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Schematic of the principal components of the fornix and the main areas to which it connects. The black rings represent the placement of the various AND and NOT gates used for the tract reconstructions, as well as the seed ring around the body of the fornix. Abbreviations: MB, mammillary bodies.
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The fornix connects the hippocampal formation with structures beyond the temporal lobe. Previous tractography studies have typically reconstructed the fornix as one unified bundle. However, the fornix contains two rostral divisions: the precommissural fornix and the postcommissural fornix. Each division has distinct anatomical connections and, henc...
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... majority of previous studies into age and disease related chang- es in fornix microstructure, including their relationships with episodic memory, have treated the fornix as a unified tract. Anatomical studies show, however, that the rostral fornix separates into two main branches, split by the anterior commissure ( Poletti and Creswell, 1977; Fig. 1). The precommissural fornix principally innervates the basal forebrain (including the septum), ventral striatum and prefrontal cortex, as well as containing fibres projecting from the septum to the hippocampus. Meanwhile, the postcommissural fornix principally in- nervates the anterior thalamus and the mammillary bodies ( Poletti and ...Context 2
... and postcommissural divisions contain roughly similar numbers of fibres (Daitz, 1953;Powell et al., 1957). It can be anticipated that the postcommissural reconstructions predominantly involved the con- nections of the hippocampus with the hypothalamus, including the mammillary bodies (Poletti and Creswell, 1977;Aggleton et al., 2005; Fig. 1). Although the postcommissural fornix also contains many hippo- campal projections to the anterior thalamic nuclei (Aggleton et al,. 1986), these fibres were largely excluded from the present study as they turn caudally into the rostral thalamus, just as the columns of the fornix begin to descend (Poletti and Creswell, 1977; Fig. ...Context 3
... et al., 2005; Fig. 1). Although the postcommissural fornix also contains many hippo- campal projections to the anterior thalamic nuclei (Aggleton et al,. 1986), these fibres were largely excluded from the present study as they turn caudally into the rostral thalamus, just as the columns of the fornix begin to descend (Poletti and Creswell, 1977; Fig. ...Context 4
... running posterior to the anterior commissure were included (Fig. 2C). The delineation took advantage of how the precommissural and postcommissural fibres separate at the anterior columns of the fornix. To minimise overlap, reconstructions of the precommissural and postcommissural division only included fibres up to the crus of the for- nix ( Fig. 1), i.e., fibres bending downwards towards the medial temporal lobes and hippocampus were excluded using tract segmentation tools (the "splitter" tool) within ExploreDTI 4.8.3. This procedure was also chosen to avoid tract "jumping" in areas where tracts pass close or across each other, whereby one tract voxel "jumps" onto a neighboring ...Context 5
... striatum, basal forebrain, hypothalamus, and thalamus, along with return inputs to the hippocampus from the hypothalamus, basal forebrain, and midbrain (Poletti and Creswell, 1977;Swanson et al., 1987;Saunders and Aggleton, 2007). These various hippocampal connections differentially involve the precommissural fornix and postcommissural fornix (Fig. 1). The additional appreciation that the hip- pocampal formation has multiple functions highlights how these various connections might play different roles (O'Mara, 2005;Fanselow and Dong, 2010;Aggleton, 2012;Strange et al., 2014). For this reason, it would be valuable to distinguish hippocampal connections using in vivo imaging methods. ...Context 6
... with a more complete reconstruction of the anterior body of the fornix, the 'abFornix'. As noted, the abFornix was not simply the sum of the precommissural and postcommissural reconstructions as it could addi- tionally include the hippocampal projections to the anterior thalamus, which were excluded from the postcommissural fornix reconstructions (Fig. ...Similar publications
Purpose: To quantitatively investigate the microstructural properties of the optic nerve (ON) in vivo using diffusion magnetic resonance imaging (dMRI) tractography in an elderly population and to determine the differences between the ON diffusion properties stratified by basic demographics.
Methods: We measured fractional anisotropy (FA), mean dif...
Background: The corpus callosum (CC) is the most prominent white matter connection for interhemispheric information transfer. It is implicated in a variety of cognitive functions, which tend to decline with age. The region-specific projections of the fiber bundles with microstructural heterogeneity of the CC are associated with cognitive functions...
Diffusion weighted MRI (dMRI) provides a non invasive virtual reconstruction of the brain's white matter structures through tractography. Analyzing dMRI measures along the trajectory of white matter bundles can provide a more specific investigation than considering a region of interest or tract-averaged measurements. However, performing group analy...
The hippocampus supports multiple cognitive functions including episodic memory. Recent work has highlighted functional differences along the anterior-posterior axis of the human hippocampus but the neuroanatomical underpinnings of these differences remain unclear. We leveraged track-density imaging to systematically examine anatomical connectivity...
Background
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by age-inappropriate levels of inattention and/or hyperactivity-impulsivity (HI). ADHD has been related to differences in white matter (WM) microstructure. However, much remains unclear regarding the nature of these WM differences, and which cl...
Citations
... 19 Microstructural changes in the limbic tracts, [20][21][22] particularly in the fornix, 21,22 have already been detected among individuals with mild cognitive impairment (MCI). Moreover, altered microstructure of limbic tracts has been correlated with poorer memory function 22,23 and progression to AD. 21,[24][25][26] Diffusion magnetic resonance imaging (MRI) allows the microstructure of white matter to be studied in vivo by measuring water diffusion. 27 However, conventional diffusion tensor imaging (DTI) measures have limitations, such as partial volume effects, which may be particularly important in the AD continuum where atrophy leads to ex vacuo increases of cerebrospinal fluid and free water (FW) in brain tissue. ...
... Lower FA T and higher diffusivities in the left fornix were significantly associated with poorer RAVLT scores (Table 4). Consistent with our findings, the degree of fornix damage has been correlated with memory impairment in normal aging 23,25 and MCI. 21,22 Histopathological studies have reported degeneration of the fornix in mouse models of AD 64 and human patients with AD. 65 Congruent with the histopathological findings, DTI studies have reported fornix microstructural abnormalities in MCI and AD. ...
INTRODUCTION
The limbic system is critical for memory function and degenerates early in the Alzheimer's disease continuum. Whether obstructive sleep apnea (OSA) is associated with alterations in the limbic white matter tracts remains understudied.
METHODS
Polysomnography, neurocognitive assessment, and brain magnetic resonance imaging (MRI) were performed in 126 individuals aged 55–86 years, including 70 cognitively unimpaired participants and 56 participants with mild cognitive impairment (MCI). OSA measures of interest were the apnea‐hypopnea index and composite variables of sleep fragmentation and hypoxemia. Microstructural properties of the cingulum, fornix, and uncinate fasciculus were estimated using free water‐corrected diffusion tensor imaging.
RESULTS
Higher levels of OSA‐related hypoxemia were associated with higher left fornix diffusivities only in participants with MCI. Microstructure of the other white matter tracts was not associated with OSA measures. Higher left fornix diffusivities correlated with poorer episodic verbal memory.
DISCUSSION
OSA may contribute to fornix damage and memory dysfunction in MCI.
Highlights
Sleep apnea‐related hypoxemia was associated with altered fornix integrity in MCI.
Altered fornix integrity correlated with poorer memory function.
Sleep apnea may contribute to fornix damage and memory dysfunction in MCI.
... Only few studies (Chen et al., 2015;Christiansen et al., 2016) address the fornix across ages. A possible reason is fornix' artefact-susceptibility induced from its proximity to the cerebrospinal-fluid, while being a small tubular region. ...
... Potentially, the consequences of age-related fornix changes thereby affect functionality of a selection of brain regions, such as the hippocampus. While several studies have presented ageing-related fornix microstructure changes in humans (Chen et al., 2015;Christiansen et al., 2016) and monkeys (Peters et al., 2010) activations, metabolic, and GM changes after fornix deep-brain-stimulation, antagonizing the progression of neurodegenerative disorders (Jakobs et al., 2020). ...
... Hence, fornix changes might play an important role in known ageing-dependent temporal lobe changes, and specifically hippocampal changes for ageing-related pathological developments(Cabeza et al., 2018;Burke & Barnes, 2006;Hedden & Gabrieli, 2004; Pluvinage & Wyss-Coray, 2020). Previous studies presented agerelated fornix DTI metric changes(Chen et al., 2015;Christiansen et al., 2016;Metzler-Baddeley et al., 2019) which potentially appear prior to hippocampal volume changes(Chen et al., 2015;Metzler- Baddeley et al., 2019), and are related to declining episodic memory performance(Metzler-Baddeley et al., 2019). Hence, fornix changes potentially serve to predict future pathological development, suggesting fornix WM microstructure and changes in such as ageing biomarkers. ...
Unveiling the details of white matter (WM) maturation throughout ageing is a fundamental question for understanding the ageing brain. In an extensive comparison of brain age predictions and age-associations of WM features from different diffusion approaches, we analyzed UK Biobank diffusion magnetic resonance imaging (dMRI) data across midlife and older age (N = 35,749, 44.6-82.8 years of age). Conventional and advanced dMRI approaches were consistent in predicting brain age. WM-age associations indicate a steady microstructure degeneration with increasing age from midlife to older ages. Brain age was estimated best when combining diffusion approaches, showing different aspects of WM contributing to brain age. Fornix was found as the central region for brain age predictions across diffusion approaches in complement to forceps minor as another important region. These regions exhibited a general pattern of positive associations with age for intra axonal water fractions, axial, radial diffusivities, and negative relationships with age for mean diffusivities, fractional anisotropy, kurtosis. We encourage the application of multiple dMRI approaches for detailed insights into WM, and the further investigation of fornix and forceps as potential biomarkers of brain age and ageing.
... Using simulations, HMOA has further been shown to be more sensitive to alterations in anisotropy than either FA or MD (Dell' Acqua et al., 2013). Additional support for this assertion can be found in studies reporting that HMOA is able to detect white matter variation linked to verbal memory (Christiansen et al., 2016) and ageing (Rojkova et al., 2016) not detectable with standard diffusion tensor-derived measures. As such, we investigated whether APOE ε4 is associated with differences in PHCB and ILF HMOA, complementing the primary (replication) analyses. ...
The parahippocampal cingulum bundle (PHCB) interconnects regions known to be vulnerable to early Alzheimer's disease (AD) pathology, including 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 increased risk of AD. In one such study, Hodgetts et al. (2019) reported that healthy young adult carriers of the apolipoprotein-E (APOE) ε4 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 intrinsic connectivity play a significant role in increasing posteromedial cortex vulnerability to amyloid-β 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 ε4 carriers, 88 APOE ε4 non-carriers) of young adults (age range = 19–33). Extending this work, we also conducted an exploratory analysis using a more advanced measure of white matter microstructure: hindrance modulated orientational anisotropy (HMOA). Contrary to the original study, we did not observe higher FA or lower MD in the PHCB of APOE ε4 carriers relative to non-carriers. Bayes factors (BFs) further revealed moderate-to-strong evidence in support of these null findings. In addition, we observed no APOE ε4-related differences in PHCB HMOA. Our findings indicate that young adult APOE ε4 carriers and non-carriers do not differ in PHCB microstructure, casting some doubt on the notion that early-life variation in PHCB tract microstructure might enhance vulnerability to amyloid-β accumulation and/or tau spread.
... IACP often damages the surrounding hypothalamus tissue, including the mammillary bodies, which receive strong projections from the HF through the fornix. (Christiansen et al., 2016;Mielke et al., 2012) According to the DTI results in our study, the fornix of the IACP group showed significantly decreased FA (p = 0.001) and increased MD (p = 0.009) and RD (p = 0.003) as compared to those of the NACP group. The increased RD and MD of the white matter indicated demyelinating changes. ...
Adamantinomatous craniopharyngioma (ACPs) are rare embryonic tumors and often involve the hypothalamus. The underlying neural substrate of the hypothalamic involvement (HI)-related cognitive decline in patients with ACP is still unclear. We aimed to combine the multi-modal neuroimaging and histological characteristics of the ACP to explore the potential neural substrate of the HI-related cognitive decline. 45 patients with primary ACPs (invasive, 23; noninvasive, 22) and 52 healthy control subjects (HCs) were admitted to the cross-sectional study. No significant difference in cognitive domains was observed between HCs and patients with noninvasive ACPs (NACP). Patients with invasive ACPs (IACP) showed significantly lower working memory performance (WM, p=0.002) than patients with NACP. The WM decline was correlated with the disruption of the medial temporal lobe (MTL) subsystem in the default mode network (DMN) (r=0.45, p=0.004). The increased radial diffusivity of the fornix, indicating demyelinating process, was correlated with the disruption of the MTL subsystem (r=-0.48, p=0.002). Our study demonstrated that the fornix alterations link DMN disruption to HI-related cognitive decline in patients with ACPs. ACPs that invade the hypothalamus can provide a natural disease model to investigate the potential neural substrate of HI-related cognitive decline.
... White matter reductions in thalamus-related fiber tracts are an important biomarker of MCI. Firstly, our results show that white matter reduction in fornix and ATR during MCI, which is consistent with previous researches (Christiansen et al. 2016;Chen et al. 2020). Furthermore, we find that MD indexes of the ALIC connecting the thalamus and the subcortical nucleus, the slMFB and SCR connecting the thalamus to the frontal and parietal lobes are all increased significantly (Fig. 1). ...
Early diagnosis of mild cognitive impairment (MCI) fascinates screening high-risk Alzheimer’s disease (AD). White matter is found to degenerate earlier than gray matter and functional connectivity during MCI. Although studies reveal white matter degenerates in the limbic system for MCI, how other white matter degenerates during MCI remains unclear. In our method, regions of interest with a high level of resting-state functional connectivity with hippocampus were selected as seeds to track fibers based on diffusion tensor imaging (DTI). In this way, hippocampus-temporal and thalamus-related fibers were selected, and each fiber’s DTI parameters were extracted. Then, statistical analysis, machine learning classification, and Pearson’s correlations with behavior scores were performed between MCI and normal control (NC) groups. Results show that: 1) the mean diffusivity of hippocampus-temporal and thalamus-related fibers are significantly higher in MCI and could be used to classify 2 groups effectively. 2) Compared with normal fibers, the degenerated fibers detected by the DTI indexes, especially for hippocampus-temporal fibers, have shown significantly higher correlations with cognitive scores. 3) Compared with the hippocampus-temporal fibers, thalamus-related fibers have shown significantly higher correlations with depression scores within MCI. Our results provide novel biomarkers for the early diagnoses of AD.
... Meanwhile, diffusion imaging in humans has also helped to separate the precommissural fornix (which reaches frontal and striatal areas) from the postcommissural fornix (which reaches the mammillary bodies and anterior thalamus). Postcommissural fornix indices are more strongly associated with visual recall (Christiansen et al., 2016a) and the learning of spatial configurations (Coad et al., 2020). ...
After more than 80 years, Papez serial circuit remains a hugely influential concept,initially for emotion, but in more recent decades, for memory. Here, we show how this. circuit is anatomically and mechanistically naïve as well as outdated. We argue that a, new conceptualisation is necessitated by recent anatomical and functional findings that, emphasize the more equal, working partnerships between the anterior thalamic nuclei, and the hippocampal formation, along with their neocortical interactions in supporting, episodic memory. Furthermore, despite the importance of the anterior thalamic for mnemonic processing, there is growing evidence that these nuclei support multiple aspects of cognition, only some of which are directly associated with hippocampal function. By viewing the anterior thalamic nuclei as a multifunctional hub, a clearer picture emerges of extra-hippocampal regions supporting memory. The reformulation presented here underlines the need to retire Papez serially processing circuit.
... The white matter microstructure between the hippocampus and medial temporal lobe changes during MCI (Teipel et al., 2016;Zhuo et al., 2016;Dumont et al., 2019). The fornix connects the hippocampus to the thalamus, and its white matter degeneration leads to decreased memory function (Christiansen et al., 2016). Degeneration of the projection tracts connecting the thalamus to the prefrontal lobes leads to a decrease in executive function (Gu and Zhang, 2019;Liu et al., 2021). ...
Background
Detection of mild cognitive impairment (MCI) is essential to screen high risk of Alzheimer’s disease (AD). However, subtle changes during MCI make it challenging to classify in machine learning. The previous pathological analysis pointed out that the hippocampus is the critical hub for the white matter (WM) network of MCI. Damage to the white matter pathways around the hippocampus is the main cause of memory decline in MCI. Therefore, it is vital to biologically extract features from the WM network driven by hippocampus-related regions to improve classification performance.Methods
Our study proposes a method for feature extraction of the whole-brain WM network. First, 42 MCI and 54 normal control (NC) subjects were recruited using diffusion tensor imaging (DTI), resting-state functional magnetic resonance imaging (rs-fMRI), and T1-weighted (T1w) imaging. Second, mean diffusivity (MD) and fractional anisotropy (FA) were calculated from DTI, and the whole-brain WM networks were obtained. Third, regions of interest (ROIs) with significant functional connectivity to the hippocampus were selected for feature extraction, and the hippocampus (HIP)-related WM networks were obtained. Furthermore, the rank sum test with Bonferroni correction was used to retain significantly different connectivity between MCI and NC, and significant HIP-related WM networks were obtained. Finally, the classification performances of these three WM networks were compared to select the optimal feature and classifier.Results(1) For the features, the whole-brain WM network, HIP-related WM network, and significant HIP-related WM network are significantly improved in turn. Also, the accuracy of MD networks as features is better than FA. (2) For the classification algorithm, the support vector machine (SVM) classifier with radial basis function, taking the significant HIP-related WM network in MD as a feature, has the optimal classification performance (accuracy = 89.4%, AUC = 0.954). (3) For the pathologic mechanism, the hippocampus and thalamus are crucial hubs of the WM network for MCI.Conclusion
Feature extraction from the WM network driven by hippocampus-related regions provides an effective method for the early diagnosis of AD.
... A valuable refinement has allowed the isolation of the postcommissural fornix (Supplementary Box 1), which principally contains hippocampal projections to the anterior thalamic nuclei and mammillary bodies. Such studies have found correlations between the properties of this pathway and aspects of memory, including visual recall 165 and types of spatial learning 166 , suggesting that the functions of the postcommissural fornix differ from those of the precommissural fornix (which links the hippocampus with septal, striatal and frontal sites). ...
Standard models of episodic memory focus on hippocampal–parahippocampal interactions, with the neocortex supplying sensory information and providing a final repository of mnemonic representations. However, recent advances have shown that other regions make distinct and equally critical contributions to memory. In particular, there is growing evidence that the anterior thalamic nuclei have a number of key cognitive functions that support episodic memory. In this article, we describe these findings and argue for a core, tripartite memory system, comprising a ‘temporal lobe’ stream (centred on the hippocampus) and a ‘medial diencephalic’ stream (centred on the anterior thalamic nuclei) that together act on shared cortical areas. We demonstrate how these distributed brain regions form complementary and necessary partnerships in episodic memory formation. Accumulating evidence indicates that the anterior thalamic nuclei make important contributions to cognition. Aggleton and O’Mara review these findings and propose that the anterior thalamic nuclei, hippocampus and cortex act together to support episodic memory function.
... A related spherical deconvolution-based approach, called hindrance modulated orientational anisotropy (HMOA), uses the amplitude of specific lobes of the ODF as an estimate of white matter integrity for a specific fibre population 17 . HMOA of the postcommissural fornix has been shown to predict verbal memory performance in a healthy aging cohort 18 . ...
Diffusion-weighted neuroimaging approaches provide rich evidence for estimating the structural integrity of white matter in vivo, but typically do not assess white matter integrity for connections between two specific regions of the brain. Here, we present a method for deriving tract-specific diffusion statistics, based upon predefined regions of interest. Our approach derives a population distribution using probabilistic tractography, based on the Nathan Kline Institute (NKI) Enhanced Rockland sample. We determine the most likely geometry of a path between two regions and express this as a spatial distribution. We then estimate the average orientation of streamlines traversing this path, at discrete distances along its trajectory, and the fraction of diffusion directed along this orientation for each participant. The resulting participant-wise metrics (tract-specific anisotropy; TSA) can then be used for statistical analysis on any comparable population. Based on this method, we report both negative and positive associations between age and TSA for two networks derived from published meta-analytic studies (the “default mode” and “what-where” networks), along with more moderate sex differences and age-by-sex interactions. The proposed method can be applied to any arbitrary set of brain regions, to estimate both the spatial trajectory and DWI-based anisotropy specific to those regions.
... Thus, it may also play a role in memory deficits and other cognitive impairments in various clinical disorders (Sutherland and Rodriguez 1989;Raslau et al. 2015a). Diffusion tensor imaging (DTI) can virtually identify the fornix via tractography and can yield estimates of parameters indicative of microstructural features (e.g., axon packing and myelination) that have been altered in several conditions such as epilepsy (Concha et al. 2005a;Liacu et al. 2012;Campos et al. 2015;Chiang et al. 2016), mild cognitive impairment (Christiansen et al. 2016), Alzheimer's Disease (Ringman et al. 2007;Mielke et al. 2009;Zhuang et al. 2013), obesity (Metzler-Baddeley et al. 2013), schizophrenia (Kuroki et al. 2006;Oishi et al. 2012), and multiple sclerosis (Kern et al. 2012;Valdés Cabrera et al. 2020). ...
The fornix is the primary efferent pathway of the hippocampus and plays a central role in memory circuitry. Diffusion tensor imaging has shown changes in the fornix with typical development and aging. Here, the fornix was investigated in 903 healthy young adult participants aged 22–36 years old from the high-spatial resolution 1.25 mm isotropic Human Connectome Project (HCP) diffusion dataset. Manual deterministic tractography was used to assess relationships between fornix diffusion parameters and age, sex, laterality, hippocampus volume, memory scores, and genetic effects in a subgroup of mono- and dizygotic twins. Fornix diffusion metrics were weakly correlated with age over the given age span. While significant hemispheric and sex differences were observed (greater fractional anisotropy (FA) and volume in the right hemisphere; greater FA and volume in females), there was great overlap between the groups. Hippocampus volume measurements showed greater volume in the right hemisphere, were found to be larger in males, and were weakly correlated with fornix FA and volume. Interestingly, all fornix diffusion measurements correlated strongly with fornix volume, suggesting the presence of partial volume effects despite the high-spatial resolution of the data. Both fornix diffusion parameters and hippocampal volumes were able to explain some variance (0.6–5.5%) in the memory tests evaluated. The fornix diffusion parameters were influenced by both genetic and shared environmental factors, displaying greater variability in dizygotic than in monozygotic twins. These findings provide a comprehensive depiction of the fornix in healthy, young individuals, upon which future typical development/aging and pathological studies could anchor.
