The hippocampus and implicit memory.

The traditional memory-systems view is that explicit (conscious) long-term memory is associated with the hippocampus and implicit (nonconscious) memory is associated with non-hippocampal brain regions. This special issue of Cognitive Neuroscience focuses on whether the hippocampus is associated with implicit memory. An empirical fMRI paper by Miller, Kennard, Gowland, Antoniades, and Rosenthal (this issue) evaluated recognition memory performance of autobiographical amnesia patients with bilateral damage to hippocampal sub-region CA3 and found they had greater than chance recognition memory performance for spatial sequence learning, spatial item learning-same location, and non-spatial item learning, but chance performance for non-spatial sequence learning and spatial item learning-different location. These results are at odds with the view that the hippocampus is generally involved in sequence learning and complex event recognition. A discussion paper by Steinkrauss and Slotnick (this issue) considered whether fMRI studies have provided evidence that the hippocampus is associated with implicit memory. It was argued that all previous studies have been confounded by explicit memory, attentional states, stimuli, or novelty. This discussion paper is followed by commentaries from Hannula (this issue), Henke and Ruch (this issue), Rosenthal (this issue), Spaak (this issue), Thakral et al. (this issue), and Züst (this issue). The articles in this special issue illustrate that the association between the hippocampus and implicit memory is under active investigation and debate. It is hoped that the evidence and discourse in this issue will provide directions for future research.

True and false memories for spatial location evoke more similar patterns of brain activity in males than females.

True and false memories recruit a number of shared brain regions; however, they are not completely overlapping. Extensive sex differences have been identified in the brain during true memories and, recently, we identified sex differences in the brain during false memories. In the current fMRI study, we sought to determine whether sex differences existed in the location and extent of overlap between true and false memories. True and false memories activated a number of shared brain regions. Compared to females, males produced a greater number of overlapping brain regions (8 versus 2 activations for males and females, respectively) including the prefrontal cortex, parietal cortex, and early/late visual processing cortices (including V1) in males and prefrontal and parietal cortices in females. Males had significantly higher similarity between true and false memory activation maps, revealed by our novel multi-voxel pattern correlation analysis. Moreover, higher similarity between true and false memory activation maps was associated with higher false memory rates. The current results suggest that true and false memories are more similar in males than females. The significant brain-behavior relationship also suggests that males may be more susceptible to false memory errors due to their highly similar true memory-false memory cortical representations.

Is implicit memory associated with the hippocampus?

According to the traditional memory-systems view, the hippocampus is critical during explicit (conscious) long-term memory, whereas other brain regions support implicit (nonconscious) memory. In the last two decades, some fMRI studies have reported hippocampal activity during implicit memory tasks. The aim of the present discussion paper was to identify whether any implicit memory fMRI studies have provided convincing evidence that the hippocampus is associated with nonconscious processes without being confounded by conscious processes. Experimental protocol and analysis parameters included the stimulus type(s), task(s), measures of subjective awareness, explicit memory accuracy, the relevant fMRI contrast(s) or analysis, and confound(s). A systematic review was conducted to identify implicit memory studies that reported fMRI activity in the hippocampus. After applying exclusion criteria, 13 articles remained for analysis. We found that there were no implicit memory fMRI studies where subjective awareness was absent, explicit memory performance was at chance, and there were no confounds that could have driven the observed hippocampal activity. The confounds included explicit memory (including false memory), imbalanced attentional states between conditions (yielding activation of the default-mode network), imbalanced stimuli between conditions, and differential novelty. As such, not a single fMRI study provided convincing evidence that implicit memory was associated with the hippocampus. Neuropsychological evidence was also considered, and implicit memory deficits were caused by factors known to disrupt brain regions beyond the hippocampus, such that the behavioral effects could not be attributed to this region. The present results indicate that implicit memory is not associated with the hippocampus.

Can Residents With Late-Stage Dementia Still Engage?

Institutionalized persons with dementia often lack access to meaningful activity, which can lead to agitation, loneliness, and depression. Engagement in activity may improve negative symptoms but is difficult in most settings. In this study, we investigated the degree to which the Reading Buddies Program, in which occupational therapy graduate students read books with residents with dementia, engaged residents. We further assessed whether the level of engagement was affected by various parameters, including those related to interaction, environment, attention, attitude, and activity. The primary outcome measure was engagement percentage-duration of time the book was read divided by duration of time the person with dementia engaged with the book. As expected, increased attention, attitude, and activity parameters were associated with increased engagement. None of the environmental parameters significantly affected engagement. Overall, we found that reading with persons with dementia led to a very high level of engagement and appeared to reduce negative symptoms.

TMS must not harm participants: guidelines for evaluating TMS protocol safety.

Transcranial magnetic stimulation (TMS) can modulate a targeted brain region to assess whether that region is involved in a cognitive process. When TMS is employed in cognitive neuroscience, participants are typically healthy volunteers, and the technique is described as noninvasive. However, TMS parameters can be set such that stimulation produces long-lasting effects. Critically, TMS effects that have any possibility of lasting beyond a participant's time in the lab are potentially harmful. In this editorial, evidence is considered that indicates a 20-Hz multi-day TMS protocol has long-lasting effects, and a continuous theta-burst stimulation protocol needs further testing before it is deemed noninvasive. The following guidelines are provided for TMS protocol evaluation: 1) Effects must be shown to completely dissipate before participants leave the lab by testing well beyond the expected duration. 2) Participants should complete a cognitive test battery before TMS and after the effects are expected to dissipate. 3) Protocols should not be employed that produce effects lasting longer than the time in the lab. 4) The number of participants should ensure error bars are small, and results generalize to the population. 5) Results should be assessed at the group and individual-participant level, and effects should dissipate for every participant. 6) Bayesian analysis should be conducted to evaluate evidence in favor of the null hypothesis. 7) Effects should be assessed in multiple cortical regions. It is hoped that these guidelines will be employed to ensure the continued use of TMS as a valuable tool in the field of cognitive neuroscience.

Prefrontal cortex-mediated inhibition supports face recognition.

Inhibitory processes are thought to be important for memory function. A recent behavioral study that employed a face recognition paradigm reported that participants made fewer "old" responses to highly similar faces than less similar faces, providing evidence that memory for faces may rely on related-item inhibition. However, these results could also be explained by a non-inhibitory recall-to-reject process. The current study sought to use fMRI connectivity analysis to distinguish between these hypotheses. Although both hypotheses predict correct rejection of highly similar faces will produce activity in the prefrontal cortex, the inhibition hypothesis predicts negative connectivity between the prefrontal cortex and regions associated with memory retrieval and face processing, whereas the recall-to-reject hypothesis predicts positive connectivity between these regions. During the study phase, participants were presented with male and female faces. During the test phase, they viewed old faces, related face morphs (20-80% similar to old faces), and new faces, and made "old"-"new" judgements. Correct rejection of highly similar face morphs was associated with increased activity in the right lateral prefrontal cortex and negative connectivity between this region and regions associated with face processing and memory retrieval. These results indicate that prefrontal cortex-mediated memory inhibition supports face recognition.

No convincing evidence the hippocampus is associated with working memory.

In a previous discussion paper , twenty-six working memory fMRI studies that reported activity in the hippocampus were systematically analyzed. None of these studies provided convincing evidence that the hippocampus was active during the late delay phase, the only period in which working memory can be isolated from long-term memory processes. Based on these results, it was concluded that working memory does not activate the hippocampus. Six commentaries on the discussion paper were received from Courtney (2022), Kessels and Bergmann (2022), Peters and Reithler (2022), Rose and Chao (2022), Stern and Hasselmo (2022), and Wood et al. (2022). Based on these commentaries, the present response paper considered whether there is evidence of sustained hippocampal activity during the working memory delay period based on depth-electrode recording, whether there are activity-silent working memory mechanisms in the hippocampus, and whether there is hippocampal lesion evidence indicating this region is important for working memory. There was no convincing electrophysiological or neuropsychological evidence that the hippocampus is associated with working memory maintenance, and activity-silent mechanisms were arguably speculative. Given that only a small fraction (approximately 5%) of working memory fMRI studies have reported hippocampal activity and lesion evidence indicates the hippocampus is not necessary for working memory, the burden of proof is on proponents of the view that the hippocampus is important for working memory to provide compelling evidence to support their position. To date, from my perspective, there is no convincing evidence that the hippocampus is associated with working memory.

Entorhinal Cortex Functional Connectivity during Item Long-Term Memory and the Role of Sex.

A growing body of literature shows there are sex differences in the patterns of brain activity during long-term memory. However, there is a paucity of evidence on sex differences in functional brain connectivity. We previously identified sex differences in the patterns of connections with the hippocampus, a medial temporal lobe (MTL) subregion, during spatial long-term memory. The perirhinal/entorhinal cortex, another MTL subregion, plays a critical role in item memory. In the current functional magnetic resonance imaging (fMRI) study, we investigated perirhinal/entorhinal functional connectivity and the role of sex during item memory. During the study phase, abstract shapes were presented to the left or right of fixation. During the test phase, abstract shapes were presented at fixation, and the participants classified each item as previously "old" or "new". An entorhinal region of interest (ROI) was identified by contrasting item memory hits and misses. This ROI was connected to regions generally associated with visual memory, including the right inferior frontal gyrus (IFG) and visual-processing regions (the bilateral V1, bilateral cuneus, and left lingual gyrus). Males produced greater connectivity than females with the right IFG/insula and the right V1/bilateral cuneus. Broadly, these results contribute to a growing body of literature supporting sex differences in the brain.

Impaired cognitive performance in older adults is associated with deficits in item memory and memory for object features.

Amnestic mild cognitive impairment (aMCI) is associated with damage to the perirhinal/entorhinal cortex, and consequently, deficits in item/object memory. However, cognitive assessments commonly used to identify individuals with aMCI require a clinician to administer and interpret the test. We developed a novel self-administered global cognitive assessment, called the Cognitive Assessment via Keyboard (CAKe). To assess the relationship between CAKe performance and perirhinal/entorhinal cortex-dependent memory function, participants completed the CAKe, a feature source memory task, and a context memory task. During the memory tasks, participants studied line drawings with either a green or orange internal color (feature memory runs) or external color (context memory runs) and then classified each item as old and previously presented with a "green" or "orange" color, or "new". CAKe scores were correlated with item memory accuracies and source memory accuracies on both tasks. Participants with 'impaired' CAKe performance had worse item memory and worse feature source memory accuracies than those with 'normal' CAKe performance. These results demonstrate specific deficits in item memory and feature source memory and suggest that our assessments may be a valid predictor of aMCI memory deficits.

Sex is predicted by spatial memory multivariate activation patterns.

Whether sex differences exist in the brain at the macroscopic level, as measured with magnetic resonance imaging (MRI), is a topic of debate. The present spatial long-term memory functional MRI (fMRI) study predicted sex based on event-related patterns of brain activity. Within spatial memory regions of interest, patterns of activity associated with females and males were used to predict the sex of each member of left-out female-male pairs at above-chance accuracy. The current results provide evidence for sex differences in the brain processes underlying spatial long-term memory. This is the first time that sex has been predicted using event-related fMRI activation patterns. The present findings contribute to a growing body of evidence that there are functional and anatomic sex differences in the brain and, more broadly, question the widespread practice of collapsing across sex in the field of cognitive neuroscience.

The hippocampus and long-term memory.

This special issue of Cognitive Neuroscience focuses on the roles of the hippocampus during long-term memory. A discussion paper by Tallman, Clark, and Smith (this issue) found that functional connectivity of the hippocampus with the parahippocampal cortex and fusiform gyrus decreased with memory age, providing support for systems consolidation. Commentaries were received by Berdugo-Vega and Gräff (this issue), Feld and Gerchen (this issue), Gellersen and Simons (this issue), Gobbo, Mitchell-Heggs, and Tse (this issue), Gilmore, Audrain, and Martin (this issue), Kirwan (this issue), Manns (this issue), Runyan and Brooks (this issue), Santangelo (this issue), and Yang (this issue). The author response considered the content and context of memorial information along with neuroanatomy and functional specialization and conducted new analyses to clarify their findings. An empirical fMRI paper by Thakral, Yu, and Rugg (this issue) reported that the hippocampus was sensitive to the amount of contextual information retrieved, regardless of remember-know status. Another empirical study by Bjornn, Van, and Kirwan (this issue) found that hippocampal activation changes were correlated with the number of fixations at study for correct but not incorrect mnemonic discrimination judgments. A second discussion paper (Slotnick, this issue) concluded that no fMRI studies have provided evidence that the hippocampus is associated with working memory. Commentaries were received by Courtney (this issue), Kessels and Bergmann (this issue), Peters and Reithler (this issue), Rose and Chao (this issue), Stern and Hasselmo (this issue), and Wood, Clark, and Nee (this issue). The articles in this special issue illustrate that the roles of the hippocampus in long-term memory (and other types of memory) are under active investigation and provide many directions for research in the immediate future.

Does working memory activate the hippocampus during the late delay period?

The aim of the present discussion paper was to identify whether any fMRI studies have provided convincing evidence that the hippocampus is associated with working memory. The key outcome variable was the phase in which hippocampal activity was observed: study, early delay, late delay, and/or test. During working memory tasks, long-term memory processes can operate during the study phase, early delay phase (due to extended encoding), or test phase. Thus, working memory processes can be isolated from long-term memory processes during only the late delay period. Twenty-six working memory studies that reported hippocampal activity were systematically analyzed. Many experimental protocol and analysis parameters were considered including number of participants, stimulus type(s), number of items during the study phase, delay duration, task during the test phase, behavioral accuracy, relevant fMRI contrast(s), whether the information was novel or familiar, number of phases modeled, and whether activation timecourses were extracted. For studies that were able to identify activity in different phases, familiar information sometimes produced activity during the study phase and/or test phase, but never produced activity during the delay period. When early-delay phase and late-delay phase activity could be distinguished via modeling these phases separately or inspecting activation timecourses, novel information could additionally produce activity during the early delay phase. There was no convincing evidence of hippocampal activity during the late delay period. These results indicate that working memory does not activate the hippocampus and suggest a model of working memory where maintenance of novel information can foster long-term memory encoding.

It's time for sex in cognitive neuroscience.

In a discussion paper published in the special issue of Cognitive Neuroscience, Sex Differences in the Brain, we investigated whether certain experimental parameters contributed to findings in functional magnetic resonance imaging studies of sex differences during long-term memory. Experimental parameters included: the number of participants, stimulus type(s), whether or not performance was matched, whether or not sex differences were reported, the type of between-subject statistical test used, and the contrast(s) employed. None of these parameters determined whether or not differences were observed, as all included studies reported sex differences. We also conducted a meta-analysis to determine if there were any brain regions consistently activated to a greater degree in either sex. The meta-analysis identified sex differences (male > female) in the lateral prefrontal cortex, visual processing regions, parahippocampal cortex, and the cerebellum. We received eight commentaries in response to that paper. Commentaries called for an expanded discussion on various topics including the influence of sex hormones, the role of gender (and other social factors), the pros and cons of equating behavioral performance between the sexes, and interpreting group differences in patterns of brain activity. There were some common statistical assumptions discussed in the commentaries regarding the 'file drawer' issue (i.e., the lack of reporting of null results) and effect size. The current paper provides further discussion of the various topics brought up in the commentaries and addresses some statistical misconceptions in the field. Overall, the commentaries echoed a resounding call to include sex as a factor in cognitive neuroscience studies.

Sex differences in the brain.

This special issue of Cognitive Neuroscience focuses on sex differences in the brain. Berchicci, Bianco, and Di Russo found ERP auditory cortex activity was larger in females than males during sound perception. Spets, Fritch, Thakral, & Slotnick reported greater fMRI activity during high- versus low-confidence spatial memory in males than females within the lateral prefrontal cortex and other brain regions. Using fMRI resting-state data, Murray, Maurer, Peechatka, Frederick, Kaiser, and Janes observed females spent more time in transient dorsal attention/occipital/sensory-motor network states and males spent more time in transient salience network states, and de Lacy, Kutz, and Calhoun found that brain dynamism (transitioning between brain states) was correlated with anxiety/depression in males and drive/novelty-seeking/self-control in females. Kurth, Gaser, and Luders predicted the sex of girls and boys with an 80.4% accuracy using a classifier based on anatomic (MRI) data. In a discussion paper, Spets and Slotnick conducted an fMRI meta-analysis that revealed greater male than female long-term memory activity in the lateral prefrontal cortex, visual processing regions, and the parahippocampal cortex, and argued against the claim there is reporting bias in sex-differences studies. In response to this discussion paper, commentaries were written by Cahill; de Lacy; Hausmann; McGlade, Rogowska, and Yurgelun-Todd; Sneider and Silveri; Tejavibulya and Scheinost; Wiersch and Weis; Young and Compère. It is hoped that these findings will help motivate a shift in the field to consider sex as a factor in cognitive neuroscience studies.

Distinct patterns of hippocampal activity associated with color and spatial source memory.

The hippocampus is known to be involved in source memory across a wide variety of stimuli and source types. Thus, source memory activity in the hippocampus is thought to be domain-general such that different types of source information are similarly processed in the hippocampus. However, there is some evidence of domain-specificity for spatial and temporal source information. The current fMRI study aimed to determine whether patterns of activity in the hippocampus differed for two types of visual source information: spatial location and background color. Participants completed three runs of a spatial memory task and three runs of a color memory task. During the study phase, 32 line drawings of common objects and animals were presented to either the left or right of fixation for the spatial memory task or on either a red or green background for the color memory task. During the test phase of both tasks, 48 object word labels were presented in the center of the screen and participants classified the corresponding item as old and previously on the "left"/on a "green" background, old and previously on the "right"/on a "red" background, or "new." Two analysis methods were employed to assess whether hippocampal activity differed between the two source types: a general linear model analysis and a classification-based searchlight multivoxel pattern analysis (MVPA). The searchlight MVPA revealed that activity associated with spatial memory and color memory could be classified with above-chance accuracy in a region of the right anterior hippocampus, and a follow-up analysis revealed that there was a significant effect of memory accuracy. These results indicate that different types of source memory are represented by distinct patterns of activity in the hippocampus.

Support for an inhibitory model of word retrieval.

Word retrieval may involve an inhibitory process in which a target word is activated and related words are suppressed. In the current functional magnetic resonance imaging (fMRI) study, we examined the inhibition of language processing cortex by the left dorsolateral prefrontal cortex (DLPFC) during word retrieval using an anagram-solving paradigm. Participants were presented with a distractor that was read aloud followed by a to-be-solved anagram. Distractor types were defined relative to orthographic overlap with the subsequent anagram solution and included related words with one letter different (e.g., "gripe" for the anagram of "price"), related pseudo-words, and unrelated words (i.e., all five letters were different). The anagram solution reaction time was slower in both the related word and related pseudo-word distractor conditions as compared to the unrelated word distractor condition, which can be attributed to greater inhibition following related distractors. The contrast of related words and unrelated words produced one activation in the left DLPFC, a region that has been associated with memory inhibition. To identify the regions that were negatively correlated with activity in the left DLPFC for related distractors, we conducted a functional connectivity analysis between this left DLPFC region and the rest of the brain. We found negatively correlated activity between the DLPFC and language processing cortex for the related word distractor condition (and the related pseudo-word distractor condition at a relaxed threshold). These findings suggest that that the left DLPFC may inhibit related word (and pseudo-word) representations in language processing cortex.

Sex differences in hippocampal connectivity during spatial long-term memory.

Sex differences in brain activity have been reported across various types of long-term memory. To our knowledge, sex differences in functional connectivity during long-term memory have not been investigated. A previous study on the structural connectome identified that female brains have a greater degree of interhemispheric connectivity than males, whereas males have a greater degree of intrahemispheric connectivity than females. The aim of the current investigation was twofold: (a) identify which brain regions were functionally connected to the hippocampus during spatial long-term memory, and (b) determine if there were sex differences in the functionally connected regions. During the study phase, abstract shapes were presented to the left or right of fixation. During the test phase, abstract shapes were presented at fixation and participants classified each item as previously on the "left" or "right". A hippocampal region of interest (ROI) was identified by contrasting spatial memory hits and misses. The peak coordinate from this ROI was used to define the center of a sphere that was used as the seed for the functional connectivity analysis. The connectivity analysis produced many connected activations including the medial posterior frontal cortex, lateral posterior frontal cortex, left inferior frontal gyrus, posterior cingulate cortex, and caudate/putamen. Although there were no regions with greater connectivity in females than males, the male versus female comparison produced connected activations in the medial posterior frontal cortex, anterior prefrontal cortex, precuneus, and cingulate sulcus. Females also had greater interhemispheric connectivity than males. The current findings suggest collapsing across sex in cognitive neuroscience studies may not be warranted.

High confidence spatial long-term memories produce greater cortical activity in males than females.

Many functional resonance imaging (fMRI) studies have reported sex differences during long-term memory. The present fMRI investigation aimed to identify whether sex differences exist during high- versus low-confidence accurate spatial memories. During the study phase, abstract shapes were presented to the left or right of fixation. During the test phase, each shape was presented at fixation and participants made an old-"left" or old-"right" judgment followed by an "unsure" or "sure" response. The conjunction of female high- versus low-confidence spatial memory and male high- versus low-confidence spatial memory identified common activity in visual processing regions and parietal cortex, which suggests amplification of activity in some of the regions commonly associated with long-term memory yields high confidence. The contrast of female high- versus low-confidence spatial memory and male high- versus low-confidence spatial memory did not produce any significant activity. However, the reverse contrast produced greater male than female activity in the lateral prefrontal cortex, parietal cortex, sensorimotor cortex, and visual processing regions. An independent region-of-interest (ROI) analysis (ROIs were identified by contrasting hits versus misses) produced complementary results in the lateral prefrontal cortex. Greater lateral prefrontal cortex activity suggests a higher degree of subjective confidence in males than females, greater parietal cortex and visual processing activity suggests more vivid visualization in males than females, and greater activity in sensorimotor cortex indicates that males have a more reactive processing style than females. More broadly, the present and previous functional sex differences argue against the practice of collapsing across sex in cognitive neuroscience studies.

Functional connectivity with the anterior and posterior hippocampus during spatial memory.

Evidence of differential connectivity and activity patterns across the long-axis of the hippocampus has led to many hypotheses about functional specialization of the anterior and posterior hippocampus, including a hypothesis linking the anterior hippocampus to memory encoding and the posterior hippocampus to memory retrieval. The hippocampal encoding/retrieval and network (HERNET) model of memory predicts that encoding should engage the anterior hippocampus and the attention network, whereas retrieval should engage the posterior hippocampus and the default network. In a previous fMRI study that employed multivoxel pattern analysis, we found that the patterns of activity in the anterior hippocampus predicted the quadrant of spatial memory encoding. In the current fMRI study, we investigated whether the spatial memory encoding activity in the anterior hippocampus and retrieval activity in the posterior hippocampus had a higher degree of connectivity to the attention network or the default network. During the study phase, abstract shapes were presented in each quadrant of the visual field and participants were instructed to remember each shape's location while maintaining central fixation. During the test phase, the same shapes were presented in the center of the screen and participants identified the previous location of each shape. Generalized psychophysiological interaction analyses were conducted between the anatomically defined anterior and posterior hippocampus and the rest of the brain. This revealed preferential connectivity between the anterior hippocampus and regions of the attention network during encoding and between the posterior hippocampus and regions of the default network during retrieval. In addition, there were location-specific patterns of connectivity with the anterior hippocampus and posterior hippocampus during encoding and retrieval of right visual field items. These results suggest that the anterior and posterior hippocampus interact with regions of the attention network and default network during spatial memory encoding and retrieval, respectively, and support the HERNET model of memory.

Are there sex differences in brain activity during long-term memory? A systematic review and fMRI activation likelihood estimation meta-analysis.

The degree to which sex differences exist in the brain is a current topic of debate. In the present discussion paper, we reviewed eight functional magnetic resonance imaging (fMRI) papers to determine whether there are sex differences in brain activity during long-term memory retrieval. The objectives were: 1) to compare the experimental parameters in studies reporting significant versus null long-term memory sex differences, and 2) to identify whether specific brain regions were associated with sex differences during long-term memory. The following experimental parameters were extracted from each paper: the number of participants, the average age of participants, stimulus type(s), whether or not performance was matched, whether or not sex differences were reported, the type of between-subject statistical test used, and the contrast(s) employed. The particular experimental parameters employed in each study did not appear to determine whether sex differences were observed, as there were sex differences in all eight studies. An activation likelihood estimation (ALE) meta-analysis was conducted to identify brain regions activated to a greater degree by females than males or males than females. This ALE meta-analysis revealed sex differences (male > female) in the lateral prefrontal cortex, visual processing regions, parahippocampal cortex, and the cerebellum. This constitutes compelling evidence that there are substantial sex differences in brain activity during long-term memory retrieval. More broadly, the present findings question the widespread practice of collapsing across sex in the field of cognitive neuroscience.