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A cornerstone of memory science is the finding that the medial temporal lobe plays a critical role in supporting episodic long-term memory. However, the role that this brain region plays in supporting other forms of memory such as working memory is controversial. In this selective review, we describe some of the key studies that have informed our current understanding of the role that the medial temporal lobe plays in working memory. We first describe the early studies that supported the idea that the medial temporal lobe is selectively important for long-term episodic memory function, then discuss the subsequent research that indicated that the hippocampus also plays a critical role in visual perception and visual working memory. We then review more recent work suggesting that the medial temporal lobe, and particularly the hippocampus, is critical in supporting a familiarity-based memory signal in working memory, and we propose that this function may not be limited to the visual domain, but rather may support familiarity for auditory working memory as well. [ABSTRACT FROM AUTHOR]

The wide array of cognitive functions associated with the hippocampus is supported through interactions with the cerebral cortex. However, most of the direct cortical input to the hippocampus originates in the entorhinal cortex, forming the hippocampal-entorhinal system. In humans, the role of the entorhinal cortex in mediating hippocampal-cortical interactions remains unknown. In this study, we used precision neuroimaging to examine the distributed cortical anatomy associated with the human hippocampal-entorhinal system. Consistent with animal anatomy, our results associate different subregions of the entorhinal cortex with different parts of the hippocampus long axis. Furthermore, we find that the entorhinal cortex comprises three band-like zones that are associated with functionally distinct cortical networks. Importantly, the entorhinal cortex bands traverse the proposed human homologs of rodent lateral and medial entorhinal cortices. Finally, we show that the entorhinal cortex is a major convergence area of distributed cortical processing and that the topography of cortical networks associated with the anterior medial temporal lobe mirrors the macroscale structure of high-order cortical processing. • Human entorhinal cortex (ERC) is organized into three parallel band-like zones • Functionally distinct cortical networks associate with distinct ERC bands • Different longitudinal parts of the hippocampus associate with distinct ERC bands • Human ERC is a major convergence hub of distributed cortical processing Using precision neuroimaging, Reznik et al. discover that the human entorhinal cortex is organized into three band-like zones running in parallel to the collateral sulcus. Consistent with animal anatomy, these entorhinal cortex bands associate with functionally distinct cortical networks and different parts of the hippocampus long axis. [ABSTRACT FROM AUTHOR]

Background: Phosphorylated tau (p-tau) and amyloid beta (Aβ) in human plasma may provide an affordable and minimally invasive method to evaluate Alzheimer's disease (AD) pathophysiology. The medial temporal lobe (MTL) is susceptible to changes in structural integrity that are indicative of the disease progression. Among healthy adults, higher dynamic network flexibility within the MTL was shown to mediate better generalization of prior learning, a measure which has been demonstrated to predict cognitive decline and neural changes in preclinical AD longitudinally. Recent developments in cognitive, neural, and blood-based biomarkers of AD risk that may correspond with MTL changes. However, there is no comprehensive study on how these generalization biomarkers, long-term memory, MTL dynamic network flexibility, and plasma biomarkers are interrelated. This study investigated (1) the relationship between long-term memory, generalization performance, and MTL dynamic network flexibility and (2) how plasma p-tau231, p-tau181, and Aβ42/Aβ40 influence generalization, long-term memory, and MTL dynamics in cognitively unimpaired older African Americans. Methods: 148 participants (Meanage: 70.88,SDage: 6.05) were drawn from the ongoing longitudinal study, Pathways to Healthy Aging in African Americans conducted at Rutgers University–Newark. Cognition was evaluated with the Rutgers Acquired Equivalence Task (generalization task) and Rey Auditory Learning Test (RAVLT) delayed recall. MTL dynamic network connectivity was measured from functional Magnetic Resonance Imaging data. Plasma p-tau231, p-tau181, and Aβ42/Aβ40 were measured from blood samples. Results: There was a significant positive correlation between generalization performance and MTL Dynamic Network Flexibility (t = 3.372, β = 0.280, p < 0.001). There were significant negative correlations between generalization performance and plasma p-tau231 (t = -3.324, β = -0.265, p = 0.001) and p-tau181 (t = -2.408, β = -0.192, p = 0.017). A significant negative correlation was found between plasma p-tau231 and MTL Dynamic Network Flexibility (t = -2.825, β = -0.232, p = 0.005). Conclusions: Increased levels of p-tau231 are associated with impaired generalization abilities and reduced dynamic network flexibility within the MTL. Plasma p-tau231 may serve as a potential biomarker for assessing cognitive decline and neural changes in cognitively unimpaired older African Americans. [ABSTRACT FROM AUTHOR]

ABSTRACT This article focuses on familiarity, the form of memory allowing humans to recognize stimuli that have been encountered before. We aim to emphasize its complex nature which includes representational and phenomenological dimensions. The former implies that its neural correlates depend on the type and complexity of the cue stimulus, as different classes of stimuli are represented in distributed ventral visual and medial temporal regions. The second dimension relates to the subjective feeling of familiarity, which results from a fluency signal that is attributed to past encounters with the stimulus. We review mnemonic and non‐mnemonic sources of fluency that can induce a sense of familiarity, as well as cases where fluency is not attributed to memory, among which the phenomenological experience of déjà‐vu. Across these two dimensions, we highlight key questions to be answered by future studies to improve our understanding of the underpinnings of this form of memory and contribute to building an integrative neurocognitive model of familiarity. Essential to this aim is the clarification of the computational, cognitive, and neural mechanisms involved, namely global matching, fluency attribution, and sharpening. Furthermore, future research is needed to unravel the relationships between these mechanisms. We argue that to achieve these goals, researchers must use appropriate behavioral paradigms and clearly define which dimension of familiarity they investigate. [ABSTRACT FROM AUTHOR]

The perirhinal and parahippocampal cortices are key components of the medial temporal lobe memory system. Despite their essential roles in mnemonic and perceptual functions, there is limited quantitative information regarding their structural characteristics. Here, we implemented design‐based stereological techniques to provide estimates of neuron number, neuronal soma size, and volume of the different layers and subdivisions of the perirhinal and parahippocampal cortices in adult macaque monkeys (Macaca mulatta, 5–9 years of age). We found that areas 36r and 36c of the perirhinal cortex and areas TF and TH of the parahippocampal cortex exhibit relatively large superficial layers, which are characteristic of the laminar organization of higher order associational cortices. In contrast, area 35 of the perirhinal cortex exhibits relatively large deep layers. Although neuronal soma size varies between subdivisions and layers, neurons are generally larger in the perirhinal cortex than in the parahippocampal cortex and even larger in the entorhinal cortex. These morphological characteristics are consistent with the hierarchical organization of these cortices within the medial temporal lobe. Comparing data in rats, monkeys, and humans, we found species differences in the relative size of these structures, showing that the perirhinal and parahippocampal cortices have expanded in parallel to the cerebral cortex and may play a greater role in the integration of information in the neocortical–hippocampal loop in primates. Altogether, these normative data provide an essential reference to extrapolate findings from experimental studies in animals and create realistic models of the medial temporal lobe memory system. [ABSTRACT FROM AUTHOR]

It has been hypothesized that differential processing occurs along the longitudinal (anterior–posterior) axis of the hippocampus. One hypothesis is that spatial memory (during both encoding and retrieval) is associated with the posterior hippocampus. An alternative hypothesis is that memory encoding (either spatial or nonspatial) is associated with the anterior hippocampus and memory retrieval is associated with the posterior hippocampus. Of importance, during spatial memory encoding, the spatial–posterior hypothesis predicts posterior hippocampal involvement, whereas the encoding–retrieval hypothesis predicts anterior hippocampal involvement. To distinguish between these hypotheses, we conducted a coordinate‐based fMRI activation likelihood estimation (ALE) meta‐analysis of 26 studies (with a total of 435 participants) that reported hippocampal activity during spatial memory encoding and/or spatial memory retrieval. Both spatial memory encoding and spatial memory retrieval produced extensive activity along the longitudinal axis of the hippocampus as well as the entorhinal cortex, the perirhinal cortex, and the parahippocampal cortex. Critically, the contrast of spatial memory encoding and spatial memory retrieval produced activations in both the anterior hippocampus and the posterior hippocampus. That spatial memory encoding produced activity in both the anterior and posterior hippocampus can be taken to reject strict forms of the spatial–posterior hypothesis, which stipulates that all forms of spatial memory produce activity in the posterior hippocampus, and the encoding–retrieval hypothesis, which stipulates that all forms of encoding versus retrieval produce activity in only the anterior hippocampus. Our results indicate that spatial memory encoding can involve the anterior hippocampus and the posterior hippocampus. [ABSTRACT FROM AUTHOR]

The number zero holds a special status among numbers, indispensable for developing a comprehensive number theory. 1,2,3,4 Despite its importance in mathematics, the neuronal foundation of zero in the human brain is unknown. We conducted single-neuron recordings in neurosurgical patients 5,6,7 while they made judgments involving nonsymbolic number representations (dot numerosity), including the empty set, and symbolic numbers (Arabic numerals), including numeral zero. Neurons showed responsiveness to either the empty set or numeral zero, but not both. Neuronal activity to zero in both nonsymbolic and symbolic formats exhibited a numerical distance effect, indicating that zero representations are integrated together with countable numerosities and positive integers at the low end of the number line. 8,9 A boundary in neuronal coding existed between the nonsymbolic empty set and small numerosities, correlating with the relative difficulty in discriminating numerosity zero behaviorally. Conversely, no such boundary was found for symbolic zero activity, suggesting that symbolic representations integrate zero with other numerals along the number line, reconciling its outlier role. The status of zero as a special nonsymbolic numerical quantity is reflected in the activity of neurons in the human brain, which seems to serve as a scaffold for more advanced representations of zero as a symbolic number. • Single-neuron recordings in the medial temporal lobe of patients • Neurons signal both nonsymbolic and symbolic zero • Neuronal representations of zero integrated along the number line • Nonsymbolic empty sets distinctly encoded from other small numbers Kutter et al. identify and characterize single-neuron activity in the human brain correlated with the representation of both nonsymbolic (dot numerosities) and symbolic (Arabic numerals) number zero. [ABSTRACT FROM AUTHOR]

Early stages of Alzheimer's disease (AD) are associated with volume reductions in specific subregions of the medial temporal lobe (MTL). Using a manual segmentation method—the Olsen–Amaral–Palombo (OAP) protocol—previous work in healthy older adults showed that reductions in grey matter volumes in MTL subregions were associated with lower scores on the Montreal Cognitive Assessment (MoCA), suggesting atrophy may occur prior to diagnosis of mild cognitive impairment, a condition that often progresses to AD. However, current "gold standard" manual segmentation methods are labour intensive and time consuming. Here, we examined the utility of Automatic Segmentation of Hippocampal Subfields (ASHS) to detect volumetric differences in MTL subregions of healthy older adults who varied in cognitive status as determined by the MoCA. We trained ASHS on the OAP protocol to create the ASHS‐OAP atlas and then examined how well automated segmentation replicated manual segmentation. Volumetric measures obtained from the ASHS‐OAP atlas were also contrasted against those from the ASHS‐PMC atlas, a widely used atlas provided by the ASHS team. The pattern of volumetric results was similar between the ASHS‐OAP atlas and manual segmentation for anterolateral entorhinal cortex and perirhinal cortex, suggesting that ASHS‐OAP is a viable alternative to current manual segmentation methods for detecting group differences based on cognitive status. Although ASHS‐OAP and ASHS‐PMC produced varying volumes for most regions of interest, they both identified early signs of neurodegeneration in CA2/CA3/DG and identified marginal differences in entorhinal cortex. Our findings highlight the utility of automated segmentation methods but still underscore the need for a unified and harmonized MTL segmentation atlas. [ABSTRACT FROM AUTHOR]

Introduction/Purpose: As individuals age, the entorhinal cortex (ERC) and hippocampus--crucial structures for memory--tend to atrophy, with related cognitive decline. Simultaneously, lifestyle factors that can be modified, such as exercise and sleep, have been separately linked to slowing of brain atrophy and functional decline. However, the synergistic impact of fitness and sleep on susceptible brain structures in aging adults remains uncertain. Methods: We examined both independent and interactive associations of fitness and subjective sleep quality with regard to ERC thickness and hippocampal volume in 598middle-aged and older adults from the Human Connectome Lifespan Aging Project. Cardiorespiratory fitness was assessed using the 2-min walk test, whereas subjective sleep quality was measured with the continuous Pittsburgh Sleep Quality Index global score. High-resolution structural magnetic resonance imaging was used to examine mean ERC thickness and bilateral hippocampal volume. Through multiple linear regression analyses, we investigated the moderating effects of subjective sleep quality on the association between fitness and brain structure, accounting for age, sex, education, body mass index, gait speed, and subjective physical activity. Results: We found that greater cardiorespiratory fitness, but not subjective sleep quality, was positively associated with bilateral hippocampal volume and ERC thickness. Notably, significant interaction effects suggest that poor subjective sleep quality was associated with a weaker association between fitness and both hippocampal volume and ERC thickness. Conclusions: Findings suggest the potential importance of both cardiorespiratory fitness and subjective sleep quality in preserving critical, age-vulnerable brain structures. Interventions targeting brain health should consider potential combined effects of sleep and fitness on brain health. [ABSTRACT FROM AUTHOR]

Abacus‐based mental calculation (AMC) is a widely used educational tool for enhancing math learning, offering an accessible and cost‐effective method for classroom implementation. Despite its universal appeal, the neurocognitive mechanisms that drive the efficacy of AMC training remain poorly understood. Notably, although abacus training relies heavily on the rapid recall of number positions and sequences, the role of memory systems in driving long‐term AMC learning remains unknown. Here, we sought to address this gap by investigating the role of the medial temporal lobe (MTL) memory system in predicting long‐term AMC training gains in second‐grade children, who were longitudinally assessed up to fifth grade. Leveraging multimodal neuroimaging data, we tested the hypothesis that MTL systems, known for their involvement in associative memory, are instrumental in facilitating AMC‐induced improvements in math skills. We found that gray matter volume in bilateral MTL, along with functional connectivity between the MTL and frontal and ventral temporal‐occipital cortices, significantly predicted learning gains. Intriguingly, greater gray matter volume but weaker connectivity of the posterior parietal cortex predicted better learning outcomes, offering a more nuanced view of brain systems at play in AMC training. Our findings not only underscore the critical role of the MTL memory system in AMC training but also illuminate the neurobiological factors contributing to individual differences in cognitive skill acquisition. A video abstract of this article can be viewed at https://youtu.be/StVooNRc7T8. Research Highlights: We investigated the role of medial temporal lobe (MTL) memory system in driving children's math learning following abacus‐based mental calculation (AMC) training.AMC training improved math skills in elementary school children across their second and fifth grade.MTL structural integrity and functional connectivity with prefrontal and ventral temporal‐occipital cortices predicted long‐term AMC training‐related gains. [ABSTRACT FROM AUTHOR]

The human medial temporal lobe (MTL) plays a crucial role in recognizing visual objects, a key cognitive function that relies on the formation of semantic representations. Nonetheless, it remains unknown how visual information of general objects is translated into semantic representations in the MTL. Furthermore, the debate about whether the human MTL is involved in perception has endured for a long time. To address these questions, we investigated three distinct models of neural object coding--semantic coding, axisbased feature coding, and region-based feature coding--in each subregion of the human MTL, using high-resolution fMRI in two male and six female participants. Our findings revealed the presence of semantic coding throughout the MTL, with a higher prevalence observed in the parahippocampal cortex (PHC) and perirhinal cortex (PRC), while axis coding and region coding were primarily observed in the earlier regions of the MTL. Moreover, we demonstrated that voxels exhibiting axis coding supported the transition to region coding and contained information relevant to semantic coding. Together, by providing a detailed characterization of neural object coding schemes and offering a comprehensive summary of visual coding information for each MTL subregion, our results not only emphasize a clear role of the MTL in perceptual processing but also shed light on the translation of perceptiondriven representations of visual features into memory-driven representations of semantics along the MTL processing pathway. [ABSTRACT FROM AUTHOR]

Tau pathology accumulates in the perirhinal cortex (PRC) of the medial temporal lobe (MTL) during the earliest stages of the Alzheimer's disease (AD), appearing decades before clinical diagnosis. Here, we leveraged perceptual discrimination tasks that target PRC function to detect subtle cognitive impairment even in nominally healthy older adults. Older adults who did not have a clinical diagnosis or subjective memory complaints were categorized into "at‐risk" (score <26; n = 15) and "healthy" (score ≥26; n = 23) groups based on their performance on the Montreal Cognitive Assessment. The task included two conditions known to recruit the PRC: faces and complex objects (greebles). A scene condition, known to recruit the hippocampus, and a size control condition that does not rely on the MTL were also included. Individuals in the at‐risk group were less accurate than those in the healthy group for discriminating greebles. Performance on either the face or size control condition did not predict group status above and beyond that of the greeble condition. Visual discrimination tasks that are sensitive to PRC function may detect early cognitive decline associated with AD. [ABSTRACT FROM AUTHOR]

Objective: Statistical learning, the fundamental cognitive ability of humans to extract regularities across experiences over time, engages the medial temporal lobe (MTL) in the healthy brain. This leads to the hypothesis that statistical learning (SL) may be impaired in patients with epilepsy (PWE) involving the temporal lobe, and that this impairment could contribute to their varied memory deficits. In turn, studies done in collaboration with PWE, that evaluate the necessity of MTL circuitry through disease and causal perturbations, provide an opportunity to advance basic understanding of SL. Methods: We implemented behavioral testing, volumetric analysis of the MTL substructures, and direct electrical brain stimulation to examine SL across a cohort of 61 PWE and 28 healthy controls. Results: We found that behavioral performance in an SL task was negatively associated with seizure frequency irrespective of seizure origin. The volume of hippocampal subfields CA1 and CA2/3 correlated with SL performance, suggesting a more specific role of the hippocampus. Transient direct electrical stimulation of the hippocampus disrupted SL. Furthermore, the relationship between SL and seizure frequency was selective, as behavioral performance in an episodic memory task was not impacted by seizure frequency. Significance: Overall, these results suggest that SL may be hippocampally dependent and that the SL task could serve as a clinically useful behavioral assay of seizure frequency that may complement existing approaches such as seizure diaries. Simple and short SL tasks may thus provide patient‐centered endpoints for evaluating the efficacy of novel treatments in epilepsy. [ABSTRACT FROM AUTHOR]

Mounting evidence indicates marked hippocampal degeneration in semantic dementia (SD) however, the spatial distribution of hippocampal atrophy profiles in this syndrome remains unclear. Using a recently developed parcellation approach, we extracted hippocampal volumes from four distinct subregions running from anterior to posterior along the longitudinal axis (anterior, intermediate rostral, intermediate caudal, and posterior). Volumetric differences in hippocampal subregions were compared between 21 SD, 24 matched Alzheimer's disease (AD), and 27 healthy older Control participants. Despite comparable overall hippocampal volume loss, SD and AD groups diverged in terms of the magnitude of atrophy along the anterior-posterior axis of the hippocampus. Global hippocampal atrophy was observed in AD, with no discernible gradation or lateralisation. In contrast, SD patients displayed graded bilateral hippocampal atrophy, most pronounced on the left-hand side, and concentrated in anterior relative to posterior subregions. Finally, we found preliminary evidence that disease-specific vulnerability along the anterior-posterior axis of the hippocampus was associated with canonical clinical features of these syndromes. • The spatial profile of hippocampal atrophy in semantic dementia (SD) is unclear. • We explored structural vulnerability along the hippocampal long axis in SD. • SD patients showed an anterior-posterior graded profile of hippocampal atrophy. • While anterior subregions were atrophied, right posterior hippocampus was intact. • Graded hippocampal atrophy likely contributes to distinct cognitive outcomes in SD. [ABSTRACT FROM AUTHOR]

Background: The endoscopic transorbital approach provides a direct access to the medial temporal lobe (MTL). However, when excising a highly vascular tumour, a wider access route that enables the concurrent use of standard neurosurgical instruments with both hands is preferable. Method: We described the concept and technique of the lateral orbital wall approach (LOWA), which comprises orbitotomy and mini-craniotomy to treat MTL lesions using an exoscope and endoscope. Conclusion: The LOWA provides a safe and natural surgical corridor to the MTL and enables 2- or 3-hand surgery. Hence, LOWA can potentially improve safety and efficiency to treat MTL lesions. [ABSTRACT FROM AUTHOR]

Direct human brain recordings have confirmed the presence of high-frequency oscillatory events, termed ripples, during awake behavior. While many prior studies have focused on medial temporal lobe (MTL) ripples during memory retrieval, here we investigate ripples during memory encoding. Specifically, we ask whether ripples during encoding predict whether and how memories are subsequently recalled. Detecting ripples from MTL electrodes implanted in 116 neurosurgical participants (n = 61 male) performing a verbal episodic memory task, we find that encoding ripples do not distinguish recalled from not recalled items in any MTL region, even as high-frequency activity during encoding predicts recall in these same regions. Instead, hippocampal ripples increase during encoding of items that subsequently lead to recall of temporally and semantically associated items during retrieval, a phenomenon known as clustering. This subsequent clustering effect arises specifically when hippocampal ripples co-occur during encoding and retrieval, suggesting that ripples mediate both encoding and reinstatement of episodic memories. [ABSTRACT FROM AUTHOR]

Cardiorespiratory fitness has a potent effect on neurocognitive health, especially regarding the hippocampal memory system. However, less is known about the impact of cardiorespiratory fitness on medial temporal lobe extrahippocampal neocortical regions. Specifically, it is unclear how cardiorespiratory fitness modulates these brain regions in young adulthood and if these regions are differentially related to cardiorespiratory fitness in young versus older adults. The primary goal of this study was to investigate if cardiorespiratory fitness predicted medial temporal lobe cortical thickness which, with the hippocampus, are critical for spatial learning and memory. Additionally, given the established role of these cortices in spatial navigation, we sought to determine if cardiorespiratory fitness and medial temporal lobe cortical thickness would predict greater subjective sense of direction in both young and older adults. Cross‐sectional data from 56 young adults (20–35 years) and 44 older adults (55–85 years) were included. FreeSurfer 6.0 was used to automatically segment participants' 3T T1‐weighted images. Using hierarchical multiple regression analyses, we confirmed significant associations between greater cardiorespiratory fitness and greater left entorhinal, left parahippocampal, and left perirhinal cortical thickness in young, but not older, adults. Left parahippocampal cortical thickness interacted with age group to differentially predict subjective sense of direction in young and older adults. Young adults displayed a positive, and older adults a negative, correlation between left parahippocampal cortical thickness and sense of direction. Our findings extend previous work on the association between cardiorespiratory fitness and hippocampal subfield structure in young adults to left medial temporal lobe neocortical regions. [ABSTRACT FROM AUTHOR]

Background: The endoscopic transorbital approach provides a direct access to the medial temporal lobe (MTL). However, when excising a highly vascular tumour, a wider access route that enables the concurrent use of standard neurosurgical instruments with both hands is preferable. Method: We described the concept and technique of the lateral orbital wall approach (LOWA), which comprises orbitotomy and mini-craniotomy to treat MTL lesions using an exoscope and endoscope. Conclusion: The LOWA provides a safe and natural surgical corridor to the MTL and enables 2- or 3-hand surgery. Hence, LOWA can potentially improve safety and efficiency to treat MTL lesions. [ABSTRACT FROM AUTHOR]

Neurofibrillary tangles (NFTs) contain abnormally phosphorylated tau proteins, which spread within components of the medial temporal lobe (MTL) memory circuit in Alzheimer's disease (AD). Here, we used quantitative immunohistochemistry to determine the density of posttranslational oligomeric (TOC1 and TNT1), phosphorylated (AT8), and late truncated (TauC3) tau epitopes within the MTL subfields including entorhinal cortex (EC) layer II, subiculum, Cornu Ammonis (CA) subfields, and dentate gyrus (DG) in subjects who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD. We also examined whether alterations of the nuclear alternative splicing protein, SRSF2, are associated with tau pathology. Although a significant increase in TOC1, TNT1, and AT8 neuron density occurred in the EC in MCI and AD, subicular, DG granule cell, and CA1 and CA3 densities were only significantly higher in AD. TauC3 counts were not different between connectome regions and clinical groups. SRSF2 intensity in AT8‐positive cells decreased significantly in all regions independent of the clinical groups examined. CA1 and subicular AT8, TauC3, and oligomeric densities correlated across clinical groups. EC AT8 counts correlated with CA subfields and subicular and DG values across clinical groups. Oligomeric and AT8 CA1, EC, and subicular density correlated with Braak stage. Decreased nuclear SRSF2 in the presence of cytoplasmic phosphorylated tau suggests a dual‐hit process in NFT formation within the entorhinal hippocampal connectome during the onset of AD. Although oligomeric and phosphorylated tau follow a stereotypical pattern, clinical disease stage determined density of tau deposition and not anatomic location within the entorhinal–hippocampal connectome. [ABSTRACT FROM AUTHOR]

Immature neurons expressing the Bcl2 protein are present in various regions of the mammalian brain, including the amygdala and the entorhinal and perirhinal cortices. Their functional role is unknown but we have previously shown that neonatal and adult hippocampal lesions increase their differentiation in the monkey amygdala. Here, we assessed whether hippocampal lesions similarly affect immature neurons in the entorhinal and perirhinal cortices. Since Bcl2‐positive cells were found mainly in areas Eo, Er, and Elr of the entorhinal cortex and in layer II of the perirhinal cortex, we also used Nissl‐stained sections to determine the number and soma size of immature and mature neurons in layer III of area Er and layer II of area 36 of the perirhinal cortex. We found different structural changes in these regions following hippocampal lesions, which were influenced by the time of the lesion. In neonate‐lesioned monkeys, the number of immature neurons in the entorhinal and perirhinal cortices was generally higher than in controls. The number of mature neurons was also higher in layer III of area Er of neonate‐lesioned monkeys but no differences were found in layer II of area 36. In adult‐lesioned monkeys, the number of immature neurons in the entorhinal cortex was lower than in controls but did not differ from controls in the perirhinal cortex. The number of mature neurons in layer III of area Er did not differ from controls, but the number of small, mature neurons in layer II of area 36 was lower than in controls. In sum, hippocampal lesions impacted populations of mature and immature neurons in discrete regions and layers of the entorhinal and perirhinal cortices, which are interconnected with the amygdala and provide major cortical inputs to the hippocampus. These structural changes may contribute to some functional recovery following hippocampal injury in an age‐dependent manner. [ABSTRACT FROM AUTHOR]

Neurosurgeons are in a unique position to shed light on the neural basis for consciousness, not only by their clinical care of patients with compromised states of consciousness, but also by employing neurostimulation and neuronal recordings through intracranial electrodes in awake surgical patients, as well as during stages of sleep and anethesia. In this review, we discuss several aspects of consciousness, i.e., perception, memory, and willed actions, studied by electrical stimulation and single neuron recordings in the human brain. We demonstrate how specific neuronal activity underlie the emergence of concepts, memories, and intentions in human consciousness. We discuss the representation of specific conscious content by temporal lobe neurons and present the discovery of "concept cells" and the encoding and retrieval of memories by neurons in the medial temporal lobe. We review prefrontal and parietal neuronal activation that precedes conscious intentions to act. Taken together with other studies in the field, these findings suggest that specific conscious experience may arise from stochastic fluctuations of neuronal activity, reaching a dynamic threshold. Advances in brain recording and stimulation technology coupled with the rapid rise in artificial intelligence are likely to increase the amount and analysis capabilities of data obtained from the human brain, thereby improving the decoding of conscious and preconscious states and open new horizons for modulation of human cognitive functions such as memory and volition. [ABSTRACT FROM AUTHOR]

The term "memory" typically refers to conscious retrieval of events and experiences from our past, but experience can also change our behaviour without corresponding awareness of the learning process or the associated outcome. Based primarily on early neuropsychological work, theoretical perspectives have distinguished between conscious memory, said to depend critically on structures in the medial temporal lobe (MTL), and a collection of performance‐based memories that do not. The most influential of these memory systems perspectives, the declarative memory theory, continues to be a mainstay of scientific work today despite mounting evidence suggesting that contributions of MTL structures go beyond the kinds or types of memory that can be explicitly reported. Consistent with these reports, more recent perspectives have focused increasingly on the processing operations supported by particular brain regions and the qualities or characteristics of resulting representations whether memory is expressed with or without awareness. These alternatives to the standard model generally converge on two key points. First, the hippocampus is critical for relational memory binding and representation even without awareness and, second, there may be little difference between some types of priming and explicit, familiarity‐based recognition. Here, we examine the evolution of memory systems perspectives and critically evaluate scientific evidence that has challenged the status quo. Along the way, we highlight some of the challenges that researchers encounter in the context of this work, which can be contentious, and describe innovative methods that have been used to examine unconscious memory in the lab. This article is categorized under: Psychology > MemoryPsychology > Theory and MethodsPhilosophy > Consciousness [ABSTRACT FROM AUTHOR]

A.V. is a young herpes simplex encephalitis (HSE) survivor who suffered extensive bilateral damage to the medial temporal lobe (MTL) leading to a severe and pervasive form of anterograde amnesia. Structural Magnetic Resonance Imaging (MRI) revealed lesions that encompass the hippocampus and amygdala in both hemispheres and that extend more laterally in the right temporal lobe. At the same time, detailed neuropsychological testing showed that the disparity between A.V.'s preserved intellectual functioning (Full Scale IQ: 115) and severe memory deficit (Delayed Memory Index: 42) is one of the largest on record. Despite this deficit, A.V. has regained a higher level of functioning and autonomy compared to previously documented amnesic cases with major bilateral MTL lesions. As a millennial, one advantage which A.V. has over prior amnesic cases is fluency with digital technology - particularly the smartphone. The analysis of his phone and specific app usage showed a pattern that is consistent with the strategy to offload cognitive tasks that would normally be supported by the MTL. A.V.'s behavior is significant in terms of rehabilitation and may have broader implications at the societal level and for public health given the ubiquity of smartphone technology and its potential to become integrated with neural mnemonic functions. [ABSTRACT FROM AUTHOR]

Investigations into how individual neurons encode behavioral variables of interest have revealed specific representations in single neurons, such as place and object cells, as well as a wide range of cells with conjunctive encodings or mixed selectivity. However, as most experiments examine neural activity within individual tasks, it is currently unclear if and how neural representations change across different task contexts. Within this discussion, the medial temporal lobe is particularly salient, as it is known to be important for multiple behaviors including spatial navigation and memory, however the relationship between these functions is currently unclear. Here, to investigate how representations in single neurons vary across different task contexts in the medial temporal lobe, we collected and analyzed single‐neuron activity from human participants as they completed a paired‐task session consisting of a passive‐viewing visual working memory and a spatial navigation and memory task. Five patients contributed 22 paired‐task sessions, which were spike sorted together to allow for the same putative single neurons to be compared between the different tasks. Within each task, we replicated concept‐related activations in the working memory task, as well as target‐location and serial‐position responsive cells in the navigation task. When comparing neuronal activity between tasks, we first established that a significant number of neurons maintained the same kind of representation, responding to stimuli presentations across tasks. Further, we found cells that changed the nature of their representation across tasks, including a significant number of cells that were stimulus responsive in the working memory task that responded to serial position in the spatial task. Overall, our results support a flexible encoding of multiple, distinct aspects of different tasks by single neurons in the human medial temporal lobe, whereby some individual neurons change the nature of their feature coding between task contexts. [ABSTRACT FROM AUTHOR]

Entorhinal cortex is the major gateway between the neocortex and the hippocampus and thus plays an essential role in subserving episodic memory and spatial navigation. It can be divided into the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC), which are commonly theorized to be critical for spatial (context) and non‐spatial (content) inputs, respectively. Consistent with this theory, LEC neurons are found to carry little information about allocentric self‐location, even in cue‐rich environments, but they exhibit egocentric spatial information about external items in the environment. The superficial and deep layers of LEC are believed to mediate the input to and output from the hippocampus, respectively. As earlier studies mainly examined the spatial firing properties of superficial‐layer LEC neurons, here we characterized the deep‐layer LEC neurons and made direct comparisons with their superficial counterparts in single unit recordings from behaving rats. Because deep‐layer LEC cells received inputs from hippocampal regions, which have strong selectivity for self‐location, we hypothesized that deep‐layer LEC neurons would be more informative about allocentric position than superficial‐layer LEC neurons. We found that deep‐layer LEC cells showed only slightly more allocentric spatial information and higher spatial consistency than superficial‐layer LEC cells. Egocentric coding properties were comparable between these two subregions. In addition, LEC neurons demonstrated preferential firing at lower speeds, as well as at the boundary or corners of the environment. These results suggest that allocentric spatial outputs from the hippocampus are transformed in deep‐layer LEC into the egocentric coding dimensions of LEC, rather than maintaining the allocentric spatial tuning of the CA1 place fields. [ABSTRACT FROM AUTHOR]

Electrical stimulation of the medial temporal lobe (MTL) has the potential to uncover causal circuit mechanisms underlying memory function. However, little is known about how MTL stimulation alters information flow with frontoparietal cortical regions implicated in episodic memory. We used intracranial EEG recordings from humans (14 participants, 10 females) to investigate how MTL stimulation alters directed information flow between MTL and PFC and between MTL and posterior parietal cortex (PPC). Participants performed a verbal episodic memory task during which they were presented with words and asked to recall them after a delay of;20 s; 50 Hz stimulation was applied to MTL electrodes on selected trials during memory encoding. Directed information flow was examined using phase transfer entropy. Behaviorally, we observed that MTL stimulation reduced memory recall. MTL stimulation decreased top-down PFC→MTL directed information flow during both memory encoding and subsequent memory recall, revealing aftereffects more than 20 s after end of stimulation. Stimulation suppressed top-down PFC→MTL influences to a greater extent than PPC→MTL. Finally, MTL→PFC information flow on stimulation trials was significantly lower for successful, compared with unsuccessful, memory recall; in contrast, MTL→ventral PPC information flow was higher for successful, compared with unsuccessful, memory recall. Together, these results demonstrate that the effects of MTL stimulation are behaviorally, regionally, and directionally specific, that MTL stimulation selectively impairs directional signaling with PFC, and that causal MTL-ventral PPC circuits support successful memory recall. Findings provide new insights into dynamic casual circuits underling episodic memory and their modulation by MTL stimulation. [ABSTRACT FROM AUTHOR]

The hierarchically organized structures of the medial temporal lobe are critically important for episodic memory function. Accumulating evidence suggests dissociable information processing pathways are maintained throughout these structures including in the medial and lateral entorhinal cortex. Cortical layers provide an additional dimension of dissociation as the primary input to the hippocampus derives from layer 2 neurons in the entorhinal cortex, whereas the deeper layers primarily receive output from the hippocampus. Here, novel high-resolution T2-prepared functional MRI methods were successfully used to mitigate susceptibility artifacts typically affecting MRI signals in this region providing uniform sensitivity across the medial and lateral entorhinal cortex. During the performance of a memory task, healthy human subjects (age 25-33 years, mean age 28.2 ± 3.3 years, 4 female) showed differential functional activation in the superficial and deep layers of the entorhinal cortex associated with task-related encoding and retrieval conditions, respectively. The methods provided here offer an approach to probe layer-specific activation in normal cognition and conditions contributing to memory impairment. [ABSTRACT FROM AUTHOR]

Hearing impairment is considered a leading modifiable risk factor of cognitive decline and dementia. While most evidence has been established on clinical assessment of peripheral hearing loss, understanding of how central hearing in real‐world conditions is associated with cognitive aging is limited. This study analyzed the data of 473 unrelated healthy adults aged 36–100 years old from the Lifespan Human Connectome Project in Aging. Central hearing was evaluated using the Words‐in‐Noise decibel threshold. Cognitive functions were evaluated by the performance on cognitive tests, and cortical thickness was estimated from magnetic resonance imaging (MRI) data. Here, we show that a higher hearing threshold was associated with a lower performance on immediate and delayed episodic memory retrieval, switching aspect of executive function, working memory, reading decoding, and vocabulary comprehension. Cortical thickness in the left parahippocampal cortex (lPHC) was negatively associated with the hearing threshold and acted as a significant partial mediator in the association of central hearing with immediate recall, switching, reading decoding, and vocabulary comprehension. These findings suggest that cortical thickness in the lPHC, an early target of dementia, partially links central hearing and performance in multiple cognitive domains in aging. [ABSTRACT FROM AUTHOR]

The estimation of incidentally encoded durations of time intervals (retrospective duration processing) is thought to rely on the retrieval of contextual information associated with a sequence of events, automatically encoded in medial temporal lobe regions. "Time cells" have been described in the hippocampus (HC), encoding the temporal progression of events and their duration. However, whether the HC supports explicit retrospective duration judgments in humans, and which neural dynamics are involved, is still poorly understood. Here we used resting-state fMRI to test the relation between variations in intrinsic connectivity patterns of the HC, and individual differences in retrospective duration processing, assessed using a novel task involving the presentation of ecological stimuli. Results showed that retrospective duration discrimination performance predicted variations in the intrinsic connectivity of the bilateral HC with the right precentral gyrus; follow-up exploratory analyses suggested a role of the CA1 and CA4/DG subfields in driving the observed pattern. Findings provide insights on neural networks associated with implicit processing of durations in the second range. [ABSTRACT FROM AUTHOR]

Background: In preclinical Alzheimer’s disease, it is unclear why some individuals with amyloid pathologic change are asymptomatic (stage 1), whereas others experience subjective cognitive decline (SCD, stage 2). Here, we examined the association of stage 1 vs. stage 2 with structural brain reserve in memory-related brain regions. Methods: We tested whether the volumes of hippocampal subfields and parahippocampal regions were larger in individuals at stage 1 compared to asymptomatic amyloid-negative older adults (healthy controls, HCs). We also tested whether individuals with stage 2 would show the opposite pattern, namely smaller brain volumes than in amyloid-negative individuals with SCD. Participants with cerebrospinal fluid (CSF) biomarker data and bilateral volumetric MRI data from the observational, multi-centric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study were included. The sample comprised 95 amyloid-negative and 26 amyloid-positive asymptomatic participants as well as 104 amyloid-negative and 47 amyloid-positive individuals with SCD. Volumes were based on high-resolution T2-weighted images and automatic segmentation with manual correction according to a recently established high-resolution segmentation protocol. Results: In asymptomatic individuals, brain volumes of hippocampal subfields and of the parahippocampal cortex were numerically larger in stage 1 compared to HCs, whereas the opposite was the case in individuals with SCD. MANOVAs with volumes as dependent data and age, sex, years of education, and DELCODE site as covariates showed a significant interaction between diagnosis (asymptomatic versus SCD) and amyloid status (Aß42/40 negative versus positive) for hippocampal subfields. Post hoc paired comparisons taking into account the same covariates showed that dentate gyrus and CA1 volumes in SCD were significantly smaller in amyloid-positive than negative individuals. In contrast, CA1 volumes were significantly (p = 0.014) larger in stage 1 compared with HCs. Conclusions: These data indicate that HCs and stages 1 and 2 do not correspond to linear brain volume reduction. Instead, stage 1 is associated with larger than expected volumes of hippocampal subfields in the face of amyloid pathology. This indicates a brain reserve mechanism in stage 1 that enables individuals with amyloid pathologic change to be cognitively normal and asymptomatic without subjective cognitive decline. [ABSTRACT FROM AUTHOR]

Cognitive tests sensitive to the integrity of the medial temporal lobe (MTL), such as mnemonic discrimination of perceptually similar stimuli, may be useful early markers of risk for cognitive decline in older populations. Perceptual discrimination of stimuli with overlapping features also relies on MTL but remains relatively unexplored in this context. We assessed mnemonic discrimination in two test formats (Forced Choice, Yes/No) and perceptual discrimination of objects and scenes in 111 community-dwelling older adults at different risk status for cognitive impairment based on neuropsychological screening. We also investigated associations between performance and MTL sub-region volume and thickness. The at-risk group exhibited reduced entorhinal thickness and impaired perceptual and mnemonic discrimination. Perceptual discrimination impairment partially explained group differences in mnemonic discrimination and correlated with entorhinal thickness. Executive dysfunction accounted for Yes/No deficits in at-risk adults, demonstrating the importance of test format for the interpretation of memory decline. These results suggest that perceptual discrimination tasks may be useful tools for detecting incipient cognitive impairment related to reduced MTL integrity in nonclinical populations. [ABSTRACT FROM AUTHOR]

Background: Education is believed to contribute positively to brain structure and function, as well as to cognitive reserve. One of the brain regions most impacted by education is the medial temporal lobe (MTL), a region that houses the hippocampus, which has an important role in learning processes and in consolidation of memories, and is also known to undergo neurogenesis in adulthood. We aimed to investigate the influence of education on the absolute cell numbers of the MTL (comprised by the hippocampal formation, amygdala, and parahippocampal gyrus) of men without cognitive impairment. Methods: The Isotropic Fractionator technique was used to allow the anisotropic brain tissue to be transformed into an isotropic suspension of nuclei, and therefore assess the absolute cell composition of the MTL. We dissected twenty-six brains from men aged 47 to 64 years, with either low or high education. Results: A significant difference between groups was observed in brain mass, but not in MTL mass. No significant difference was found between groups in the number of total cells, number of neurons, and number of non-neuronal cells. Regression analysis showed that the total number of cells, number of neurons, and number of non-neuronal cells in MTL were not affected by education. Conclusions: The results indicate a resilience of the absolute cellular composition of the MTL of typical men to low schooling, suggesting that the cellularity of brain regions is not affected by formal education. [ABSTRACT FROM AUTHOR]

We sought to systematically review and meta-analy the role of cerebral blood flow (CBF) in the medial temporal lobe (MTL) using arterial spin labeling magnetic resonance imaging (ASL-MRI) and compare this in patients with Alzheimer's disease (AD), individuals with mild cognitive impairment (MCI), and cognitively normal adults (CN). The prevalence of AD is increasing and leading to high healthcare costs. A potential biomarker that can identify people at risk of developing AD, whilst cognition is normal or only mildly affected, will enable risk-stratification and potential therapeutic interventions in the future. All studies investigated the role of CBF in the MTL and compared this among AD, MCI, and CN participants. A total of 26 studies were included in the systematic review and 11 in the meta-analysis. Three separate meta-analyses were conducted. Four studies compared CBF in the hippocampus of AD compared with the CN group and showed that AD participants had 2.8 mL/min/100 g lower perfusion compared with the CN group. Eight studies compared perfusion in the hippocampus of MCI vs. CN group, which showed no difference. Three studies compared perfusion in the MTL of MCI vs. CN participants and showed no statistically significant differences. CBF measured via ASL-MRI showed impairment in AD compared with the CN group in subregions of the MTL. CBF difference was significant in hippocampus between the AD and CN groups. However, MCI and CN group showed no significant difference in subregions of MTL. [ABSTRACT FROM AUTHOR]

Objectives Amnestic mild cognitive impairment (aMCI) is associated with cortical thinning in perirhinal and entorhinal cortices, key regions of the brain supporting familiarity. Individuals with aMCI demonstrate familiarity deficits in their behavior, often repeating questions in the same conversation. While familiarity deficits in healthy aging are minimal, past studies measuring familiarity in aMCI have mixed results, perhaps due to the influence of recollection. We therefore used a paradigm that minimized the influence of recollection, and hypothesized that familiarity would be impaired in aMCI relative to age-matched controls, but not in healthy older adults relative to younger adults. We also hypothesized that familiarity deficits in aMCI would be greater for objects than words because the perirhinal cortex plays a significant role in visual discrimination. Methods A sample of 36 younger adults, 38 cognitively intact older adults, and 30 older adults with aMCI made absolute frequency judgments for words and objects seen a variable number of times in an incidental encoding task. Estimates of familiarity were derived from correlating participants' frequency judgments with the actual frequency of presentation. Results Familiarity was largely spared in healthy aging, with minor deficits in familiarity for words. Familiarity deficits were evident in aMCI comparably for words and objects. Discussion The present research underscores the need to study familiarity in contexts minimizing recollection, particularly when comparing groups with different levels of recollection, and adds to our understanding of the phenomenology of aMCI. Familiarity deficits may provide an early biomarker of dementia risk. [ABSTRACT FROM AUTHOR]

High-frequency oscillatory events, termed ripples, represent synchrony of neural activity in the brain. Recent evidence suggests that medial temporal lobe (MTL) ripples support memory retrieval. However, it is unclear if ripples signal the reinstatement of episodic memories. Analyzing electrophysiological MTL recordings from 245 neurosurgical participants performing episodic recall tasks, we find that the rate of hippocampal ripples rises just prior to the free recall of recently formed memories. This prerecall ripple effect (PRE) is stronger in the CA1 and CA3/dentate gyrus (CA3/DG) subfields of the hippocampus than the neighboring MTL regions entorhinal and parahippocampal cortex. PRE is also stronger prior to the retrieval of temporally and semantically clustered, as compared with unclustered, recalls, indicating the involvement of ripples in contextual reinstatement, which is a hallmark of episodic memory. [ABSTRACT FROM AUTHOR]

Simple Summary: Memory disturbances are amongst the most common and disruptive symptoms of chemotherapy-related cognitive impairment. Chemotherapy treatments commonly cause neurotoxicity within the hippocampus, creating a vulnerability to memory impairment. Most clinical assessments of long-term memory in breast cancer survivors assess basic verbal and visual memory processing, and do not capture the complexities of everyday event memories, including episodic and autobiographical memory. This review focuses on structural and functional neuroimaging studies identifying disruptions in the hippocampus and recollection network, and related episodic memory impairments in chemotherapy-treated breast cancer survivors. We argue for the need to better characterize memory dysfunction following chemotherapy treatments. Given the importance of episodic and autobiographical memory to a person's personal history and quality of life, an under-appreciation of how this memory domain is impacted by standard cancer treatments potentially diminishes the negative experiences of breast cancer survivors, and neglects cognitive problems that could benefit from intervention strategies. Long-term memory disturbances are amongst the most common and disruptive cognitive symptoms experienced by breast cancer survivors following chemotherapy. To date, most clinical assessments of long-term memory dysfunction in breast cancer survivors have utilized basic verbal and visual memory tasks that do not capture the complexities of everyday event memories. Complex event memories, including episodic memory and autobiographical memory, critically rely on hippocampal processing for encoding and retrieval. Systemic chemotherapy treatments used in breast cancer commonly cause neurotoxicity within the hippocampus, thereby creating a vulnerability to memory impairment. We review structural and functional neuroimaging studies that have identified disruptions in the recollection network and related episodic memory impairments in chemotherapy-treated breast cancer survivors, and argue for the need to better characterize hippocampally mediated memory dysfunction following chemotherapy treatments. Given the importance of autobiographical memory for a person's sense of identity, ability to plan for the future, and general functioning, under-appreciation of how this type of memory is impacted by cancer treatment can lead to overlooking or minimizing the negative experiences of breast cancer survivors, and neglecting a cognitive domain that may benefit from intervention strategies. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease is characterized by the accumulation of amyloid-β (Aβ) into plaques, aggregation of tau into neurofibrillary tangles, and neurodegenerative processes including atrophy. However, there is a poorly understood spatial discordance between initial Aβ deposition and local neurodegeneration.Objective: Here, we test the hypothesis that the cingulum bundle links Aβ deposition in the cingulate cortex to medial temporal lobe (MTL) atrophy.Methods: 21 participants with mild cognitive impairment (MCI) from the UMC Utrecht memory clinic (UMCU, discovery sample) and 37 participants with MCI from Alzheimer's Disease Neuroimaging Initiative (ADNI, replication sample) with available Aβ-PET scan, T1-weighted and diffusion-weighted MRI were included. Aβ load of the cingulate cortex was measured by the standardized uptake value ratio (SUVR), white matter integrity of the cingulum bundle was assessed by mean diffusivity and atrophy of the MTL by normalized MTL volume. Relationships were tested with linear mixed models, to accommodate multiple measures for each participant.Results: We found at most a weak association between cingulate Aβ and MTL volume (added R2 <0.06), primarily for the posterior hippocampus. In neither sample, white matter integrity of the cingulum bundle was associated with cingulate Aβ or MTL volume (added R2 <0.01). Various sensitivity analyses (Aβ-positive individuals only, posterior cingulate SUVR, MTL sub region volume) provided similar results.Conclusion: These findings, consistent in two independent cohorts, do not support our hypothesis that loss of white matter integrity of the cingulum is a connecting factor between cingulate gyrus Aβ deposition and MTL atrophy. [ABSTRACT FROM AUTHOR]

Objective: The medial temporal lobe (MTL) encodes and recalls memories and can be a predominant site for interictal spikes (IS) in patients with focal epilepsy. It is unclear whether memory deficits are due to IS in the MTL producing a transient decline. Here, we investigated whether IS in the MTL subregions and lateral temporal cortex impact episodic memory encoding and recall. Methods: Seventy‐eight participants undergoing presurgical evaluation for medically refractory focal epilepsy with depth electrodes placed in the temporal lobe participated in a verbal free recall task. IS were manually annotated during the pre‐encoding, encoding, and recall epochs. We examined the effect of IS on word recall using mixed‐effects logistic regression. Results: IS in the left hippocampus (odds ratio [OR] =.73, 95% confidence interval [CI] =.63–.84, p <.001) and left middle temporal gyrus (OR =.46, 95% CI =.27–.78, p <.05) during word encoding decreased subsequent recall performance. Within the left hippocampus, this effect was specific for area CA1 (OR =.76, 95% CI =.66–.88, p <.01) and dentate gyrus (OR =.74, 95% CI =.62–.89, p <.05). IS in other MTL subregions or inferior and superior temporal gyrus and IS occurring during the prestimulus window did not affect word encoding (p >.05). IS during retrieval in right hippocampal (OR =.22, 95% CI =.08–.63, p =.01) and parahippocampal regions (OR =.24, 95% CI =.07–.8, p <.05) reduced the probability of recalling a word. Significance: IS in medial and lateral temporal cortex contribute to transient memory decline during verbal episodic memory. [ABSTRACT FROM AUTHOR]

[Display omitted] • The basolateral amygdala (BLA) enables memory modulation in other brain areas. • The BLA is crucial for memory enhancement by entorhinal cortex (EC) stimulation. • We review interactions between the BLA and EC in synaptic plasticity and memory. • The EC mediates influences from the BLA that are relayed to the hippocampus. The amygdala, specifically its basolateral nucleus (BLA), is a critical site integrating neuromodulatory influences on memory consolidation in other brain areas. Almost 20 years ago, we reported the first direct evidence that BLA activity is required for modulatory interventions in the entorhinal cortex (EC) to affect memory consolidation (Roesler, Roozendaal, and McGaugh, 2002). Since then, significant advances have been made in our understanding of how the EC participates in memory. For example, the characterization of grid cells specialized in processing spatial information in the medial EC (mEC) that act as major relayers of information to the hippocampus (HIP) has changed our view of memory processing by the EC; and the development of optogenetic technologies for manipulation of neuronal activity has recently enabled important new discoveries on the role of the BLA projections to the EC in memory. Here, we review the current evidence on interactions between the BLA and EC in synaptic plasticity and memory formation. The findings suggest that the EC may function as a gateway and mediator of modulatory influences from the BLA, which are then processed and relayed to the HIP. Through extensive reciprocal connections among the EC, HIP, and several cortical areas, information related to new memories is then consolidated by these multiple brain systems, through various molecular and cellular mechanisms acting in a distributed and highly concerted manner, during several hours after learning. A special note is made on the contribution by Ivan Izquierdo to our understanding of memory consolidation at the brain system level. [ABSTRACT FROM AUTHOR]

A necessary condition for forming episodic memories is the construction of specific episodes demarcated from other episodes in space and time. Evidence from studies of episodic memory formation using rodent models suggest that the medial temporal lobe (MTL) supports the representation of boundary information. Building on recent work using human microelectrode recordings as well, we hypothesized of human MTL neurons with firing rates sensitive to episodic boundary information. We identified 27 episodic boundary neurons out of 736 single neurons recorded across 27 subjects. Firing of these neurons increased at the beginning and end of mnemonically relevant episodes in the free recall task. We distinguish episodic boundary neurons from a population of ramping neurons (n = 58), which are time‐sensitive neurons whose activity provides complementary information during episodic representation. Episodic boundary neurons exhibited a U‐shaped activity pattern demonstrating increased activity after both beginning and end boundaries of encoding and retrieval epochs. We also describe evidence that the firing of boundary neurons within episodic boundaries is organized by hippocampal theta oscillations, using spike‐field coherence metrics. [ABSTRACT FROM AUTHOR]

Behavioral flexibility depends on our capacity to build and leverage abstract knowledge about tasks. Recently, two separate lines of research have implicated distinct brain networks in representing abstract task information: a frontoparietal cortical network, and a network involving the medial temporal lobe (MTL), medial prefrontal, and orbitofrontal cortex (OMPFC). These observations have mostly been made in parallel, with little attempt to understand their relationship. Here, we hypothesize that abstract task representations in these networks differ primarily in format, not content. Namely, that the MTL–OMPFC network maintains task knowledge in a flexible cognitive map, while the frontoparietal network formats this knowledge as productions that facilitate action selection. We discuss novel implications and predictions for behavioral flexibility arising from this hypothesis. Recent research has identified two distinct cortical networks representing abstract task knowledge: a frontoparietal network, and a network involving the MTL and OMPFC. Here, we suggest that these networks differ in format but not content, with the MTL–OMPFC network maintaining abstract task knowledge in a cognitive map, while frontoparietal cortex uses this knowledge to build rules for action selection. This format distinction would allow the MTL–OMPFC network to form novel inferences and plan trajectories in an abstract state space, and for the frontoparietal network to rapidly apply abstract rules without referencing a more elaborate internal task model. This hypothesis makes novel predictions about the function of these networks in learning and promoting flexible behavior. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The primary aim of this review is to examine the brain activity patterns that are related to subjectively perceived memory confidence. We focus on the main brain regions involved in episodic memory: the medial temporal lobe (MTL), prefrontal cortex (PFC), and posterior parietal cortex (PPC), and relate activity in their subregions to memory confidence. How this brain activity in both the encoding and retrieval phase is related to (subsequent) memory confidence ratings will be discussed. Specifically, encoding related activity in MTL regions and ventrolateral PFC mainly shows a positive linear increase with subsequent memory confidence, while dorsolateral and ventromedial PFC activity show mixed patterns. In addition, encoding‐related PPC activity seems to only have indirect effects on memory confidence ratings. Activity during retrieval in both the hippocampus and parahippocampal cortex increases with memory confidence, especially during high‐confident recognition. Retrieval‐related activity in the PFC and PPC show mixed relationships with memory confidence, likely related to post‐retrieval monitoring and attentional processes, respectively. In this review, these MTL, PFC, and PPC activity patterns are examined in detail and related to their functional roles in memory processes. This insight into brain activity that underlies memory confidence is important for our understanding of brain–behaviour relations and memory‐guided decision making. [ABSTRACT FROM AUTHOR]

The medial temporal lobe (MTL) is a set of interconnected brain regions that have been shown to play a central role in behavior as well as in neurological disease. Recent studies using resting-state functional magnetic resonance imaging (rsfMRI) have attempted to understand the MTL in terms of its functional connectivity with the rest of the brain. However, the exact characterization of the whole-brain networks that co-activate with the MTL as well as how the various sub-regions of the MTL are associated with these networks remains poorly understood. Here, we attempted to advance these issues by exploiting the high spatial resolution 7T rsfMRI dataset from the Human Connectome Project with a data-driven analysis approach that relied on independent component analysis (ICA) restricted to the MTL. We found that four different well-known resting-state networks co-activated with a unique configuration of MTL subcomponents. Specifically, we found that different sections of the parahippocampal cortex were involved in the default mode, visual and dorsal attention networks; sections of the hippocampus in the somatomotor and default mode networks; and the lateral entorhinal cortex in the dorsal attention network. We replicated this set of results in a validation sample. These results provide new insight into how the MTL and its subcomponents contribute to known resting-state networks. The participation of the MTL in an expanded range of resting-state networks is in line with recent proposals on MTL function. [ABSTRACT FROM AUTHOR]

The medial temporal lobe (MTL) is connected to the rest of the brain through two main networks: the anterior-temporal (AT) and the posterior-medial (PM) systems. Given the crucial role of the MTL and networks in the physiopathology of Alzheimer's disease (AD), the present study aimed at (1) investigating whether MTL atrophy propagates specifically within the AT and PM networks, and (2) evaluating the vulnerability of these networks to AD proteinopathies. To do that, we used neuroimaging data acquired in human male and female in three distinct cohorts: (1) resting-state functional MRI (rs-fMRI) from the aging brain cohort (ABC) to define the AT and PM networks (n=68); (2) longitudinal structural MRI from Alzheimer's disease neuroimaging initiative (ADNI)GO/2 to highlight structural covariance patterns (n=349); and (3) positron emission tomography (PET) data from ADNI3 to evaluate the networks' vulnerability to amyloid and tau (n=186). Our results suggest that the atrophy of distinct MTL subregions propagates within the AT and PM networks in a dissociable manner. Brodmann area (BA)35 structurally covaried within the AT network while the parahippocampal cortex (PHC) covaried within the PM network. In addition, these networks are differentially associated with relative tau and amyloid burden, with higher tau levels in AT than in PM and higher amyloid levels in PM than in AT. Our results also suggest differences in the relative burden of tau species. The current results provide further support for the notion that two distinct MTL networks display differential alterations in the context of AD. These findings have important implications for disease spread and the cognitive manifestations of AD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• Age-related atrophy patterns indicated increased atrophy in early Braak regions • Phospho-tau levels were associated with hippocampal atrophy • Phospho-tau levels partially mediate age effects on the hippocampus • Primary age-related tauopathy may drive age-related medial temporal lobe changes Hippocampal atrophy is endemic in 'normal aging' but it is unclear what factors drive age-related changes in medial temporal lobe (MTL) structural measures. We investigated cross-sectional (n = 191) and longitudinal (n = 164) MTL atrophy patterns in cognitively normal older adults from ADNI-GO/2 with no to low cerebral β-amyloid and assessed whether white matter hyperintensities (WMHs) and cerebrospinal fluid (CSF) phospho tau (p-tau) levels can explain age-related changes in the MTL. Age was significantly associated with hippocampal volumes and Brodmann Area (BA) 35 thickness, regions affected early by neurofibrillary tangle pathology, in the cross-sectional analysis and with anterior and/or posterior hippocampus, entorhinal cortex and BA35 in the longitudinal analysis. CSF p-tau was significantly associated with hippocampal volumes and atrophy rates. Mediation analyses showed that CSF p-tau levels partially mediated age effects on hippocampal atrophy rates. No significant associations were observed for WMHs. These findings point toward a role of tau pathology, potentially reflecting Primary Age-Related Tauopathy, in age-related MTL structural changes and suggests a potential role for tau-targeted interventions in age-associated neurodegeneration and memory decline. [ABSTRACT FROM AUTHOR]

The medial temporal lobe (MTL) is the core neural construction related to associative memory. This study sought to explore the dynamic functional connectivity (dFC) between the subdivisions of MTL and other regions in the whole brain. Additionally, it sought to determine relationships between connectivity stability and associative memory function, to elucidate the neural foundation of associative memory from the perspectives of dFC. A Wechsler Memory Scale China revised edition (WMS-RC) measurement and a resting-state functional magnetic resonance imaging were conducted to clarify adults' function of associative memory and dFC patterns in subdivisions of the MTL. A multiple regression analysis was carried out to analyze the relationships described above. The results demonstrated that (i) connectivity in the left brain included the anterior hippocampus (aHIP) and right fusiform (Fusiform_R), middle hippocampus (mHIP) and right inferior parietal lobule (IPL_R), posterior hippocampus (pHIP) and left inferior parietal lobule (IPL_L), perirhinal cortex (PRC) and left supramarginal gyrus (SMG_L), entorhinal cortex (ERC) and [left middle temporal gyrus (MTG_L), left superior parietal lobule (SPL_L), right fusiform (Fusiform_R)], anterior parahippocampal cortex (aPHC) and right precentral gyrus (PCG_R); (ii) connectivity in the right brain included the aHIP and right supramarginal gyrus (SMG_R), mHIP and left paracentral lobule (PCL_L), pHIP and left superior occipital gyrus (SOG_L), PRC and left middle occipital gyrus (MOG_L), ERC and right middle occipital gyrus (MOG_R); (iii) for most connectivity patterns, the more stable the dFC, the better are the associative memory functions. This study elucidates the neural foundations of associative memory in terms of dFC patterns. [ABSTRACT FROM AUTHOR]

Background: Little is known about the heterogeneous etiology of suspected non-Alzheimer's pathophysiology (SNAP), a group of subjects with neurodegeneration in the absence of β-amyloid. Using antemortem MRI and pathological data, we investigated the etiology of SNAP and the association of neurodegenerative pathologies with structural medial temporal lobe (MTL) measures in β-amyloid-negative subjects. Methods: Subjects with antemortem MRI and autopsy data were selected from ADNI (n=63) and the University of Pennsylvania (n=156). Pathological diagnoses and semi-quantitative scores of MTL tau, neuritic plaques, α-synuclein, and TDP-43 pathology and MTL structural MRI measures from antemortem T1-weighted MRI scans were obtained. β-amyloid status (A+/A−) was determined by CERAD score and neurodegeneration status (N+/N−) by hippocampal volume. Results: SNAP reflects a heterogeneous group of pathological diagnoses. In ADNI, SNAP (A−N+) had significantly more neuropathological diagnoses than A+N+. In the A− group, tau pathology was associated with hippocampal, entorhinal cortex, and Brodmann area 35 volume/thickness and TDP-43 pathology with hippocampal volume. Conclusion: SNAP had a heterogeneous profile with more mixed pathologies than A+N+. Moreover, a role for TDP-43 and tau pathology in driving MTL neurodegeneration in the absence of β-amyloid was supported. [ABSTRACT FROM AUTHOR]

Psychological theories posit that the hippocampus rapidly forms associations among ongoing events as they unfold. During a subsequent maturation process, so‐called systems memory consolidation, these associations are gradually stabilized within distributed neocortical circuits through close interactions between the hippocampus and neocortex. In the past 50 years, a major effort in neurobiological research has been directed towards translating these descriptive accounts into tangible, biological processes in the brain. Until the early 2000s, most studies exclusively focused on examining whether the hippocampus becomes unnecessary for memory retrieval once the memory has been consolidated. With recent methodological advances, however, the field shifted attention to several other theoretical accounts and began to uncover the genetic, physiological and structural underpinnings of systems memory consolidation at an unprecedented level of precision. Here I review these neurobiological findings in the past 15 years within a framework of six essential predictions extracted from the psychological theories. Genetic approaches have made it possible to tag neurons that were activated during memory encoding and investigate their physiological and genetic profiles as well as reactivation patterns during subsequent retrieval. In parallel, electrophysiological and imaging approaches detected signs of the gradual refinement of memory representations and its underlying hippocampal–neocortical dialogue in millisecond‐resolved neural firing patterns, the inter‐region coupling of neural activity, across‐day stability of neural ensemble activity and functional connectome. This summary represents substantial progress in our understanding of neurobiological mechanisms of systems memory consolidation whilst also identifying several essential remaining questions for future investigations. [ABSTRACT FROM AUTHOR]