodromal AD. Relative to age-matched, cognitively normal controls, MCI patients not only displayed impairment on object-location conjunctions but were similarly impaired for non-bound objects and locations. Moreover, across all participants, these conditions displayed dissociable correlations of cortical thinning along the long axis of the MTL and associated cortical nodes of anterior and posterior MTL networks. These findings support the role of the MTL in visual STM tasks and the division of labor of MTL in support of different types of memory representations, overlapping with findings in LTM.

Inter-individual variation in fronto-temporal connectivity predicts the ability to learn different types of associations.

The uncinate fasciculus connects portions of the anterior and medial temporal lobes to the lateral orbitofrontal cortex, so it has long been thought that this limbic fiber pathway plays an important role in episodic memory. Some types of episodic memory are impaired after damage to the uncinate, while others remain intact. Because of this, the specific role played by the uncinate fasciculus in episodic memory remains undetermined. In the present study, we tested the hypothesis that the uncinate fasciculus is involved in episodic memory tasks that have high competition between representations at retrieval. To test this hypothesis, healthy young adults performed three tasks: Experiment 1 in which they learned to associate names with faces through feedback provided at the end of each trial; Experiment 2 in which they learned to associate fractals with cued locations through feedback provided at the end of each trial; and Experiment 3 in which unique faces were remembered in a paradigm with low retrieval competition. Diffusion tensor imaging and deterministic tractography methods were used to extract measures of uncinate fasciculus microstructure. Results revealed that microstructural properties of the uncinate, but not a control tract, the inferior longitudinal fasciculus, significantly predicted individual differences in performance on the face-name and fractal-location tasks. However, no relationship was observed for simple face memory (Experiment 3). These findings suggest that the uncinate fasciculus may be important for adjudicating between competing memory representations at the time of episodic retrieval.

Anhedonia and individual differences in orbitofrontal cortex sulcogyral morphology.

Three types of orbitofrontal cortex (OFC) sulcogyral patterns that have been identified in the population, and the distribution of these three types in clinically diagnosed schizophrenic patients has been found to be distinct from the normal population. Schizophrenia is associated with increased levels of social and physical anhedonia. In this study, we asked whether variation in anhedonia in a neurologically normal population is associated with altered sulcogyral pattern frequency. OFC sulcogyral type was classified and anhedonia was measured in 58 normal young adults, and the relationship between OFC sulcogyral type and anhedonia was explored. In line with other studies conducted in chronic schizophrenia, individuals with higher levels of physical anhedonia demonstrated atypical sulcogyral patterns. Individuals with higher physical anhedonia showed a reduced incidence of Type I OFC and an increased incidence of Type II OFC in the left hemisphere compared to individuals with lower physical anhedonia. These findings support the notion that Type I OFC sulcogyral pattern is protective of anhedonia compared to Type II, even in individuals that are not schizophrenic. Overall, these results support the view that symptoms and neural indices typically associated with neuropsychiatric disorders actually reflect quantitative traits that are continuously distributed throughout the general population. Hum Brain Mapp 37:3873-3881, 2016. © 2016 Wiley Periodicals, Inc.

Individual differences in white matter microstructure predict semantic control.

In everyday conversation, we make many rapid choices between competing concepts and words in order to convey our intent. This process is termed semantic control, and it is thought to rely on information transmission between a distributed semantic store in the temporal lobes and a more discrete region, optimized for retrieval and selection, in the left inferior frontal gyrus. Here, we used diffusion tensor imaging in a group of neurologically normal young adults to investigate the relationship between semantic control and white matter tracts that have been implicated in semantic memory retrieval. Participants completed a verb generation task that taps semantic control (Snyder & Munakata, 2008; Snyder et al., 2010) and underwent a diffusion imaging scan. Deterministic tractography was performed to compute indices representing the microstructural properties of the inferior fronto-occipital fasciculus (IFOF), the uncinate fasciculus (UF), and the inferior longitudinal fasciculus (ILF). Microstructural measures of the UF failed to predict semantic control performance. However, there was a significant relationship between microstructure of the left IFOF and ILF and individual differences in semantic control. Our findings support the view put forth by Duffau (2013) that the IFOF is a key structural pathway in semantic retrieval.