Psilocybin desynchronizes the human brain.

A single dose of psilocybin, a psychedelic that acutely causes distortions of space-time perception and ego dissolution, produces rapid and persistent therapeutic effects in human clinical trials1-4. In animal models, psilocybin induces neuroplasticity in cortex and hippocampus5-8. It remains unclear how human brain network changes relate to subjective and lasting effects of psychedelics. Here we tracked individual-specific brain changes with longitudinal precision functional mapping (roughly 18 magnetic resonance imaging visits per participant). Healthy adults were tracked before, during and for 3 weeks after high-dose psilocybin (25 mg) and methylphenidate (40 mg), and brought back for an additional psilocybin dose 6-12 months later. Psilocybin massively disrupted functional connectivity (FC) in cortex and subcortex, acutely causing more than threefold greater change than methylphenidate. These FC changes were driven by brain desynchronization across spatial scales (areal, global), which dissolved network distinctions by reducing correlations within and anticorrelations between networks. Psilocybin-driven FC changes were strongest in the default mode network, which is connected to the anterior hippocampus and is thought to create our sense of space, time and self. Individual differences in FC changes were strongly linked to the subjective psychedelic experience. Performing a perceptual task reduced psilocybin-driven FC changes. Psilocybin caused persistent decrease in FC between the anterior hippocampus and default mode network, lasting for weeks. Persistent reduction of hippocampal-default mode network connectivity may represent a neuroanatomical and mechanistic correlate of the proplasticity and therapeutic effects of psychedelics.

Insights into hippocampal perfusion using high-resolution, multi-modal 7T MRI.

We present a comprehensive study on the non-invasive measurement of hippocampal perfusion. Using high-resolution 7 tesla arterial spin labeling (ASL) data, we generated robust perfusion maps and observed significant variations in perfusion among hippocampal subfields, with CA1 exhibiting the lowest perfusion levels. Notably, these perfusion differences were robust and already detectable with 50 perfusion-weighted images per subject, acquired in 5 min. To understand the underlying factors, we examined the influence of image quality metrics, various tissue microstructure and morphometric properties, macrovasculature, and cytoarchitecture. We observed higher perfusion in regions located closer to arteries, demonstrating the influence of vascular proximity on hippocampal perfusion. Moreover, ex vivo cytoarchitectonic features based on neuronal density differences appeared to correlate stronger with hippocampal perfusion than morphometric measures like gray matter thickness. These findings emphasize the interplay between microvasculature, macrovasculature, and metabolic demand in shaping hippocampal perfusion. Our study expands the current understanding of hippocampal physiology and its relevance to neurological disorders. By providing in vivo evidence of perfusion differences between hippocampal subfields, our findings have implications for diagnosis and potential therapeutic interventions. In conclusion, our study provides a valuable resource for extensively characterizing hippocampal perfusion.

Depressive symptoms during the transition to adolescence: Left hippocampal volume as a marker of social context sensitivity.

The transition to adolescence is a critical period for mental health development. Socio-experiential environments play an important role in the emergence of depressive symptoms with some adolescents showing more sensitivity to social contexts than others. Drawing on recent developmental neuroscience advances, we examined whether hippocampal volume amplifies social context effects in the transition to adolescence. We analyzed 2-y longitudinal data from the Adolescent Brain Cognitive Development (ABCD®) study in a diverse sample of 11,832 youth (mean age: 9.914 y; range: 8.917 to 11.083 y; 47.8% girls) from 21 sites across the United States. Socio-experiential environments (i.e., family conflict, primary caregiver's depressive symptoms, parental warmth, peer victimization, and prosocial school environment), hippocampal volume, and a wide range of demographic characteristics were measured at baseline. Youth's symptoms of major depressive disorder were assessed at both baseline and 2 y later. Multilevel mixed-effects linear regression analyses showed that negative social environments (i.e., family conflict, primary caregiver's depressive symptoms, and peer victimization) and the absence of positive social environments (i.e., parental warmth and prosocial school environment) predicted greater increases in youth's depressive symptoms over 2 y. Importantly, left hippocampal volume amplified social context effects such that youth with larger left hippocampal volume experienced greater increases in depressive symptoms in more negative and less positive social environments. Consistent with brain-environment interaction models of mental health, these findings underscore the importance of families, peers, and schools in the development of depression during the transition to adolescence and show how neural structure amplifies social context sensitivity.

Sex and mental health are related to subcortical brain microstructure.

Some mental health problems such as depression and anxiety are more common in females, while others such as autism and attention deficit/hyperactivity (AD/H) are more common in males. However, the neurobiological origins of these sex differences are poorly understood. Animal studies have shown substantial sex differences in neuronal and glial cell structure, while human brain imaging studies have shown only small differences, which largely reflect overall body and brain size. Advanced diffusion MRI techniques can be used to examine intracellular, extracellular, and free water signal contributions and provide unique insights into microscopic cellular structure. However, the extent to which sex differences exist in these metrics of subcortical gray matter structures implicated in psychiatric disorders is not known. Here, we show large sex-related differences in microstructure in subcortical regions, including the hippocampus, thalamus, and nucleus accumbens in a large sample of young adults. Unlike conventional T1-weighted structural imaging, large sex differences remained after adjustment for age and brain volume. Further, diffusion metrics in the thalamus and amygdala were associated with depression, anxiety, AD/H, and antisocial personality problems. Diffusion MRI may provide mechanistic insights into the origin of sex differences in behavior and mental health over the life course and help to bridge the gap between findings from experimental, epidemiological, and clinical mental health research.

Hippocampal contributions to novel spatial learning are both age-related and age-invariant.

Older adults show declines in spatial memory, although the extent of these alterations is not uniform across the healthy older population. Here, we investigate the stability of neural representations for the same and different spatial environments in a sample of younger and older adults using high-resolution functional MRI of the medial temporal lobes. Older adults showed, on average, lower neural pattern similarity for retrieving the same environment and more variable neural patterns compared to young adults. We also found a positive association between spatial distance discrimination and the distinctiveness of neural patterns between environments. Our analyses suggested that one source for this association was the extent of informational connectivity to CA1 from other subfields, which was dependent on age, while another source was the fidelity of signals within CA1 itself, which was independent of age. Together, our findings suggest both age-dependent and independent neural contributions to spatial memory performance.

Diffusion MRI of the Hippocampus.

The hippocampus is a brain structure that plays key roles in a variety of cognitive processes. Critically, a wide range of neurological disorders are associated with degeneration of the hippocampal microstructure, defined as neurons, dendrites, glial cells, and more. Thus, the hippocampus is a key target for methods that are sensitive to these microscale properties. Diffusion MRI is one such method, which can noninvasively probe neural architecture. Here we review the extensive use of diffusion MRI to capture hippocampal microstructure in both health and disease. The results of these studies indicate that (1) diffusion tensor imaging is sensitive but not specific to the hippocampal microstructure; (2) biophysical modeling of diffusion MRI signals is a promising avenue to capture more specific aspects of the hippocampal microstructure; (3) use of ultra-short diffusion times have shown unique laminar-specific microstructure and response to hippocampal injury; (4) dispersion of microstructure is likely abundant in the hippocampus; and (5) the angular richness of the diffusion MRI signal can be leveraged to improve delineation of the internal hippocampal circuitry. Overall, extant findings suggest that diffusion MRI offers a promising avenue for characterizing hippocampal microstructure.

Chinese Verbal Fluency Deficiency in Temporal Lobe Epilepsy with and without Hippocampal Sclerosis: A Multiscale Study.

To test a Chinese character version of the phonemic verbal fluency task in patients with temporal lobe epilepsy (TLE) and assess the verbal fluency deficiency pattern in TLE with and without hippocampal sclerosis, a cross-sectional study was conducted including 30 patients with TLE and hippocampal sclerosis (TLE-HS), 28 patients with TLE and without hippocampal sclerosis (TLE-NHS), and 29 demographically matched healthy controls (HC). Both sexes were enrolled. Participants finished a Chinese character verbal fluency (VFC) task during functional MRI. The activation/deactivation maps, functional connectivity, degree centrality, and community features of the left frontal and temporal regions were compared. A neural network classification model was applied to differentiate TLE-HS and TLE-NHS using functional statistics. The VFC scores were correlated with semantic fluency in HC while correlated with phonemic fluency in TLE-NHS. Activation and deactivation deficiency was observed in TLE-HS and TLE-NHS (p < 0.001, k ≥ 10). Functional connectivity, degree centrality, and community features of anterior inferior temporal gyri were impaired in TLE-HS and retained or even enhanced in TLE-NHS (p < 0.05, FDR-corrected). The functional connectivity was correlated with phonemic fluency (p < 0.05, FDR-corrected). The neural network classification reached an area under the curve of 0.90 in diagnosing hippocampal sclerosis. The VFC task is a Chinese phonemic verbal fluency task suitable for clinical application in TLE. During the VFC task, functional connectivity of phonemic circuits was impaired in TLE-HS and was enhanced in TLE-NHS, representing a compensative phonemic searching strategy applied by patients with TLE-NHS.

The Hippocampus Represents Information about Movements in Their Temporal Position in a Learned Motor Sequence.

Our repertoire of motor skills is filled with sequential movements that need to be performed in a specific order. Here, we used functional magnetic resonance imaging to investigate whether the human hippocampus, a region known to support temporal order in non-motor memory, represents information about the order of sequential motor actions in human participants (both sexes). We also examined such representations in other regions of the motor network (i.e., the premotor cortex, supplementary motor area, anterior superior parietal lobule, and striatum) already known for their critical role in motor sequence learning. Results showed that the hippocampus represents information about movements in their learned temporal position in the sequence, but not about movements or temporal positions in random movement patterns. Other regions of the motor network coded for movements in their learned temporal position, as well as movements and positions in random movement patterns. Importantly, movement coding contributed to sequence learning patterns in primary, supplementary, and premotor cortices but not in striatal and parietal regions. Our findings deepen our understanding of how striatal and cortical regions contribute to motor sequence learning and point to the capacity of the hippocampus to represent movements in their temporal context, an ability possibly explaining its contribution to motor learning.

An Enduring Role for Hippocampal Pattern Completion in Addition to an Emergent Nonhippocampal Contribution to Holistic Episodic Retrieval after a 24†h Delay.

Episodic memory retrieval is associated with the holistic neocortical reinstatement of all event information, an effect driven by hippocampal pattern completion. However, whether holistic reinstatement occurs, and whether hippocampal pattern completion continues to drive reinstatement, after a period of consolidation is unclear. Theories of systems consolidation predict either a time-variant or time-invariant role of the hippocampus in the holistic retrieval of episodic events. Here, we assessed whether episodic events continue to be reinstated holistically and whether hippocampal pattern completion continues to facilitate holistic reinstatement following a period of consolidation. Female and male human participants learned "events" that comprised multiple overlapping pairs of event elements (e.g., person-location, object-location, location-person). Importantly, encoding occurred either immediately before or 24 h before retrieval. Using fMRI during the retrieval of events, we show evidence for holistic reinstatement, as well as a correlation between reinstatement and hippocampal pattern completion, regardless of whether retrieval occurred immediately or 24 h after encoding. Thus, hippocampal pattern completion continues to contribute to holistic reinstatement after a delay. However, our results also revealed that some holistic reinstatement can occur without evidence for a corresponding signature of hippocampal pattern completion after a delay (but not immediately after encoding). We therefore show that hippocampal pattern completion, in addition to a nonhippocampal process, has a role in holistic reinstatement following a period of consolidation. Our results point to a consolidation process where the hippocampus and neocortex may work in an additive, rather than compensatory, manner to support episodic memory retrieval.

Dissociable Contributions of the Medial Parietal Cortex to Recognition Memory.

Human neuroimaging studies of episodic memory retrieval routinely observe the engagement of specific cortical regions beyond the medial temporal lobe. Of these, medial parietal cortex (MPC) is of particular interest given its distinct functional characteristics during different retrieval tasks. Specifically, while recognition and autobiographical recall tasks are both used to probe episodic retrieval, these paradigms consistently drive distinct spatial patterns of response within MPC. However, other studies have emphasized alternate MPC functional dissociations in terms of brain network connectivity profiles or stimulus category selectivity. As the unique contributions of MPC to episodic memory remain unclear, adjudicating between these different accounts can provide better consensus regarding MPC function. Therefore, we used a precision-neuroimaging dataset (7T functional magnetic resonance imaging) to examine how MPC regions are differentially engaged during recognition memory and how these task-related dissociations may also reflect distinct connectivity and stimulus category functional profiles. We observed interleaved, though spatially distinct, subregions of MPC where responses were sensitive to either recognition decisions or the semantic representation of stimuli. In addition, this dissociation was further accentuated by functional subregions displaying distinct profiles of connectivity with the hippocampus during task and rest. Finally, we show that recent observations of dissociable person and place selectivity within the MPC reflect category-specific responses from within identified semantic regions that are sensitive to mnemonic demands. Together, by examining precision functional mapping within individuals, these data suggest that previously distinct observations of functional dissociation within MPC conform to a common principle of organization throughout hippocampal-neocortical memory systems.

Iron Deposition and Distribution Across the Hippocampus Is Associated with Pattern Separation and Pattern Completion in Older Adults at Risk for Alzheimer's Disease.

Elevated iron deposition in the brain has been observed in older adult humans and persons with Alzheimer's disease (AD), and has been associated with lower cognitive performance. We investigated the impact of iron deposition, and its topographical distribution across hippocampal subfields and segments (anterior, posterior) measured along its longitudinal axis, on episodic memory in a sample of cognitively unimpaired older adults at elevated familial risk for AD (N = 172, 120 females, 52 males; mean age = 68.8 ± 5.4 years). MRI-based quantitative susceptibility maps were acquired to derive estimates of hippocampal iron deposition. The Mnemonic Similarity Task was used to measure pattern separation and pattern completion, two hippocampally mediated episodic memory processes. Greater hippocampal iron load was associated with lower pattern separation and higher pattern completion scores, both indicators of poorer episodic memory. Examination of iron levels within hippocampal subfields across its long axis revealed topographic specificity. Among the subfields and segments investigated here, iron deposition in the posterior hippocampal CA1 was the most robustly and negatively associated with the fidelity memory representations. This association remained after controlling for hippocampal volume and was observed in the context of normal performance on standard neuropsychological memory measures. These findings reveal that the impact of iron load on episodic memory performance is not uniform across the hippocampus. Both iron deposition levels as well as its spatial distribution, must be taken into account when examining the relationship between hippocampal iron and episodic memory in older adults at elevated risk for AD.

Hippocampal Perfusion Affects Motor and Cognitive Functions in Parkinson Disease: An Early Phase 18 F-FP-CIT Positron Emission Tomography Study.

OBJECTIVE: We investigated whether hippocampal perfusion changes are associated with cognitive decline, motor deficits, and the risk of dementia conversion in patients with Parkinson disease (PD). METHODS: We recruited patients with newly diagnosed and nonmedicated PD and healthy participants who underwent dual phase 18 F-N-(3-fluoropropyl)-2ß-carboxymethoxy-3ß-(4-iodophenyl) nortropane positron emission tomography scans. Patients were classified into 3 groups according to hippocampal perfusion measured by standard uptake value ratios (SUVRs): (1) PD hippocampal hypoperfusion group (1 standard deviation [SD] below the mean hippocampal SUVR of healthy controls; PD-hippo-hypo), (2) PD hippocampal hyperperfusion group (1 SD above the mean; PD-hippo-hyper), and (3) the remaining patients (PD-hippo-normal). We compared the baseline cognitive performance, severity of motor deficits, hippocampal volume, striatal dopamine transporter (DAT) availability, and risk of dementia conversion among the groups. RESULTS: We included 235 patients (PD-hippo-hypo, n = 21; PD-hippo-normal, n = 157; PD-hippo-hyper, n = 57) and 48 healthy participants. Patients in the PD-hippo-hypo group were older and had smaller hippocampal volumes than those in the other PD groups. The PD-hippo-hypo group showed less severely decreased DAT availability in the putamen than the other groups despite similar severities of motor deficit. The PD-hippo-hypo group had a higher risk of dementia conversion compared to the PD-hippo-normal (hazard ratio = 2.59, p = 0.013) and PD-hippo-hyper (hazard ratio = 3.73, p = 0.006) groups, despite similar cognitive performance at initial assessment between groups. INTERPRETATION: Hippocampal hypoperfusion may indicate a reduced capacity to cope with neurodegenerative processes in terms of the development of motor deficits and cognitive decline in patients with PD. ANN NEUROL 2024;95:388-399.

Cognitive Trajectories and Alzheimer Disease Biomarkers: From Successful Cognitive Aging to Clinical Impairment.

OBJECTIVE: Cross-sectional definitions of successful cognitive aging have been widely utilized, but longitudinal measurements can identify people who do not decline. We performed this study to contrast maintenance with declining trajectories, including clinical conversion. METHODS: We included baseline cognitively unimpaired Alzheimer's Disease Neuroimaging Initiative participants with 3 or more cognitive testing sessions (n = 539, follow-up 6.1 ± 3.5 years) and calculated slopes of an episodic memory composite (MEM) to classify them into two groups: maintainers (slope ≥ 0) and decliners (slope < 0). Within decliners, we examined a subgroup of individuals who became clinically impaired during follow-up. These groups were compared on baseline characteristics and cognitive performance, as well as both cross-sectional and longitudinal Alzheimer disease (AD) biomarker measures (beta-amyloid [Aß], tau, and hippocampal volume). RESULTS: Forty-one percent (n = 221) of the cohort were MEM maintainers, and 33% (n = 105) of decliners converted to clinical impairment during follow-up. Compared to those with superior baseline scores, maintainers had lower education and were more likely to be male. Maintainers and decliners did not differ on baseline MEM scores, but maintainers did have higher non-MEM cognitive scores. Maintainers had lower baseline global Aß, lower tau pathology, and larger hippocampal volumes than decliners, even after removing converters. There were no differences in rates of change of any AD biomarkers between any cognitive trajectory groups except for a higher rate of hippocampal atrophy in clinical converters compared to maintainers. INTERPRETATION: Using longitudinal data to define cognitive trajectory groups reduces education and sex bias and reveals the prognostic importance of early onset of accumulation of AD pathology. ANN NEUROL 2024;96:378-389.

Population imaging of neural activity in awake behaving mice.

A longstanding goal in neuroscience has been to image membrane voltage across a population of individual neurons in an awake, behaving mammal. Here we describe a genetically encoded fluorescent voltage indicator, SomArchon, which exhibits millisecond response times and is compatible with optogenetic control, and which increases the sensitivity, signal-to-noise ratio, and number of neurons observable several-fold over previously published fully genetically encoded reagents1-8. Under conventional one-photon microscopy, SomArchon enables the routine population analysis of around 13 neurons at once, in multiple brain regions (cortex, hippocampus, and striatum) of head-fixed, awake, behaving mice. Using SomArchon, we detected both positive and negative responses of striatal neurons during movement, as previously reported by electrophysiology but not easily detected using modern calcium imaging techniques9-11, highlighting the power of voltage imaging to reveal bidirectional modulation. We also examined how spikes relate to the subthreshold theta oscillations of individual hippocampal neurons, with SomArchon showing that the spikes of individual neurons are more phase-locked to their own subthreshold theta oscillations than to local field potential theta oscillations. Thus, SomArchon reports both spikes and subthreshold voltage dynamics in awake, behaving mice.

Dissociable contributions of the hippocampus and orbitofrontal cortex to representing task space in a social context.

The hippocampus (HC) and the orbitofrontal cortex (OFC) jointly encode a map-like representation of a task space to guide behavior. It remains unclear how the OFC and HC interact in encoding this map-like representation, though previous studies indicated that both regions have different functions. We acquired the functional magnetic resonance imaging data under a social navigation task in which participants interacted with characters in a two-dimensional "social space." We calculate the social relationships between the participants and characters and used a drift-diffusion model to capture the inner process of social interaction. Then we used multivoxel pattern analysis to explore the brain-behavior relationship. We found that (i) both the HC and the OFC showed higher activations during the selective trial than the narrative trial; (ii) the neural pattern of the right HC was associated with evidence accumulation during social interaction, and the pattern of the right lateral OFC was associated with the social relationship; (iii) the neural pattern of the HC can decode the participants choices, while the neural pattern of the OFC can decode the task information about trials. The study provided evidence for distinct roles of the HC and the OFC in encoding different information when representing social space.

Sex- and age-based differences in fetal and early childhood hippocampus maturation: a cross-sectional and longitudinal analysis.

The hippocampus, essential for cognitive and affective processes, develops exponentially with differential trajectories seen in girls and boys, yet less is known about its development during early fetal life until early childhood. In a cross-sectional and longitudinal study, we examined the sex-, age-, and laterality-related developmental trajectories of hippocampal volumes in fetuses, infants, and toddlers associated with age. Third trimester fetuses (27-38 weeks' gestational age), newborns (0-4 weeks' postnatal age), infants (5-50 weeks' postnatal age), and toddlers (2-3 years postnatal age) were scanned with magnetic resonance imaging. A total of 133 datasets (62 female, postmenstrual age [weeks] M = 69.38, SD = 51.39, range = 27.6-195.3) were processed using semiautomatic segmentation methods. Hippocampal volumes increased exponentially during the third trimester and the first year of life, beginning to slow at approximately 2 years. Overall, boys had larger hippocampal volumes than girls. Lateralization differences were evident, with left hippocampal growth beginning to plateau sooner than the right. This period of rapid growth from the third trimester, continuing through the first year of life, may support the development of cognitive and affective function during this period.

The associations of peripheral interleukin alterations and hippocampal subfield volume deficits in schizophrenia.

The hippocampus is one of the brain regions most vulnerable to inflammatory insults, and the relationships between peripheral inflammation and hippocampal subfields in patients with schizophrenia remain unclear. In this study, forty-six stably medicated patients with schizophrenia and 48 demographically matched healthy controls (HCs) were recruited. The serum levels of IL - 1ß, IL-6, IL-10, and IL-12p70 were measured, and 3D high-resolution T1-weighted magnetic resonance imaging was performed. The IL levels and hippocampal subfield volumes were both compared between patients and HCs. The associations of altered IL levels with hippocampal subfield volumes were assessed in patients. Patients with schizophrenia demonstrated higher serum levels of IL-6 and IL-10 but lower levels of IL-12p70 than HCs. In patients, the levels of IL-6 were positively correlated with the volumes of the left granule cell layer of the dentate gyrus (GCL) and cornu Ammonis (CA) 4, while the levels of IL-10 were negatively correlated with the volumes of those subfields. IL-6 and IL-10 might have antagonistic roles in atrophy of the left GCL and CA4. This suggests a complexity of peripheral cytokine dysregulation and the potential for its selective effects on hippocampal substructures, which might be related to the pathophysiology of schizophrenia.

Sense of own body shapes neural processes of memory encoding and reinstatement.

How is the fundamental sense of one's body, a basic aspect of selfhood, incorporated into memories for events? Disrupting bodily self-awareness during encoding impairs functioning of the left posterior hippocampus during retrieval, which implies weakened encoding. However, how changes in bodily self-awareness influence neural encoding is unknown. We investigated how the sense of body ownership, a core aspect of the bodily self, impacts encoding in the left posterior hippocampus and additional core memory regions including the angular gyrus. Furthermore, we assessed the degree to which memories are reinstated according to body ownership during encoding and vividness during retrieval as a measure of memory strength. We immersed participants in naturalistic scenes where events unfolded while we manipulated feelings of body ownership with a full-body-illusion during functional magnetic resonance imaging scanning. One week later, participants retrieved memories for the videos during functional magnetic resonance imaging scanning. A whole brain analysis revealed that patterns of activity in regions including the right hippocampus and angular gyrus distinguished between events encoded with strong versus weak body ownership. A planned region-of-interest analysis showed that patterns of activity in the left posterior hippocampus specifically could predict body ownership during memory encoding. Using the wider network of regions sensitive to body ownership during encoding and the left posterior hippocampus as separate regions-of-interest, we observed that patterns of activity present at encoding were reinstated more during the retrieval of events encoded with strong body ownership and high memory vividness. Our results demonstrate how the sense of physical self is bound within an event during encoding, which facilitates reactivation of a memory trace during retrieval.

Unlocking the link: how hippocampal glutathione-glutamate coupling predicts cognitive impairment in multiple sclerosis patients.

Cognitive impairment is a common symptom of multiple sclerosis and profoundly impacts quality of life. Glutathione (GSH) and glutamate (Glu) are tightly linked in the brain, participating in cognitive function. However, GSH-Glu couplings in cognitive brain regions and their relationship with cognitive impairment in relapsing-remitting multiple sclerosis (RRMS) remains unclear. Forty-one RRMS patients and 43 healthy controls underwent magnetic resonance spectroscopy to measure GSH and Glu levels in the posterior cingulate cortex, medial prefrontal cortex and left hippocampus. Neuropsychological tests were used to evaluate the cognitive function. The Glu/GSH ratio was used to indicate the coupling between GSH and Glu and was tested as a predictor of cognitive performance. The results show that RRMS patients exhibited reduced hippocampal GSH and Glu levels, which were found to be significant predictors of worse verbal and visuospatial memory, respectively. Moreover, GSH levels were dissociated from Glu levels in the left hippocampus of RRMS patients. Hippocampal Glu/GSH ratio is significantly correlated with processing speed and has a greater predictive effect. Here we show the hippocampal Glu/GSH ratio could serve as a new potential marker for characterizing cognitive impairment in RRMS, providing a new direction for clinical detection of cognitive impairment.

Interactions between physical exercise, associative memory, and genetic risk for Alzheimer's disease.

The ε4 allele of the APOE gene heightens the risk of late onset Alzheimer's disease. ε4 carriers, may exhibit cognitive and neural changes early on. Given the known memory-enhancing effects of physical exercise, particularly through hippocampal plasticity via endocannabinoid signaling, here we aimed to test whether a single session of physical exercise may benefit memory and underlying neurophysiological processes in young ε3 carriers (ε3/ε4 heterozygotes, risk group) compared with a matched control group (homozygotes for ε3). Participants underwent fMRI while learning picture sequences, followed by cycling or rest before a memory test. Blood samples measured endocannabinoid levels. At the behavioral level, the risk group exhibited poorer associative memory performance, regardless of the exercising condition. At the brain level, the risk group showed increased medial temporal lobe activity during memory retrieval irrespective of exercise (suggesting neural compensatory effects even at baseline), whereas, in the control group, such increase was only detectable after physical exercise. Critically, an exercise-related endocannabinoid increase correlated with task-related hippocampal activation in the control group only. In conclusion, healthy young individuals carrying the ε4 allele may present suboptimal associative memory performance (when compared with homozygote ε3 carriers), together with reduced plasticity (and functional over-compensation) within medial temporal structures.