Biology subjects

Graham, K. S.

Publications and source records attributed to Graham, K. S..

14 recordsLinked to original sources

bioRxiv2025

Fornix subdivisions and spatial learning: a diffusion MRI study

The fornix is the major white matter tract linking the hippocampal formation with distal brain sites. Human and animal lesion studies show that the connections comprising the fornix are vital for specific attributes of episodic and spatial memory. The fornix, however, interconnects the hippocampal formation with an array of subcortical and cortical sites and it is not known which specific connections support spatial-mnemonic function. To address this, making use of a partly previously published dataset (Hodgetts et al., 2020), we applied a novel deterministic tractography protocol to diffusion-weighted magnetic resonance imaging (dMRI) data from a group of healthy young adult humans who separately completed a desktop-based virtual reality analogue of the Morris water maze task. The tractography protocol enabled the two main parts of the fornix, delineated previously in axonal tracing studies in rodents and primates, to be reconstructed in vivo, namely the pre-commissural fornix (connecting the hippocampus to the medial prefrontal cortex and the basal forebrain) and the post-commissural fornix (connecting the hippocampus to the medial diencephalon). We found that inter-individual differences in pre-commissural - but not, surprisingly, post-commissural - fornix microstructure (indexed by free water corrected fractional anisotropy, FA) were significantly correlated with individual differences in spatial learning, indexed by reduction in search error as individuals learned to navigate to a hidden target location from multiple starting points. This study provides novel evidence that flexible and/or precise spatial learning involves a hippocampal-basal forebrain/prefrontal network underpinned in part by the pre-commissural fornix.

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bioRxiv2024

Multimodal MEG and microstructure-MRI investigations of the human hippocampal scene network

Although several studies have demonstrated that perceptual discrimination of complex scenes relies on an extended hippocampal network, distinct from an anterotemporal network supporting the perceptual discrimination of faces, we currently have limited insight into the specific functional and structural properties of these networks. Here, combining electrophysiological (magnetoencephalography, MEG) and microstructural (multi-shell diffusion MRI, dMRI) imaging in healthy human adults (30 female/10 male), we show that both hippocampal theta power modulation and fibre restriction of the fornix (a major input/output pathway of the hippocampus) independently related to accuracy during scene, but not face, perceptual discrimination. Conversely, microstructural features of the inferior longitudinal fasciculus (a long-range occipito- anterotemporal tract) correlated with face, but not scene, perceptual discrimination accuracy. Our results provide new mechanistic insight into the neurocognitive systems underpinning complex scene and face perception, providing support for multiple-system representation-based accounts of the medial temporal lobe. Significance StatementIn contrast to theories positing segregated cortical areas for perception and memory, the specialized representations of the hippocampus may support both the perception and memory of visual scenes. To investigate, we utilised the unique window into hippocampal electrophysiological activity offered by Magnetoencephalography (MEG). We found hippocampal theta activity modulations in the hippocampus and posteromedial cortex during scene, versus face and shape-size, perceptual oddity discrimination, the magnitude of which correlated with scene, but not face or shape- size, discrimination accuracy. Moreover, multimodal white matter imaging revealed that tissue restriction of the fornix - the major hippocampal output tract - independently predicted scene discrimination performance. Our multimodal MEG-microstructure study provides novel evidence that the hippocampus and connected structures conjointly support online scene processing.

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bioRxiv2023

Scene-selectivity in CA1/subicular complex: Multivoxel pattern analysis at 7T

Prior univariate functional magnetic resonance imaging (fMRI) studies in humans suggest that the anteromedial subicular complex of the hippocampus is a hub for scene-based cognition. However, it is possible that univariate approaches were not sufficiently sensitive to detect scene-related activity in other subfields that have been implicated in spatial processing (e.g., CA1). Further, as connectivity-based functional gradients in the hippocampus do not respect classical subfield boundary definitions, category sensitivity may be distributed across anatomical subfields. Region-of-interest approaches, therefore, may limit our ability to observe category selectivity across discrete subfield boundaries. To address these issues, we applied searchlight multivariate pattern analysis to 7T fMRI data of healthy adults who undertook a simultaneous visual odd-one-out discrimination task for scene and non-scene (including face) visual stimuli, hypothesising that scene classification would be possible in multiple hippocampal regions within, but not constrained to, anteromedial subicular complex and CA1. Indeed, we found that the scene-selective searchlight map overlapped not only with anteromedial subicular complex (distal subiculum, pre/para subiculum), but also inferior CA1, alongside retrosplenial and parahippocampal cortices. Probabilistic overlap maps revealed gradients of scene category selectivity, with the strongest overlap located in the medial hippocampus, converging with searchlight findings. This was contrasted with gradients of face category selectivity, which had stronger overlap in more lateral hippocampus, supporting ideas of parallel processing streams for these two categories. Our work helps to map the scene, in contrast to, face processing networks within, and connected to, the human hippocampus.

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bioRxiv2023

Intrinsic functional connections determine how curiosity and prediction errors enhance memory

Individuals differ in the way they seek information, acquire knowledge, and form memories. Neural finger-prints of intrinsic functional connectivity distinguish between individuals and predict inter-individual differences in task performance. Both curiosity - the desire to acquire new information - and information prediction errors (IPEs) - the mismatch between information and previous expectations - enhance memory but differ considerably between individuals. The present study assessed whether inter-individual differences in functional connectivity measured using resting-state fMRI determine the extent to which individuals benefit from memory-enhancing effects of curiosity and IPEs. We found a double dissociation between individual differences in mesolimbic functional connectivity, which accounted for curiosity-driven but not IPE-related memory enhancements, and individual differences in cingulo-hippocampal functional connectivity, which predicted IPE-driven but not curiosity-related memory enhancements. These novel findings on how inter-individual differences in dissociable intrinsic functional networks determine memory enhancements stress the need to account for these differences in theoretical frameworks of curiosity and memory.

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bioRxiv2022

A Role for the Fornix in Temporal Sequence Memory

Converging evidence from studies of human and nonhuman animals suggests that the hippocampus contributes to sequence learning by using temporal context to bind sequentially occurring items. The fornix is a white matter pathway containing the major input and output pathways of the hippocampus, including projections from medial septum, and to diencephalon, striatum, and prefrontal cortex. If the fornix meaningfully contributes to hippocampal function, then individual differences in fornix microstructure might predict sequence memory. Here, we tested this prediction by performing tractography in 51 healthy adults who had undertaken a sequence memory task. Microstructure properties of the fornix were compared with those of tracts connecting medial temporal lobe regions, but not predominantly the hippocampus: the Parahippocampal Cingulum bundle (PHC) (conveying retrosplenial projections to parahippocampal cortex) and the Inferior Longitudinal Fasciculus (ILF) (conveying occipital projections to perirhinal cortex). Using principal components analysis, we combined Diffusion Tensor Imaging and Neurite Orientation Dispersion and Density Imaging measures obtained from multi-shell diffusion MRI into two informative indices, the first (PC1) capturing axonal packing/myelin, the second (PC2) capturing microstructural complexity. We found a significant correlation between fornix PC2 and implicit reaction-time indices of sequence memory, indicating that greater fornix microstructural complexity is associated with better sequence memory. No such relationship was found with measures from the PHC and ILF. This study highlights the importance of the fornix in aiding memory for objects within a temporal context, potentially reflecting a role in mediating network communication within an extended hippocampal system.

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bioRxiv2022

Tract-specific white matter microstructure alterations among young adult APOE ε4 carriers: A replication and extension study

The parahippocampal cingulum bundle (PHCB) connects regions known to be vulnerable to early Alzheimers disease (AD) pathology, such as posteromedial cortex and medial temporal lobe. While AD-related pathology has been robustly associated with alterations in PHCB microstructure, specifically lower fractional anisotropy (FA) and higher mean diffusivity (MD), emerging evidence indicates that the reverse pattern is evident in younger adults at-risk of AD. In one such study, Hodgetts et al. (2019) reported that healthy young adult carriers of the apolipoprotein-E (APOE) {varepsilon}4 allele - the strongest common genetic risk factor for AD - showed higher FA and lower MD in the PHCB but not the inferior longitudinal fasciculus (ILF). These results are consistent with proposals claiming that heightened neural activity and connectivity have a significant role in posteromedial cortex vulnerability to amyloid-{beta} and tau spread beyond the medial temporal lobe. Given the implications for understanding AD risk, here we sought to replicate Hodgetts et al.s finding in a larger sample (N = 128; 40 APOE {varepsilon}4 carriers, 88 APOE {varepsilon}4 non-carriers) of young adults (age range: 19-33). Extending this work further, we also conducted exploratory analyses using a more advanced measure of microstructure: hindrance modulated orientational anisotropy (HMOA). These analyses included an investigation of hemispheric asymmetry in PHCB and ILF HMOA. Contrary to the original study, we observed no difference in PHCB microstructure between APOE {varepsilon}4 carriers and non-carriers. Bayes factors (BFs) further revealed moderate-to-strong evidence in support of these null findings. APOE {varepsilon}4-related differences in ILF HMOA asymmetry were evident, however, with carriers demonstrating lower leftward asymmetry. Our findings indicate that young adult APOE {varepsilon}4 carriers do not show alterations in PHCB microstructure, as observed by Hodgetts et al., but may show altered asymmetry in ILF microstructure.

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bioRxiv2021

Evidence against altered excitatory/inhibitory balance in the posteromedial cortex of young adult APOE E4 carriers: a resting state 1H-MRS study

A strategy to gain insight into early changes that may predispose people to Alzheimers disease is to study the brains of younger cognitively healthy people that are at increased genetic risk of AD. The Apolipoprotein (APOE) E4 allele is the strongest genetic risk factor for AD, and several neuroimaging studies comparing APOE E4 carriers with non-carriers at age ~20-30 have detected hyperactivity (or reduced deactivation) in posteromedial cortex (PMC), a key hub of the default network (DN) which has a high susceptibility to early amyloid deposition in AD. Transgenic mouse models suggest such early network activity alterations may result from altered excitatory/inhibitory (E/I) balance, but this is yet to be examined in humans. Here we test the hypothesis that PMC fMRI hyperactivity could be underpinned by altered levels of excitatory (glutamate) and/or inhibitory (GABA) neurotransmitters in this brain region. Forty-seven participants (20 APOE E4 carriers and 27 non-carriers) aged 18-25 underwent resting-state proton magnetic resonance spectroscopy (1H-MRS), a non-invasive neuroimaging technique to measure glutamate and GABA in vivo. Metabolites were measured in a PMC voxel of interest and in a comparison voxel in the occipital cortex (OCC). There was no difference in either glutamate or GABA between the E4 carriers and non-carriers in either MRS voxel, nor in the ratio of glutamate to GABA, a measure of E/I balance. Default Bayesian t-tests revealed evidence in support of this null finding. Results suggest that PMC hyperactivity in APOE E4 carriers is unlikely to be associated with, or indeed may precede, alterations in local resting-state PMC neurotransmitters, thus informing the spatio-temporal order and the cause/effect dynamic of neuroimaging differences in APOE E4 carriers. HighlightsO_LIHyperactivity in posteromedial (PM) network in people at AD genetic risk (APOE E4) C_LIO_LISuch PM network hyperactivity may initiate pathogenic cascade that triggers AD C_LIO_LIAPOE mouse models suggest hyperactivity driven by excitatory/inhibitory imbalance C_LIO_LIUsing 1H-MRS at 3T we studied PMC E/I balance in young adult APOE E4 carriers C_LIO_LIFound evidence against altered E/I balance in young adult APOE E4 carriers C_LI

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bioRxiv2020

Brain-Environment Alignment during Movie Watching Predicts Cognitive-Affective Function in Adulthood

BOLD fMRI studies have provided compelling evidence that the human brain demonstrates substantial moment-to-moment fluctuations in both activity and functional connectivity patterns. While the role of brain signal variability in fostering cognitive adaptation to ongoing environmental demands is well-documented, the relevance of moment-to-moment changes in functional brain architecture is still debated. To probe the role of architectural variability in naturalistic information processing, we used neuroimaging and behavioural data collected during movie watching by the Cambridge Centre for Ageing and Neuroscience (N = 642, 326 women) and the Human Connectome Project (N = 176, 106 women). Both moment-to-moment and contextual change-evoked architectural variability increased from young to older adulthood. However, coupling between moment-to-moment changes in functional brain architecture and concrete environmental features was stronger at younger ages. Architectural variability (both momentary and context-evoked) was associated with age-distinct profiles of network communication, specifically, greater functional integration of the default mode network in older adulthood, but greater informational flow across neural networks implicated in environmentally driven attention and control (cingulo-opercular, salience, ventral attention) in younger adulthood. Whole-brain communication pathways anchored in default mode regions relevant to episodic and semantic context creation (i.e., angular and middle temporal gyri) contributed to greater brain reconfiguration in response to narrative context changes, as well as stronger coupling between moment-to-moment changes in functional brain architecture and changes in concrete environmental features. Cognitive adaptation was directly linked to levels of brain-environment alignment, but only indirectly associated with levels of architectural variability. Specifically, stronger coupling between moment-to-moment variability in brain architecture and concrete environmental features predicted poorer cognitive adaptation (i.e., fluid IQ) and greater affectively driven environmental vigilance. Complementarily, across the adult lifespan, higher fluid (but not crystallized) IQ was related to stronger expression of the network communication profile underlying momentary and context-based architectural variability during youth. Our results indicate that the adaptiveness of dynamic brain reconfiguration during naturalistic information processing changes across the lifespan due to the associated network communication profiles. Moreover, our findings on brain-environment alignment complement the existing literature on the beneficial consequences of modulating brain signal variability in response to environmental complexity. Specifically, they imply that coupling between moment-to-moment variability in functional brain architecture and concrete environmental features may index a bias towards perceptually-bound, rather than conceptual processing, which hinders affective functioning and strategic engagement with the external environment.

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bioRxiv2019

The role of the pre-commissural fornix in episodic autobiographical memory and simulation

Neuropsychological and functional magnetic resonance imaging (MRI) evidence suggests that the ability to vividly remember our personal past, and imagine future scenarios, involves two closely connected regions: the hippocampus and ventromedial prefrontal cortex (vmPFC). Despite evidence of a direct anatomical connection from hippocampus to vmPFC, it is unknown whether hippocampal-vmPFC structural connectivity supports both past and future-oriented episodic thinking. To address this, we applied diffusion-weighted magnetic resonance imaging (dMRI) and a novel deterministic tractography protocol to reconstruct distinct subdivisions of the fornix previously detected in axonal tracer studies, namely pre-commissural (connecting the hippocampus to vmPFC) and post-commissural (linking the hippocampus and medial diencephalon) fornix, in a group of healthy young adult humans who undertook an adapted past-future autobiographical interview. As predicted, we found that inter-individual differences in pre-commissural - but not post-commissural - fornix microstructure (fractional anisotropy) was significantly correlated with the episodic richness of both past and future autobiographical narratives. Notably, these results remained significant when controlling for both non-episodic narrative content and grey matter volumes of the hippocampus and vmPFC. This study provides novel evidence that reconstructing events from ones personal past, and constructing possible future events, involves a distinct, structurally-instantiated hippocampal-vmPFC pathway. Significance StatementA novel anatomically-guided protocol that allows the pre-commissural and post-commissural fornix fibers to be separately reconstructed in vivo (Christiansen et al., 2016) was applied to reconstruct the pre-commissural subdivision of the white matter fornix tract (anatomically linking the hippocampal formation to the vmPFC) and investigate its contribution to episodic memory and future simulation. We demonstrated that the amount of episodic details contained in past and future narratives, collected via an adapted autobiographical interview, was positively correlated with pre-, but not post-, commissural fornix microstructure. These findings highlight how inter-individual variation in the pre-commissural subdivision of the fornix underpins the construction of self-reflective, contextual events - for both the past and future.

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bioRxiv2019

Curious connections: white matter pathways supporting individual differences in epistemic and perceptual curiosity

Across the lifespan, curiosity motivates us to learn, yet curiosity varies strikingly between individuals. Such individual differences have been shown for two distinct dimensions of curiosity: epistemic curiosity (EC), the desire to acquire conceptual knowledge, and perceptual curiosity (PC), the desire for sensory information. It is not known, however, whether both dimensions of curiosity depend on different brain networks and whether inter-individual differences in curiosity depend on variation in anatomical connectivity within these networks. Here, we investigated the neuroanatomical connections underpinning individual variation in trait curiosity. Fifty-one female participants underwent a two-shell diffusion MRI sequence and completed questionnaires measuring EC and PC. Using deterministic spherical deconvolution tractography we extracted microstructural metrics (fractional anisotropy (FA) and mean diffusivity (MD)) from two key white matter tracts: the fornix (implicated in novelty processing, exploration, information seeking and episodic memory) and the inferior longitudinal fasciculus (ILF) (implicated in semantic learning and memory). In line with our predictions, we found that EC - but not PC - correlated with ILF microstructure. Fornix microstructure, in contrast, correlated with both EC and PC, with posterior hippocampal fornix fibres - associated with posterior hippocampal network connectivity - linked to PC specifically. These findings suggest that differences in distinct dimensions of curiosity map systematically onto specific white matter tracts underlying well characterized brain networks. Furthermore, the results pave the way to study the anatomical substrates of inter-individual differences in dimensions of trait curiosity that motivate the learning of distinct forms of knowledge and skills.

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bioRxiv2018

Cognitive and white-matter compartment models revealed the contribution of microstructural variability along sensorimotor tracts to simple reaction time

The speed of voluntary reaction to an external stimulus varies substantially between individuals and is impaired in ageing. However, the neuroanatomical origins of inter-individual variability in reaction time (RT) remain largely unknown. Here, we combined a cognitive model of RT and a biophysical compartmental model of diffusion-weighted MRI (DWI) to characterize the relationship between RT and microstructure of the corticospinal tract (CST) and the optic radiation (OR), the primary motor output and visual input pathways associated with visual-motor responses.\n\nWe fitted an accumulator model of RT to 46 female participants behavioral performance in a simple reaction time task. The non-decision time parameter (Ter) derived from the model was used to account for the latencies of stimulus encoding and action initiation. From multi-shell DWI data, we quantified tissue microstructure of the CST and OR with the neurite orientation dispersion and density imaging (NODDI) model as well as the conventional diffusion tensor imaging (DTI) model.\n\nUsing novel skeletonization and segmentation approaches, we showed that DWI-based microstructure metrics varied substantially along CST and OR. The Ter of individual participants was negatively correlated with the NODDI measure of the neurite density in the bilateral superior CST. At an uncorrected threshold, the Ter positively correlated with the DTI measure of fractional anisotropy in an anterior segment of left OR. Further, we found no significant correlation between the microstructural measures and mean RT. Thus, our findings suggest a link between the inter-individual variability of sensorimotor speed and selective microstructural properties in white matter tracts.

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bioRxiv2018

Neurochemical correlates of scene processing in the precuneus/posterior cingulate cortex: a multimodal fMRI and 1H-MRS study

Precuneus/posterior cingulate cortex (PCu/PCC) are key components of a midline network, activated during rest but also in tasks that involve construction of scene or situation models. Despite growing interest in PCu/PCC functional alterations in disease, the underlying neurochemical modulators of PCu/PCCs task-induced activity are largely unstudied. Here, a multimodal imaging approach was applied to investigate whether inter-individual differences in PCu/PCC fMRI activity, elicited during perceptual discrimination of scene stimuli, were correlated with local brain metabolite levels, measured during resting-state 1H-MRS. Forty healthy young adult participants (12 male) completed an fMRI perceptual odd-one-out task for scenes, objects and faces. 1H-MRS metabolites N-acetyl-aspartate (tNAA), glutamate (Glx) and {gamma}-amino-butyric acid (GABA+) were quantified via PRESS and MEGA-PRESS scans in a PCu/PCC voxel and an occipital (OCC) control voxel. Whole brain fMRI revealed a cluster in right dorsal PCu/PCC that showed a greater BOLD response to scenes versus faces and objects. When extracted from an independently defined PCu/PCC region of interest, scene activity (versus faces and objects and also versus baseline) was positively correlated with PCu/PCC, but not OCC, tNAA. A complementary fMRI analysis restricted to the PCu/PCC MRS voxel area identified a significant PCu/PCC cluster, confirming the positive correlation between scene-related BOLD activity and PCu/PCC tNAA. There were no correlations between PCu/PCC fMRI activity and Glx or GABA+ levels. These results demonstrate, for the first time, that scene activity in PCu/PCC is linked to local tNAA levels, identifying a neurochemical influence on inter-individual differences in the task-driven activity of a key brain hub.

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bioRxiv2018

The role of the fornix in human navigational learning

Studies in rodents have demonstrated that transecting the white matter pathway linking the hippocampus and anterior thalamic nuclei - the fornix - impairs flexible navigational learning in the Morris Water Maze (MWM), as well as similar spatial learning tasks. While diffusion MRI studies in humans have linked fornix microstructure to scene discrimination and memory, its role in human navigation is currently unknown. We used high-angular resolution diffusion MRI to ask whether inter-individual differences in fornix microstructure would be associated with spatial learning in a virtual MWM task. To increase sensitivity to individual learning across trials, we adopted a novel curve fitting approach to estimate a single index of learning rate. We found a significant correlation between learning rate and the microstructure (mean diffusivity) of the fornix, but not that of a control tract linking occipital and anterior temporal cortices (the inferior longitudinal fasciculus, ILF). Further, this correlation remained significant when controlling for hippocampal volume. These findings extend previous animal studies by demonstrating the functional relevance of the fornix for human navigational learning, and highlight the importance of a distributed neuroanatomical network, underpinned by key white matter pathways, such as the fornix, in complex spatial behaviour.

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bioRxiv2018

Increased posterior default mode network activity and structural connectivity in young adult APOE-ε4 carriers: a multi-modal imaging investigation

Young adult APOE-{varepsilon}4 carriers show increased activity in posterior regions of the default mode network (pDMN), but how this is related to structural connectivity is unknown. Thirty young adults (half APOE-{varepsilon}4 carriers, the other half APOE-{varepsilon}3{varepsilon}3/{varepsilon}2{varepsilon}3; mean age 20 years) were scanned using both diffusion and functional magnetic resonance imaging. Diffusion tractography was used to quantify the microstructure (mean diffusivity, MD; fractional anisotropy, FA) of the parahippocampal cingulum bundle (PHCB), which links pDMN and the medial temporal lobe. APOE-{varepsilon}4 carriers had lower MD and higher FA relative to non-carriers in PHCB. Further, PHCB microstructure was selectively associated with pDMN activity during a scene discrimination task known to be sensitive to Alzheimers disease (AD). These findings are consistent with a lifespan view of AD risk, where early-life structural and functional brain changes in specific, vulnerable networks leads to increased neural activity that may ultimately trigger amyloid-{beta} deposition.

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