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.

Impact of sex and reproductive status on the default mode network in early midlife: implications for aging of memory circuitry and function.

Alterations to the resting-state default mode network (rsDMN) are early indicators of memory decline and Alzheimer's disease (AD). Brain regions shared by the rsDMN and memory circuitry are highly sexually dimorphic. However, data are limited regarding the impact of sex and reproductive status on rsDMN connectivity and memory circuitry and function. In the current investigation, rsDMN connectivity was assessed in 180 early midlife adults aged 45 to 55 by sex and reproductive status (87 women; 93 men). Associations between left and right hippocampal connectivity of rsDMN and verbal memory encoding circuitry were examined using linear mixed models, controlled for age and parental socioeconomic status, testing interactions by sex and reproductive status. Relative to men, women exhibited greater rsDMN connectivity between the left and right hippocampus. In relation to rsDMN-memory encoding connectivity, sex differences were revealed across the menopausal transition, such that only postmenopausal women exhibited loss of the ability to decrease rsDMN left-right hippocampal connectivity during memory encoding associated with poorer memory performance. Results demonstrate that sex and reproductive status play an important role in aging of the rsDMN and interactions with memory circuitry/function. This suggests the critical importance of sex and reproductive status when studying early midlife indicators of memory decline and AD risk.

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.

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.

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.

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.

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.

Thalamic Functional Connectivity during Spatial Long-Term Memory and the Role of Sex.

The thalamus has been implicated in many cognitive processes, including long-term memory. More specifically, the anterior (AT) and mediodorsal (MD) thalamic nuclei have been associated with long-term memory. Despite extensive mapping of the anatomical connections between these nuclei and other brain regions, little is known regarding their functional connectivity during long-term memory. The current study sought to determine which brain regions are functionally connected to AT and MD during spatial long-term memory and whether sex differences exist in the patterns of connectivity. During encoding, abstract shapes were presented to the left and right of fixation. During retrieval, shapes were presented at fixation, and participants made an "old-left" or "old-right" judgment. Activations functionally connected to AT and MD existed in regions with known anatomical connections to each nucleus as well as in a broader network of long-term memory regions. Sex differences were identified in a subset of these regions. A targeted region-of-interest analysis identified anti-correlated activity between MD and the hippocampus that was specific to females, which is consistent with findings in rodents. The current results suggest that AT and MD play key roles during spatial long-term memory and suggest that these functions may be sex specific.

Similar patterns of cortical activity in females and males during item memory.

Anatomic and molecular sex differences exist in the brain, which suggests there may be functional differences. The present functional magnetic resonance imaging (fMRI) investigation aimed to identify the similarities and differences in brain activity between females and males during item memory. During encoding, abstract shapes were presented to the left or right of fixation. During retrieval, old and new shapes were presented at fixation and participants made "old-left", "old-right", or "new" judgments. Item memory was isolated by contrasting correct "old" responses to old items (with incorrect spatial memory responses; item memory hits) and "new" responses to old items (item memory misses). For both sexes, item memory produced activity in regions associated with visual long-term memory including the prefrontal cortex, parietal cortex, and visual processing regions. A sex by accuracy interaction analysis within each sub-region of activity produced largely null results, supporting common patterns of brain activity. However, there was sex-specific (male > female) activity within default network regions, which suggests males may have been less engaged in the task, and there was evidence for greater activity for females than males in language processing cortex. The present findings indicate that females and males employ similar patterns of brain activity during item memory.

Different patterns of cortical activity in females and males during spatial long-term memory.

It is generally assumed that identical neural regions mediate the same cognitive functions in females and males. However, anatomic and molecular sex differences exist in the brain, including in regions associated with long-term memory, which suggests there may be functional differences. The present functional magnetic resonance imaging (fMRI) investigation aimed to identify the differences and similarities in brain activity between females and males during spatial long-term memory. During encoding, abstract shapes were presented to the left or right of fixation. During retrieval, shapes were presented at fixation and participants made "old-left" or "old-right" judgments. For both females and males, spatial memory hits versus misses produced activity in regions commonly associated with visual long-term memory; however, the activations were almost completely distinct between the sexes. An interaction analysis revealed sex-specific activity for males in visual processing regions, the left putamen, the right caudate nucleus, and bilateral cerebellum, and sex-specific activity for females in the parietal cortex. A targeted anatomic region-of-interest (ROI) analysis identified sex-specific activity for males and females in the left hippocampus and language processing cortex, respectively. A multi-voxel pattern correlation analysis within functional ROIs between all pairs of participants showed greater within-sex than between-sex correlations, indicating the differential activations were due to sex differences rather than other individual differences between groups. These results indicate that spatial long-term memory is mediated by largely different brain regions in females and males. These findings have major implications for the field of cognitive neuroscience, where it is common practice to collapse across sex.