Working Memory Precision and Associative Binding in Mild Cognitive Impairment.

To better understand working memory (WM) deficits in Mild Cognitive Impairment (MCI), we examined information precision and associative binding in WM in 21 participants with MCI, compared to 16 healthy controls, using an item-location delayed reproduction task. WM, along with other executive functions (i.e. Trail Making Task (TMT) and Stroop task), were measured before and after a 2-h nap. The napping manipulation was intended as an exploratory element to this study exploring potential impacts of napping on executive functions.Compared to healthy participants, participants with MCI exhibited inferior performance not only in identifying encoded WM items but also on item-location associative binding and location precision even when only one item was involved. We also found changes on TMT and Stroop tasks in MCI, reflecting inferior attention and inhibitory control. Post-napping performance improved in most of these WM and other executive measures, both in MCI and their healthy peers.Our study shows that associative binding and WM precision can reliably differentiate MCIs from their healthy peers. Additionally, most measures showed no differential effect of group pre- and post-napping. These findings may contribute to better understanding cognitive deficits in MCI therefore improving the diagnosis of MCI.

Differential involvement of the anterior and posterior hippocampus, parahippocampus, and retrosplenial cortex in making precise judgments of spatial distance and object size for remotely acquired memories of environments and objects.

The hippocampus is known to support processing of precise spatial information in recently learned environments. It is less clear, but crucial for theories of systems consolidation, to know whether it also supports processing of precise spatial information in familiar environments learned long ago and whether such precision extends to objects and numbers. In this fMRI study, we asked participants to make progressively more refined spatial distance judgments among well-known Toronto landmarks (whether landmark A is closer to landmark B or C) to examine hippocampal involvement. We also tested whether the hippocampus was similarly engaged in estimating magnitude regarding sizes of familiar animals and numbers. We found that the hippocampus was only engaged in spatial judgment. Activation was greater and lasted longer in the posterior than anterior hippocampus, which instead showed greater modulation as discrimination between spatial distances became more fine grained. These findings suggest that the anterior and posterior hippocampus have different functions which are influenced differently by estimation of differential distance. Similarly, parahippocampal-place-area and retrosplenial cortex were involved only in the spatial condition. By contrast, activation of the intraparietal sulcus was modulated by precision in all conditions. Therefore, our study supports the idea that the hippocampus and related structures are implicated in retrieving and operating even on remote spatial memories whenever precision is required, as posted by some theories of systems consolidation.

High-fat-sugar diet is associated with impaired hippocampus-dependent memory in humans.

Overconsumption of high-fat and high-sugar (HFS) diet may affect the hippocampus, and consequently, memory functions. Yet, converging evidence is needed to demonstrate that the type of memory affected by HFS diet consumption is indeed hippocampus dependent. Moreover, the extent to which HFS diet can also affect executive functioning, and indirectly affect memory requires further examination. In this online study, we asked 349 young adults to report their HFS diet consumption and complete a word memory task, the Everyday Memory Questionnaire, and importantly two memory tasks that have been shown to robustly engage the hippocampus, i.e., the Pattern Separation and Associative Memory Tasks. Participants also completed two executive functioning tasks, the Trail Making Task (TMT) and the Stroop Task. These measures assess attention/cognitive flexibility and the ability to inhibit cognitive interference, respectively. After controlling for confounding variables, we found that participants who reported higher level consumption of a HFS diet performed worse on the Pattern Separation Task and that higher HFS intake was significantly associated with poorer TMT task performance and longer Stroop average reaction time (RT). TMT and Stroop RT scores indicative of reduced executive function also partially mediated the relationship between HFS diet and memory performance on the pattern separation task. Taken together, our results provide converging evidence that HFS diet may impair hippocampus-dependent memory. HFS diet may also affect executive functioning and indirectly impair memory function. The findings are consistent with human subject and animal studies and call for further investigations on the psychological and neural mechanisms underlying the dietary effects on cognitive processes.

Association of Psychological distress and Physical Health with Subjective and Objective Memory in Older Adults.

ObjectivesTo investigate how indicators of psychological stress and physical health differentially influence subjective and objective memory in older adults. Methods: 404 adults aged ≥55 without cognitive impairment participated in remote assessment of physical health (PHY; multimorbidity, body-mass-index), psychological distress (PDS; perceived stress, anxiety, depression), subjective memory complaints (SM), and task-based objective memory performance (OM). Results: Separately, both PHY and PDS significantly predicted SM (p < 0.01), but only PHY was associated with OM (p = 0.05). Combined models showed that PHY and PDS maintained significant association with SM (p < 0.01, R2 = 0.30), while only PHY was associated with OM (p = .07, R2 = 0.03; for associative OM, p = 0.04). Discussion: SM is associated with participants' psychological profile, highlighting the importance of addressing these factors when assessing SM. The results also reveal that remotely-administered OM tasks are more immune to participants' psychological profile, and support previously-established links between physical health and objective and subjective memory function.

Unrestricted eye movements strengthen effective connectivity from hippocampal to oculomotor regions during scene construction.

Scene construction is a key component of memory recall, navigation, and future imagining, and relies on the medial temporal lobes (MTL). A parallel body of work suggests that eye movements may enable the imagination and construction of scenes, even in the absence of external visual input. There are vast structural and functional connections between regions of the MTL and those of the oculomotor system. However, the directionality of connections between the MTL and oculomotor control regions, and how it relates to scene construction, has not been studied directly in human neuroimaging. In the current study, we used dynamic causal modeling (DCM) to interrogate effective connectivity between the MTL and oculomotor regions using a scene construction task in which participants' eye movements were either restricted (fixed-viewing) or unrestricted (free-viewing). By omitting external visual input, and by contrasting free- versus fixed- viewing, the directionality of neural connectivity during scene construction could be determined. As opposed to when eye movements were restricted, allowing free-viewing during construction of scenes strengthened top-down connections from the MTL to the frontal eye fields, and to lower-level cortical visual processing regions, suppressed bottom-up connections along the visual stream, and enhanced vividness of the constructed scenes. Taken together, these findings provide novel, non-invasive evidence for the underlying, directional, connectivity between the MTL memory system and oculomotor system associated with constructing vivid mental representations of scenes.

Electroencephalography complexity in resting and task states in adults with attention-deficit/hyperactivity disorder.

Analysing EEG complexity could provide insight into neural connectivity underlying attention-deficit/hyperactivity disorder symptoms. EEG complexity was calculated through multiscale entropy and compared between adults with attention-deficit/hyperactivity disorder and their peers during resting and go/nogo task states. Multiscale entropy change from the resting state to the task state was also examined as an index of the brain's ability to change from a resting to an active state. Thirty unmedicated adults with attention-deficit/hyperactivity disorder were compared with 30 match-paired healthy peers on the multiscale entropy in the resting and task states as well as their multiscale entropy change. Results showed differences in multiscale entropy between individuals with attention-deficit/hyperactivity disorder and their peers during the resting state as well as the task state. The multiscale entropy measured from the comparison group was larger than that from the attention-deficit/hyperactivity disorder group in the resting state, whereas the reverse pattern was found during the task state. Our most robust finding showed that the multiscale entropy change from individuals with attention-deficit/hyperactivity disorder was smaller than that from their peers, specifically at frontal sites. Interestingly, individuals without attention-deficit/hyperactivity disorder performed better with decreasing multiscale entropy changes, demonstrating higher accuracy, faster reaction time and less variability in their reaction times. These data suggest that multiscale entropy could not only provide insight into neural connectivity differences between adults with attention-deficit/hyperactivity disorder and their peers but also into their behavioural performance.

Neural Correlates of Subsequent Memory-Related Gaze Reinstatement.

Mounting evidence linking gaze reinstatement-the recapitulation of encoding-related gaze patterns during retrieval-to behavioral measures of memory suggests that eye movements play an important role in mnemonic processing. Yet, the nature of the gaze scanpath, including its informational content and neural correlates, has remained in question. In this study, we examined eye movement and neural data from a recognition memory task to further elucidate the behavioral and neural bases of functional gaze reinstatement. Consistent with previous work, gaze reinstatement during retrieval of freely viewed scene images was greater than chance and predictive of recognition memory performance. Gaze reinstatement was also associated with viewing of informationally salient image regions at encoding, suggesting that scanpaths may encode and contain high-level scene content. At the brain level, gaze reinstatement was predicted by encoding-related activity in the occipital pole and BG, neural regions associated with visual processing and oculomotor control. Finally, cross-voxel brain pattern similarity analysis revealed overlapping subsequent memory and subsequent gaze reinstatement modulation effects in the parahippocampal place area and hippocampus, in addition to the occipital pole and BG. Together, these findings suggest that encoding-related activity in brain regions associated with scene processing, oculomotor control, and memory supports the formation, and subsequent recapitulation, of functional scanpaths. More broadly, these findings lend support to Scanpath Theory's assertion that eye movements both encode, and are themselves embedded in, mnemonic representations.

Aging changes the interactions between the oculomotor and memory systems.

The use of multi-modal approaches, particularly in conjunction with multivariate analytic techniques, can enrich models of cognition, brain function, and how they change with age. Recently, multivariate approaches have been applied to the study of eye movements in a manner akin to that of neural activity (i.e., pattern similarity). Here, we review the literature regarding multi-modal and/or multivariate approaches, with specific reference to the use of eyetracking to characterize age-related changes in memory. By applying multi-modal and multivariate approaches to the study of aging, research has shown that aging is characterized by moment-to-moment alterations in the amount and pattern of visual exploration, and by extension, alterations in the activity and function of the hippocampus and broader medial temporal lobe (MTL). These methodological advances suggest that age-related declines in the integrity of the memory system has consequences for oculomotor behavior in the moment, in a reciprocal fashion. Age-related changes in hippocampal and MTL structure and function may lead to an increase in, and change in the patterns of, visual exploration in an effort to upregulate the encoding of information. However, such visual exploration patterns may be non-optimal and actually reduce the amount and/or type of incoming information that is bound into a lasting memory representation. This research indicates that age-related cognitive impairments are considerably broader in scope than previously realized.

Visuospatial Working Memory Capacity in the Brain After Working Memory Training in College Students With ADHD: A Randomized Controlled Trial.

Objective: ADHD has been associated with persistent problems of working memory. This study investigated the efficacy of an intensive and adaptive computerized working memory treatment (CWMT) at behavioral and neural levels. Method: College students (n = 89; 40 females) with ADHD were randomized into a standard-length CWMT (45 min/session, 25 sessions, n = 29), shortened-length CWMT (15 min/session, 25 sessions, n = 32), and a waitlist group (n = 28). Both CWMT groups received treatment for 5 days a week for 5 weeks. Lab sessions before and after CWMT assessed electroencephalography (EEG) indicators of working memory, behavioral indicators of working memory performance, and ADHD symptomatology. Results: No evidence was found for neural or any other behavioral transfer effects of improvement for the CWMT treatment groups over the active control or waitlist group. Conclusion: Our study does not provide evidence for the benefits of CWMT at neural or behavioral levels.

Restricting Visual Exploration Directly Impedes Neural Activity, Functional Connectivity, and Memory.

We move our eyes to explore the visual world, extract information, and create memories. The number of gaze fixations-the stops that the eyes make-has been shown to correlate with activity in the hippocampus, a region critical for memory, and with later recognition memory. Here, we combined eyetracking with fMRI to provide direct evidence for the relationships between gaze fixations, neural activity, and memory during scene viewing. Compared to free viewing, fixating a single location reduced: 1) subsequent memory, 2) neural activity along the ventral visual stream into the hippocampus, 3) neural similarity between effects of subsequent memory and visual exploration, and 4) functional connectivity among the hippocampus, parahippocampal place area, and other cortical regions. Gaze fixations were uniquely related to hippocampal activity, even after controlling for neural effects due to subsequent memory. Therefore, this study provides key causal evidence supporting the notion that the oculomotor and memory systems are intrinsically related at both the behavioral and neural level. Individual gaze fixations may provide the basic unit of information on which memory binding processes operate.

The intersection between the oculomotor and hippocampal memory systems: empirical developments and clinical implications.

Decades of cognitive neuroscience research has shown that where we look is intimately connected to what we remember. In this article, we review findings from human and nonhuman animals, using behavioral, neuropsychological, neuroimaging, and computational modeling methods, to show that the oculomotor and hippocampal memory systems interact in a reciprocal manner, on a moment-to-moment basis, mediated by a vast structural and functional network. Visual exploration serves to efficiently gather information from the environment for the purpose of creating new memories, updating existing memories, and reconstructing the rich, vivid details from memory. Conversely, memory increases the efficiency of visual exploration. We call for models of oculomotor control to consider the influence of the hippocampal memory system on the cognitive control of eye movements, and for models of hippocampal and broader medial temporal lobe function to consider the influence of the oculomotor system on the development and expression of memory. We describe eye movement-based applications for the detection of neurodegeneration and delivery of therapeutic interventions for mental health disorders for which the hippocampus is implicated and memory dysfunctions are at the forefront.

Neural processing of working memory in adults with ADHD in a visuospatial change detection task with distractors.

Individuals with Attention-Deficit Hyperactivity Disorder (ADHD) are often characterized by deficits in working memory (WM), which manifest in academic, professional, and mental health difficulties. To better understand the underlying mechanisms of these presumed WM deficits, we compared adults with ADHD to their peers on behavioral and neural indices of WM. We used a visuospatial change detection task with distractors which was designed to assess the brain's ability to effectively filter out distractors from WM, in addition to testing for effects of WM load. Twenty-seven unmedicated adults with ADHD were compared to 27 matched peers on event-related potential (ERP) measures of WM, i.e., the contralateral delay activity (CDA). Despite severe impairments in everyday life functioning, findings showed no difference in deficits in behavioral tests of working memory for adults with ADHD compared to their peers. Interestingly, there were differences in neural activity between individuals with ADHD and their peers showing that the CDA of individuals with ADHD did not distinguish between high, distractor, and low memory load conditions. These data suggest, in the face of comparable behavioral performance, a difference in neural processing efficiency, wherein the brains of individuals with ADHD may not be as selective in the allocation of neural resources to perform a WM task.

Age-related changes in the relationship between visual exploration and hippocampal activity.

Deciphering the mechanisms underlying age-related memory declines remains an important goal in cognitive neuroscience. Recently, we observed that visual sampling behavior predicted activity within the hippocampus, a region critical for memory. In younger adults, increases in the number of gaze fixations were associated with increases in hippocampal activity (Liu et al., 2017). This finding suggests a close coupling between the oculomotor and memory system. However, the extent to which this coupling is altered with aging has not been investigated. In this study, we gave older adults the same face processing task used in Liu et al. (2017) and compared their visual exploration behavior and neural activation in the hippocampus and the fusiform face area (FFA) to those of younger adults. Compared to younger adults, older adults showed an increase in visual exploration as indexed by the number of gaze fixations. However, the relationship between visual exploration and neural responses in the hippocampus and FFA was weaker than that of younger adults. Older adults also showed weaker responses to novel faces and a smaller repetition suppression effect in the hippocampus and FFA compared to younger adults. All together, this study provides novel evidence that the capacity to bind visually sampled information, in real-time, into coherent representations along the ventral visual stream and the medial temporal lobe declines with aging.

Multiple Scales of Representation along the Hippocampal Anteroposterior Axis in Humans.

The ability to represent the world accurately relies on simultaneous coarse and fine-grained neural information coding, capturing both gist and detail of an experience. The longitudinal axis of the hippocampus may provide a gradient of representational granularity in spatial and episodic memory in rodents and humans [1-8]. Rodent place cells in the ventral hippocampus exhibit significantly larger place fields and greater autocorrelation than those in the dorsal hippocampus [1, 9-11], which may underlie a coarser and slower changing representation of space [10, 12]. Recent evidence suggests that properties of cellular dynamics in rodents can be captured with fMRI in humans during spatial navigation [13] and conceptual learning [14]. Similarly, mechanisms supporting granularity along the long axis may also be extrapolated to the scale of fMRI signal. Here, we provide the first evidence for separable scales of representation along the human hippocampal anteroposterior axis during navigation and rest by showing (1) greater similarity among voxel time courses and (2) higher temporal autocorrelation in anterior hippocampus (aHPC), relative to posterior hippocampus (pHPC), the human homologs of ventral and dorsal rodent hippocampus. aHPC voxels exhibited more similar activity at each time point and slower signal change over time than voxels in pHPC, consistent with place field organization in rodents. Importantly, similarity between voxels was related to navigational strategy and episodic memory. These findings provide evidence that the human hippocampus supports an anterior-to-posterior gradient of coarse-to-fine spatiotemporal representations, suggesting the existence of a cross-species mechanism, whereby lower neural similarity supports more complex coding of experience.

The effect of prior knowledge on post-encoding brain connectivity and its relation to subsequent memory.

It is known that prior knowledge can facilitate memory acquisition. It is unclear, however, whether prior knowledge can affect post-encoding brain activity to facilitate memory consolidation. In this fMRI study, we asked participants to associate novel houses with famous/nonfamous faces and investigated how associative-encoding tasks with/without prior knowledge differentially affected post-encoding brain connectivity during rest. Besides memory advantages in the famous condition, we found that post-encoding hippocampal connectivity with the fusiform face area (FFA) and ventral-medial-prefrontal cortex (vmPFC) was stronger following encoding of associations with famous than non-famous faces. Importantly, post-encoding functional connectivity between the hippocampus (HPC) and FFA, and between the anterior temporal pole region (aTPL) and posterior perceptual regions (i.e., FFA and the parahippocampal place area), together predicted a large proportion of the variance in subsequent memory performance. This prediction was specific for face-house associative memory, not face/house item memory, and only in the famous condition where prior knowledge was involved. These results support the idea that when prior knowledge is involved, the HPC, vmPFC, and aTPL, which support prior episodic, social-evaluative/schematic, and semantic memories, respectively, continue to interact with each other and posterior perceptual brain regions during the post-encoding rest to facilitate off-line processing of the newly formed memory, and enhance memory consolidation.

Visual Sampling Predicts Hippocampal Activity.

Eye movements serve to accumulate information from the visual world, contributing to the formation of coherent memory representations that support cognition and behavior. The hippocampus and the oculomotor network are well connected anatomically through an extensive set of polysynaptic pathways. However, the extent to which visual sampling behavior is related to functional responses in the hippocampus during encoding has not been studied directly in human neuroimaging. In the current study, participants engaged in a face processing task while brain responses were recorded with fMRI and eye movements were monitored simultaneously. The number of gaze fixations that a participant made on a given trial was correlated significantly with hippocampal activation such that more fixations were associated with stronger hippocampal activation. Similar results were also found in the fusiform face area, a face-selective perceptual processing region. Notably, the number of fixations was associated with stronger hippocampal activation when the presented faces were novel, but not when the faces were repeated. Increases in fixations during viewing of novel faces also led to larger repetition-related suppression in the hippocampus, indicating that this fixation-hippocampal relationship may reflect the ongoing development of lasting representations. Together, these results provide novel empirical support for the idea that visual exploration and hippocampal binding processes are inherently linked. SIGNIFICANCE STATEMENT: The hippocampal and oculomotor networks have each been studied extensively for their roles in the binding of information and gaze function, respectively. Despite the evidence that individuals with amnesia whose damage includes the hippocampus show alterations in their eye movement patterns and recent findings that the two systems are anatomically connected, it has not been demonstrated whether visual exploration is related to hippocampal activity in neurologically intact adults. In this combined fMRI-eye-tracking study, we show how hippocampal responses scale with the number of gaze fixations made during viewing of novel, but not repeated, faces. These findings provide new evidence suggesting that the hippocampus plays an important role in the binding of information, as sampled by gaze fixations, during visual exploration.

Effects of Prior-Knowledge on Brain Activation and Connectivity During Associative Memory Encoding.

Forming new associations is a fundamental process of building our knowledge system. At the brain level, how prior-knowledge influences acquisition of novel associations has not been thoroughly investigated. Based on recent cognitive neuroscience literature on multiple-component memory processing, we hypothesize that prior-knowledge triggers additional evaluative, semantic, or episodic-binding processes, mainly supported by the ventromedial prefrontal cortex (vmPFC), anterior temporal pole (aTPL), and hippocampus (HPC), to facilitate new memory encoding. To test this hypothesis, we scanned 20 human participants with functional magnetic resonance imaging (fMRI) while they associated novel houses with famous or nonfamous faces. Behaviorally, we found beneficial effects of prior-knowledge on associative memory. At the brain level, we found that the vmPFC and HPC, as well as the parahippocampal place area (PPA) and fusiform face area, showed stronger activation when famous faces were involved. The vmPFC, aTPL, HPC, and PPA also exhibited stronger activation when famous faces elicited stronger emotions and memories, and when associations were later recollected. Connectivity analyses also suggested that HPC connectivity with the vmPFC plays a more important role in the famous than nonfamous condition. Taken together, our results suggest that prior-knowledge facilitates new associative encoding by recruiting additional perceptual, evaluative, or associative binding processes.

Effects of working memory training on neural correlates of Go/Nogo response control in adults with ADHD: A randomized controlled trial.

Working memory and response control are conceptualized as functions that are part of a closely connected and integrated executive function system mediated by the prefrontal cortex and other related brain structures. In the present paper, we asked whether effects of intensive and adaptive computerized working memory training (CWMT) would generalize to enhancements in response control at behavioral and neural levels. A total of 135 postsecondary students with Attention-Deficit/Hyperactivity Disorder (ADHD), a condition associated with executive function impairments, were randomized into a Standard-length CWMT (45-min /session, 25 sessions), Shortened-length CWMT (15min/session, 25 sessions), and a waitlist group. Both training groups received CWMT for 5 days a week for 5 weeks long. All participants completed a Go-Nogo task while neural activity was measured using Electroencephalography (EEG), before and after CWMT. Behavioral results showed trend level evidence (p=0.061) for benefits of CWMT on response control (i.e., improved accuracy of Go responses). Among several neural measures results showed statistically significant changes after CWMT only for the Go trial ERP N2 and P3 in frontal electrodes (p=0.039 and 0.001, respectively). However, given the lack of relationship between behavioral and neural changes and especially the clear lack of predicted does effects (i.e., standard length > short length > control), we conclude that there is no convincing evidence that the working memory training per se changes neural activation patterns in untrained executive functions. The positive finding of general training related changes in this study should have no clinical implications, but may contribute to the literature in better understanding the relationship between neural plasticity and transfer.

EEG alpha power during maintenance of information in working memory in adults with ADHD and its plasticity due to working memory training: A randomized controlled trial.

OBJECTIVE: The present study examined whether neural indices of working memory maintenance differ between young adults with ADHD and their healthy peers (Study 1), and whether this neural index would change after working memory training (Study 2). METHODS: Study 1 involved 136 college students with ADHD and 41 healthy peers (aged 18-35 years) and measured their posterior alpha activity during a visual delayed-match-to-sample task using electroencephalography (EEG). Study 2 involved 99 of the participants with ADHD who were randomized into a standard-length or shortened-length Cogmed working memory training program or a waitlist control group. RESULTS: The ADHD group tended to be less accurate than the peers. Similarly, the ADHD group exhibited lower posterior alpha power at a trend level compared to their healthy peers. There were no training effects on participants' performance and only marginal increases in posterior alpha power in training groups compared to the waitlist group. CONCLUSIONS: Considering that the training effects were small and there was no load and dose effect, we conclude that the current study provides no convincing evidence for specific effects of Cogmed. SIGNIFICANCE: These findings provide unique insights into neuroplasticity, or lack thereof, with near-transfer tasks in individuals with ADHD.

Neural Rhythms of Change: Long-Term Improvement after Successful Treatment in Children with Disruptive Behavior Problems.

Neural changes were investigated for children with disruptive behavior problems one year after a treatment program ended. Thirty-nine children and their parents visited the research lab before, after, and a year after treatment ended. During those lab visits, electroencephalography (EEG) was recorded during a challenging Go/No-go task. Treatment consisted of intensive 14-week combined cognitive behavioral therapy and parent management training sessions. For the analysis, participants were divided into long-term improvers (IMPs) and long-term nonimprovers (NIMPs) based on changes in their externalizing problem scores. The results showed early no-go theta power (4-8 Hz, 100-250 ms) decreased for long-term IMPs compared to NIMPs. When participants were divided based on changes in their comorbid internalizing symptoms, effects were stronger and reductions in theta power were found for early as well as later phases (250-650 ms). We provided preliminary evidence that theta power is a useful neural measure to trace behavioral change linked to improved self-regulation even up to a year after treatment ended. Results may have implications for the characterization of children with disruptive behavior problems and may lead to the development of novel markers of treatment success.