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INTRODUCTION: The influence of hippocampal connectivity on memory performance is well established in individuals with high educational attainment. However, the role of hippocampal connectivity in illiterate populations remains poorly understood. METHODS: Thirty-five illiterate adults were administered a literacy assessment (Test of Functional Health Literacy in Adults [TOFHLA]), structural and resting state functional magnetic resonance imaging, and an episodic memory test (Free and Cued Selective Reminding Test). Illiteracy was defined as a TOFHLA score < 53. We evaluated the correlation between hippocampal connectivity at rest and both free recall and literacy scores. RESULTS: Participants were mostly female (57.1%) and self-declared as being Black individuals (84.8%), with a median age of 50 years. The median TOFHLA literacy score was 28.0 [21.0; 42.5] out of 100 points and the median free recall score was 30.0 [26.2; 35] out of 48 points. The median gray matter volume of both the left and right hippocampi was 2.3 [2.1; 2.4] cm3. We observed a significant connectivity between both hippocampi and the precuneus and the ventral medial prefrontal cortex. The right hippocampal connectivity positively correlated with the literacy scores (ß = 0.58, P = 0.008). There was no significant association between episodic memory and hippocampal connectivity. Neither memory nor literacy scores correlated with hippocampal gray matter volume. DISCUSSION: Low literacy levels correlated with hippocampal connectivity in illiterate adults. The lack of association with memory scores might be associated with low brain reserve in this sample. Highlights: A significant link was found between health literacy and hippocampal connectivity.Enhanced hippocampus- ventromedial prefrontal cortex connectivity suggests potential cognitive reserve improvement.Higher cognitive reserve may protect against hippocampal atrophy and neurodegeneration.Health literacy improvements could help prevent cognitive impairment in illiterate populations.Study highlights importance of considering structural racism in brain connectivity research.

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Although no longer considered a public health threat, post-COVID cognitive syndrome continues to impact on a considerable proportion of individuals who were infected with COVID-19. Recent studies have also suggested that COVID may be represent a critical risk factor for the development of Alzheimer's disease (AD). We compared 17 COVID patients with 20 controls and evaluated the effects of COVID-19 on general cognitive performance, hippocampal volume, and connections using structural and seed-based connectivity analysis. We showed that COVID patients exhibited considerably worse cognitive functioning and increased hippocampal connectivity supported by the strong correlation between hippocampal connectivity and cognitive scores. Our findings of higher hippocampal connectivity with no observable hippocampal morphological changes even in mild COVID cases may be represent evidence of a prestructural compensatory mechanism for stimulating additional neuronal resources to combat cognitive dysfunction as recently shown for the prodromal stages of degenerative cognitive disorders. Our findings may be also important in light of recent data showing that other viral infections as well as COVID may constitute a critical risk factor for the development of AD. To our knowledge, this is the first study that investigated network differences in COVID patients, with a particular focus on compensatory hippocampal connectivity.

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Background: The influence of hippocampal connectivity on memory performance is well established in individuals with high educational attainment. However, the role of hippocampal connectivity in illiterate populations remains poorly understood. Methods: Thirty-five illiterate adults were administered a literacy assessment (Test of Functional Health Literacy in Adults - TOFHLA), structural and resting state functional MRI and an episodic memory test (Free and Cued Selective Reminding Test). Illiteracy was defined as a TOFHLA score below 53. We evaluated the correlation between hippocampal connectivity at rest and both free recall and literacy scores. Results: Participants were mostly female (57.1%) and Black (84.8%), with a median age of 50 years. The median TOFHLA literacy score was 28.0 [21.0;42.5] out of 100 points and the median free recall score was 30.0 [26.2;35] out of 48 points. The median gray matter volume of both the left and right hippocampi was 2.3 [2.1; 2.4] cm3. We observed a significant connectivity between both hippocampi and the precuneus and the ventral medial prefrontal cortex. Interestingly, the right hippocampal connectivity positively correlated with the literacy scores (ß = 0.58, p = 0.008). There was no significant association between episodic memory and hippocampal connectivity. Neither memory nor literacy scores correlated with hippocampal gray matter volume. Conclusions: Low literacy levels correlate with hippocampal connectivity in illiterate adults. The lack of association with memory scores might be associated with low brain reserve in illiterate adults.

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With rapid aging of the population worldwide, the number of people with dementia is dramatically increasing. Some studies have emphasized that metabolic syndrome, which includes obesity and diabetes, leads to increased risks of dementia and cognitive decline. Factors such as insulin resistance, hyperglycemia, high blood pressure, dyslipidemia, and central obesity in metabolic syndrome are associated with synaptic failure, neuroinflammation, and imbalanced neurotransmitter levels, leading to the progression of dementia. Due to the positive correlation between diabetes and dementia, some studies have called it "type 3 diabetes". Recently, the number of patients with cognitive decline due to metabolic imbalances has considerably increased. In addition, recent studies have reported that neuropsychiatric issues such as anxiety, depressive behavior, and impaired attention are common factors in patients with metabolic disease and those with dementia. In the central nervous system (CNS), the amygdala is a central region that regulates emotional memory, mood disorders, anxiety, attention, and cognitive function. The connectivity of the amygdala with other brain regions, such as the hippocampus, and the activity of the amygdala contribute to diverse neuropathological and neuropsychiatric issues. Thus, this review summarizes the significant consequences of the critical roles of amygdala connectivity in both metabolic syndromes and dementia. Further studies on amygdala function in metabolic imbalance-related dementia are needed to treat neuropsychiatric problems in patients with this type of dementia.

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Recurrent connectivity between excitatory neurons and the strength of feedback from inhibitory neurons are critical determinants of the dynamics and computational properties of neuronal circuits. Toward a better understanding of these circuit properties in regions CA1 and CA3 of the hippocampus, we performed optogenetic manipulations combined with large-scale unit recordings in rats under anesthesia and in quiet waking, using photoinhibition and photoexcitation with different light-sensitive opsins. In both regions, we saw striking paradoxical responses: subsets of cells increased firing during photoinhibition, while other cells decreased firing during photoexcitation. These paradoxical responses were more prominent in CA3 than in CA1, but, notably, CA1 interneurons showed increased firing in response to photoinhibition of CA3. These observations were recapitulated in simulations where we modeled both CA1 and CA3 as inhibition-stabilized networks in which strong recurrent excitation is balanced by feedback inhibition. To directly test the inhibition-stabilized model, we performed large-scale photoinhibition directed at (GAD-Cre) inhibitory cells and found that interneurons in both regions increased firing when photoinhibited, as predicted. Our results highlight the often-paradoxical circuit dynamics that are evidenced during optogenetic manipulations and indicate that, contrary to long-standing dogma, both CA1 and CA3 hippocampal regions display strongly recurrent excitation, which is stabilized through inhibition.

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Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy and is associated with a variety of structural and psychological alterations. Recently, there has been renewed interest in using brain tissue resected during epilepsy surgery, in particular 'non-epileptic' brain samples with normal histology that can be found alongside epileptic tissue in the same epileptic patients - with the aim being to study the normal human brain organization using a variety of methods. An important limitation is that different medical characteristics of the patients may modify the brain tissue. Thus, to better determine how 'normal' the resected tissue is, it is fundamental to know certain clinical, anatomical and psychological characteristics of the patients. Unfortunately, this information is frequently not fully available for the patient from which the resected tissue has been obtained - or is not fully appreciated by the neuroscientists analyzing the brain samples, who are not necessarily experts in epilepsy. In order to present the full picture of TLE in a way that would be accessible to multiple communities (e.g., basic researchers in neuroscience, neurologists, neurosurgeons and psychologists), we have reviewed 34 TLE patients, who were selected due to the availability of detailed clinical, anatomical, and psychological information for each of the patients. Our aim was to convey the full complexity of the disorder, its putative anatomical substrates, and the wide range of individual variability, with a view toward: (1) emphasizing the importance of considering critical patient information when using brain samples for basic research and (2) gaining a better understanding of normal and abnormal brain functioning. In agreement with a large number of previous reports, this study (1) reinforces the notion of substantial individual variability among epileptic patients, and (2) highlights the common but overlooked psychopathological alterations that occur even in patients who become "seizure-free" after surgery. The first point is based on pre- and post-surgical comparisons of patients with hippocampal sclerosis and patients with normal-looking hippocampus in neuropsychological evaluations. The second emerges from our extensive battery of personality and projective tests, in a two-way comparison of these two types of patients with regard to pre- and post-surgical performance.

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Repetitive transcranial magnetic stimulation (rTMS) can be used to enhance the associative memory of healthy subjects and patients with Alzheimer's disease (AD). However, the question of where the stimulation should be applied is still unresolved. In a preliminary survey for an effective and feasible solution to this problem, we identified three representative rTMS targets using cortico-hippocampal connectivity, calculated using resting-state fMRI (rs-fMRI) data from 80 young, healthy subjects: (1) the cortical area with the strongest connectivity across the whole cerebral cortical area; (2) the whole lateral parietal cortical area; and (3) the whole medial prefrontal cortical area. We then compared the short-term effects on associative memory, which was tested using face-cued word recall by applying rTMS to three identified targets in a single population of eight healthy adults. Each treatment lasted for 2 days. Associative memory performance was measured at four time points: before and after stimulation on the first day (baseline and post 1) and before and after stimulation on the second day (post 2 and post 3). Compared with baseline levels, 20 min of high-frequency rTMS delivered to target 2 or target 3 produced a significant increase in the mean accuracy of associative memory performance at the post 3 time point alone (target 2, P = 0.0035; target 3, P = 0.0012). Compared with the sham conditions, significant increases in the mean associative memory performance were observed when high-frequency rTMS was delivered to target 2 (P = 0.02) and target 3 (P = 0.012), but not when delivered to target 1 (P = 0.1). Compared with baseline levels, 20 min of high-frequency rTMS delivered to target 3 produced a significant reduction in the mean reaction time of associative memory only at time points post 1 (P = 0.0464) and post 3 (P = 0.0477). Compared with the sham conditions, significant reductions in the mean reaction time of associative memory were observed when high-frequency rTMS was delivered to target 3 (P = 0.006), but not when delivered to target 1 (P = 0.471) or target 2 (P = 0.365). Our findings indicate that stimulation of the locations with the strongest cortico-hippocampal connectivity within the lateral parietal cortical or medial prefrontal cortical areas is effective in enhancing face-word recall-based associative memory in the short term.

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Memory impairment in schizophrenia has been linked to abnormal functioning of fronto-temporal networks. In this pilot study, we investigated whether 12-weeks of exercise improved hippocampal-dependent memory functions and resting-state functional connectivity in middle-aged adults with schizophrenia. The exercise regimen was feasible, well-attended, and safe. There was a pre- to post-intervention increase in spatial memory accuracy that was correlated to an increase in hippocampal-prefrontal cortex connectivity. No increase was found in pattern separation performance or hippocampal volume. A controlled trial is needed to replicate these findings and elucidate the functional brain networks underlying exercise-induced cognitive improvement in schizophrenia.

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Among the major psychiatric disorders, anxious-depressive disorders stand out as one of the more prevalent and more frequently associated with hypothalamic-pituitary-adrenal (HPA) axis abnormalities. Methylation at the exon 1F of the glucocorticoid receptor gene NR3C1 has been associated with both early stress exposure and risk for developing a psychiatric disorder; however, other NR3C1 promoter regions have been underexplored. Exon 1D emerges as a suggestive new target in stress-related disorders epigenetically sensitive to early adversity. After assessment of 48 monozygotic twin pairs (n=96 subjects) informative for lifetime history of anxious-depressive disorders, they were classified as concordant, discordant or healthy in function of whether both, one or neither twin in each pair had a lifetime diagnosis of anxious-depressive disorders. DNA for epigenetic analysis was extracted from peripheral blood. Exon 1F and exon 1D CpG-specific methylation was analysed by means of pyrosequencing technology. Functional magnetic resonance imaging was available for 54 subjects (n=27 twin pairs). Exon 1D CpG-specific methylation within a glucocorticoid responsive element (GRE) was correlated with familial burden of anxious-depressive disorders (r=0.35, z=2.26, p=0.02). Right hippocampal connectivity was significantly associated with CpG-specific GRE methylation (ß=-2.33, t=-2.85, p=0.01). Exon 1F was uniformly hypomethylated across all subgroups of the present sample. GRE hypermethylation at exon 1D of the NR3C1 gene in monozygotic twins concordant for anxious-depressive disorders suggests this region plays a role in increasing vulnerability to psychosocial stress, partly mediated by altered hippocampal connectivity.

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In the last two decades, the avian hippocampus has been repeatedly studied with respect to its architecture, neurochemistry, and connectivity pattern. We review these insights and conclude that we unfortunately still lack proper knowledge on the interaction between the different hippocampal subregions. To fill this gap, we need information on the functional connectivity pattern of the hippocampal network. These data could complement our structural connectivity knowledge. To this end, we conducted a resting-state fMRI experiment in awake pigeons in a 7-T MR scanner. A voxel-wise regression analysis of blood oxygenation level-dependent (BOLD) fluctuations was performed in 6 distinct areas, dorsomedial (DM), dorsolateral (DL), triangular shaped (Tr), dorsolateral corticoid (CDL), temporo-parieto-occipital (TPO), and lateral septum regions (SL), to establish a functional connectivity map of the avian hippocampal network. Our study reveals that the system of connectivities between CDL, DL, DM, and Tr is the functional backbone of the pigeon hippocampal system. Within this network, DM is the central hub and is strongly associated with DL and CDL BOLD signal fluctuations. DM is also the only hippocampal region to which large Tr areas are functionally connected. In contrast to published tracing data, TPO and SL are only weakly integrated in this network. In summary, our findings uncovered a structurally otherwise invisible architecture of the avian hippocampal formation by revealing the dynamic blueprints of this network.

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Connectomics of brain disorders seeks to reveal how altered brain function emerges from the architecture of cerebral networks; however the causal impact of targeted cellular damage on the whole brain functional and structural connectivity remains unknown. In the central nervous system, demyelination is typically the consequence of an insult targeted at the oligodendrocytes, the cells forming and maintaining the myelin. This triggered perturbation generates cascades of pathological events that most likely alter the brain connectome. Here we induced oligodendrocyte death and subsequent demyelinating pathology via cuprizone treatment in mice and combining mouse brain resting state functional Magnetic Resonance Imaging and diffusion tractography we established functional and structural pathology-to-network signatures. We demonstrated that demyelinated brain fundamentally reorganizes its intrinsic functional connectivity paralleled by widespread damage of the structural scaffolding. We evidenced default mode-like network as core target of demyelination-induced connectivity modulations and hippocampus as the area with strongest connectional perturbations.

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Successful memory for an image can be supported by retrieval of one's personal reaction to the image (i.e., internal vividness), as well as retrieval of the specific details of the image itself (i.e., external vividness). Prior research suggests that memory vividness relies on regions within the medial temporal lobe, particularly the hippocampus, but it is unclear whether internal and external vividness are supported by the hippocampus in a similar way. To address this open question, the current study examined hippocampal connectivity associated with enhanced internal and external vividness ratings during retrieval. Participants encoded complex visual images paired with verbal titles. During a scanned retrieval session, they were presented with the titles and asked whether each had been seen with an image during encoding. Following retrieval of each image, participants were asked to rate internal and external vividness. Increased hippocampal activity was associated with higher vividness ratings for both scales, supporting prior evidence implicating the hippocampus in retrieval of memory detail. However, different patterns of hippocampal connectivity related to enhanced external and internal vividness. Further, hippocampal connectivity with medial prefrontal regions was associated with increased ratings of internal vividness, but with decreased ratings of external vividness. These findings suggest that the hippocampus may contribute to increased internal and external vividness via distinct mechanisms and that external and internal vividness of memories should be considered as separable measures.

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BACKGROUND: Memory impairment is frequent in multiple sclerosis (MS), but it is unclear what functional brain changes underlie this cognitive deterioration. OBJECTIVE: To investigate functional hippocampal activation and connectivity, in relation to memory performance in MS. METHODS: Structural and functional magnetic resonance imaging data were acquired for 57 MS patients and 28 healthy controls (HCs), yielding hippocampal measures of volume, lesions, functional activation during a memory task and functional connectivity at rest. Memory function was based on two subtests of a larger neuropsychological test battery and related to hippocampal neuroimaging measures, using linear regression. RESULTS: Hippocampal volume was lower in MS patients, as compared to HCs. In MS, hippocampal activation during the task was increased in cognitively preserved, but decreased in cognitively impaired, patients. Increased hippocampal connectivity was detected in MS patients, as compared to HCs, between the left hippocampus and the right posterior cingulate. Memory impairment in MS was explained (adjusted R(2) = 0.27) by male gender, decreased hippocampal activation and increased hippocampal connectivity (p = 0.001). CONCLUSIONS: Decreased activation of the hippocampus, increased connectivity and male gender were associated with worse memory performance in MS. These results indicate that increased activation and increased connectivity do not always coincide, and relate differently to cognitive dysfunction in MS.

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