-
Brain Connectivity Sep 2020The fornix is the primary axonal tract of the hippocampus, connecting it to modulatory subcortical structures. This review reveals that fornix damage causes cognitive... (Review)
Review
The fornix is the primary axonal tract of the hippocampus, connecting it to modulatory subcortical structures. This review reveals that fornix damage causes cognitive deficits that closely mirror those resulting from hippocampal lesions. We reviewed the literature on the fornix, spanning non-human animal lesion research, clinical case studies of human patients with fornix damage, as well as diffusion-weighted imaging (DWI) work that evaluates fornix microstructure in vivo. The fornix is essential for memory formation because it serves as the conduit for theta rhythms and acetylcholine, as well as providing mnemonic representations to deep brain structures that guide motivated behavior, such as when and where to eat. In rodents and non-human primates, fornix lesions lead to deficits in conditioning, reversal learning, and navigation. In humans, damage to the fornix manifests as anterograde amnesia. DWI research reveals that the fornix plays a key role in mild cognitive impairment and Alzheimer's Disease, and can potentially predict conversion from the former to the latter. Emerging DWI findings link perturbations in this structure to schizophrenia, mood disorders, and eating disorders. Cutting-edge research has investigated how deep brain stimulation of the fornix can potentially attenuate memory loss, control epileptic seizures, and even improve mood. The fornix is essential to a fully functioning memory system and is implicated in nearly all neurological functions that rely on the hippocampus. Future research needs to use optimized DWI methods to study the fornix in vivo, which we discuss, given the difficult nature of fornix reconstruction. Impact Statement The fornix is a white matter tract that connects the hippocampus to several subcortical brain regions and is pivotal for episodic memory functioning. Functionally, the fornix transmits essential neurotransmitters, as well as theta rhythms, to the hippocampus. In addition, it is the conduit by which memories guide decisions. The fornix is biomedically important because lesions to this tract result in irreversible anterograde amnesia. Research using in vivo imaging methods has linked fornix pathology to cognitive aging, mild cognitive impairment, psychosis, epilepsy, and, importantly, Alzheimer's Disease.
Topics: Animals; Diffusion Magnetic Resonance Imaging; Female; Fornix, Brain; Memory Disorders; Memory, Episodic; Mental Disorders; Neural Pathways
PubMed: 32567331
DOI: 10.1089/brain.2020.0749 -
NeuroImage Aug 2022Extracellular free water (FW) increases are suggested to better provide pathophysiological information in brain aging than conventional biomarkers such as fractional...
Extracellular free water (FW) increases are suggested to better provide pathophysiological information in brain aging than conventional biomarkers such as fractional anisotropy. The aim of the present study was to determine the relationship between conventional biomarkers, FW in white matter hyperintensities (WMH), FW in normal appearing white matter (NAWM) and in white matter tracts and executive functions (EF) with a speed component in elderly persons. We examined 226 healthy elderly participants (median age 69.83 years, IQR: 56.99-74.42) who underwent brain MRI and neuropsychological examination. FW in WMH and in NAWM as well as FW corrected diffusion metrics and measures derived from conventional MRI (white matter hyperintensities, brain volume, lacunes) were used in partial correlation (adjusted for age) to assess their correlation with EF with a speed component. Random forest analysis was used to assess the relative importance of these variables as determinants. Lastly, linear regression analyses of FW in white matter tracts corrected for risk factors of cognitive and white matter deterioration, were used to examine the role of specific tracts on EF with a speed component, which were then ranked with random forest regression. Partial correlation analyses revealed that almost all imaging metrics showed a significant association with EF with a speed component (r = -0.213 - 0.266). Random forest regression highlighted FW in WMH and in NAWM as most important among all diffusion and structural MRI metrics. The fornix (R=0.421, p = 0.018) and the corpus callosum (genu (R = 0.418, p = 0.021), prefrontal (R = 0.416, p = 0.026), premotor (R = 0.418, p = 0.021)) were associated with EF with a speed component in tract based regression analyses and had highest variables importance. In a normal aging population FW in WMH and NAWM is more closely related to EF with a speed component than standard DTI and brain structural measures. Higher amounts of FW in the fornix and the frontal part of the corpus callosum leads to deteriorating EF with a speed component.
Topics: Aged; Biomarkers; Diffusion Magnetic Resonance Imaging; Diffusion Tensor Imaging; Executive Function; Healthy Aging; Humans; Leukoaraiosis; Water; White Matter
PubMed: 35568345
DOI: 10.1016/j.neuroimage.2022.119303 -
Frontiers in Neurology 2023Parkinson's disease (PD) is an idiopathic disease of the central nervous system characterized by both motor and non-motor symptoms. It is the second most common...
INTRODUCTION
Parkinson's disease (PD) is an idiopathic disease of the central nervous system characterized by both motor and non-motor symptoms. It is the second most common neurodegenerative disease. Magnetic resonance imaging (MRI) can reveal underlying brain changes associated with PD.
OBJECTIVE
In this study, structural connectivity and white matter networks were analyzed by diffusion MRI and graph theory in a cohort of patients with PD and a cohort of healthy controls (HC) obtained from the Parkinson's Progression Markers Initiative (PPMI) database in a cross-sectional analysis. Furthermore, we investigated longitudinal changes in the PD cohort over 36 months.
RESULT
Compared with the control group, participants with PD showed lower structural connectivity in several brain areas, including the corpus callosum, fornix, and uncinate fasciculus, which were also confirmed by a large effect-size. Additionally, altered connectivity between baseline and after 36 months was found in different network paths inside the white matter with a medium effect-size. Network analysis showed trends toward lower network density in PD compared with HC at baseline and after 36 months, though not significant after correction. Significant differences were observed in nodal degree and strength in several nodes.
CONCLUSION
In conclusion, altered structural and network metrics in several brain regions, such as corpus callosum, fornix, and cingulum were found in PD, compared to HC. We also report altered connectivity in the PD group after 36 months, reflecting the impact of both PD pathology and aging processes. These results indicate that structural and network metrics might yield insight into network reorganization that occurs in PD.
PubMed: 37034088
DOI: 10.3389/fneur.2023.1137780 -
Cerebral Circulation - Cognition and... 2023Risk factors of late-onset Alzheimer's disease (AD) such as aging, type 2 diabetes, obesity, heart failure, and traumatic brain injury can facilitate the appearance of... (Review)
Review
Risk factors of late-onset Alzheimer's disease (AD) such as aging, type 2 diabetes, obesity, heart failure, and traumatic brain injury can facilitate the appearance of cognitive decline and dementia by triggering cerebrovascular pathology and neuroinflammation. White matter (WM) microstructure and function are especially vulnerable to these conditions. Microstructural WM changes, assessed with diffusion weighted magnetic resonance imaging, can already be detected at preclinical stages of AD, and in the presence of the aforementioned risk factors. Particularly, the limbic system and cortico-cortical association WM tracts, which myelinate late during brain development, degenerate at the earliest stages. The fornix, a C-shaped WM tract that originates from the hippocampus, is one of the limbic tracts that shows early microstructural changes. Fornix integrity is necessary for ensuring an intact executive function and memory performance. Thus, a better understanding of the mechanisms that cause fornix degeneration is critical in the development of therapeutic strategies aiming to prevent cognitive decline in populations at risk. In this literature review, i) we deepen the idea that partial loss of forniceal integrity is an early event in AD, ii) we describe the role that common risk factors of AD can play in the degeneration of the fornix, and iii) we discuss some potential cellular and physiological mechanisms of WM degeneration in the scenario of cerebrovascular disease and inflammation.
PubMed: 36703699
DOI: 10.1016/j.cccb.2023.100158 -
Neural Regeneration Research Aug 2014The fornix is involved in the transfer of information on episodic memory as a part of the Papez circuit. Diffusion tensor imaging enables to estimate the neural... (Review)
Review
The fornix is involved in the transfer of information on episodic memory as a part of the Papez circuit. Diffusion tensor imaging enables to estimate the neural connectivity of the fornix. The anterior fornical body has high connectivity with the anterior commissure, and brain areas relevant to cholinergic nuclei (septal forebrain region and brainstem) and memory function (medial temporal lobe). In the normal subjects, by contrast, the posterior fornical body has connectivity with the cerebral cortex and brainstem through the splenium of the corpus callosum. We believe that knowledge of the neural connectivity of the fornix would be helpful in investigation of the neural network associated with memory and recovery mechanisms following injury of the fornix.
PubMed: 25317154
DOI: 10.4103/1673-5374.139459 -
Frontiers in Aging Neuroscience 2022In this study, we examined the independent contributions of structural and functional connectivity markers to individual differences in episodic memory performance in...
In this study, we examined the independent contributions of structural and functional connectivity markers to individual differences in episodic memory performance in 107 cognitively normal older adults from the BIOCARD study. Structural connectivity, defined by the diffusion tensor imaging (DTI) measure of radial diffusivity (RD), was obtained from two medial temporal lobe white matter tracts: the fornix and hippocampal cingulum, while functional connectivity markers were derived from network-based resting state functional magnetic resonance imaging (rsfMRI) of five large-scale brain networks: the control, default, limbic, dorsal attention, and salience/ventral attention networks. Hierarchical and stepwise linear regression methods were utilized to directly compare the relative contributions of the connectivity modalities to individual variability in a composite delayed episodic memory score, while also accounting for age, sex, cerebrospinal fluid (CSF) biomarkers of amyloid and tau pathology (i.e., Aβ/Aβ and p-tau), and gray matter volumes of the entorhinal cortex and hippocampus. Results revealed that fornix RD, hippocampal cingulum RD, and salience network functional connectivity were each significant independent predictors of memory performance, while CSF markers and gray matter volumes were not. Moreover, in the stepwise model, the addition of sex, fornix RD, hippocampal cingulum RD, and salience network functional connectivity each significantly improved the overall predictive value of the model. These findings demonstrate that both DTI and rsfMRI connectivity measures uniquely contributed to the model and that the combination of structural and functional connectivity markers best accounted for individual variability in episodic memory function in cognitively normal older adults.
PubMed: 35903538
DOI: 10.3389/fnagi.2022.951076 -
Scientific Reports Jan 2023Delta age is a biomarker of brain aging that captures differences between the chronological age and the predicted biological brain age. Using multimodal data of brain...
Delta age is a biomarker of brain aging that captures differences between the chronological age and the predicted biological brain age. Using multimodal data of brain MRI, genomics, and blood-based biomarkers and metabolomics in UK Biobank, this study investigates an explainable and causal basis of high delta age. A visual saliency map of brain regions showed that lower volumes in the fornix and the lower part of the thalamus are key predictors of high delta age. Genome-wide association analysis of the delta age using the SNP array data identified associated variants in gene regions such as KLF3-AS1 and STX1. GWAS was also performed on the volumes in the fornix and the lower part of the thalamus, showing a high genetic correlation with delta age, indicating that they share a genetic basis. Mendelian randomization (MR) for all metabolomic biomarkers and blood-related phenotypes showed that immune-related phenotypes have a causal impact on increasing delta age. Our analysis revealed regions in the brain that are susceptible to the aging process and provided evidence of the causal and genetic connections between immune responses and brain aging.
Topics: Humans; Genome-Wide Association Study; Genetic Predisposition to Disease; Biomarkers; Phenotype; Brain; Mendelian Randomization Analysis; Polymorphism, Single Nucleotide
PubMed: 36707530
DOI: 10.1038/s41598-023-27903-x -
Surgical Neurology International 2018Dementia is among the leading causes of severe and long-term disability worldwide, decreasing the quality of life of individuals and families. Moreover, it induces an... (Review)
Review
BACKGROUND
Dementia is among the leading causes of severe and long-term disability worldwide, decreasing the quality of life of individuals and families. Moreover, it induces an enormous economic burden on societies. The most prevalent cause of dementia is Alzheimer's disease (AD). Because current treatment options for AD are limited, deep brain stimulation (DBS) has been considered.
METHODS
The aim of this review is to survey the current understanding regarding the effects of DBS in AD and possibly shed light on the mechanisms of DBS in AD. We searched PubMed and Cochrane for various studies in English literature describing DBS in patients with AD and relevant preclinical studies. All related studies published from December 2013 to March 2017 were included in this review.
RESULTS
Our understanding of the neural circuitry underlying learning and memory in both rodent models and human patients has grown over the past years and provided potential therapeutic targets for DBS such as the fornix and the nucleus basalis of Meynert. Clinical results indicate that DBS is most beneficial for patients who are in the early stages of AD. Potential mechanisms of action of DBS in AD comprise long-term structural plasticity, including hippocampal enlargement as well as enhanced neurotransmitter release.
CONCLUSION
It is still premature to conclude that DBS can be used in the treatment of AD, and the field will wait for the results of ongoing and future clinical trials.
PubMed: 29576909
DOI: 10.4103/sni.sni_342_17 -
Brain : a Journal of Neurology Jul 2015This scientific commentary refers to ‘Visual-spatial memory may be enhanced with theta burst deep brain stimulation of the fornix: a preliminary investigation with...
This scientific commentary refers to ‘Visual-spatial memory may be enhanced with theta burst deep brain stimulation of the fornix: a preliminary investigation with four cases’, by Miller (doi:10.1093/brain/awv095).
Topics: Deep Brain Stimulation; Epilepsy, Temporal Lobe; Female; Fornix, Brain; Humans; Male; Spatial Memory
PubMed: 26106093
DOI: 10.1093/brain/awv121 -
Frontiers in Aging Neuroscience 2022Research aimed at understanding cognitive and brain aging in adults with autism spectrum disorder (ASD) is growing, but critical longitudinal work is scant. Adults with...
Research aimed at understanding cognitive and brain aging in adults with autism spectrum disorder (ASD) is growing, but critical longitudinal work is scant. Adults with ASD struggle with tasks involving visual memory compared with neurotypical adults (NT). This may be related to differences in size or integrity of the hippocampus and its' primary structural connectivity pathway, the fornix. The aim of this study was to describe preliminary findings of longitudinal aging trajectories in short- and long-term visual memory abilities in middle-age and older adults with ASD, compared with matched NT adults. We then evaluated baseline multi-modal imaging metrics of the hippocampal system, including the relatively novel metric of free-water, as potential correlates of longitudinal memory change in the ASD group. Middle-age and older adults with ASD ( = 25) and matched NT adults ( = 25) between the ages of 40 and 70 years were followed longitudinally at ~2-year intervals (range 2-5 years). Participants completed the Wechsler Memory Scale III Visual Reproduction task. Longitudinal mixed models were utilized to detect group differences in memory change with baseline age and sex as covariates. Hippocampal volume was measured T1-weighted MRI images with FreeSurfer. Fornix fractional anisotropy and hippocampal and fornix free-water were measured from diffusion tensor imaging scans. Exploratory correlations were run between individual hippocampal system metrics and longitudinal slopes of visual memory change. There was a significant group by time interaction for long-term visual memory, such that middle-age and older adults with ASD declined faster than matched NT adults. There was no group by time interaction for short-term visual memory. Baseline hippocampal free-water was the only hippocampal system metric that correlated with long-term visual memory change in the ASD group. As one of the first longitudinal cognitive and brain aging studies in middle-age and older adults with ASD, our findings suggest vulnerabilities for accelerated long-term visual memory decline, compared to matched NT adults. Further, baseline hippocampal free-water may be a predictor of visual memory change in middle-age and older adults with ASD. These preliminary findings lay the groundwork for future prognostic applications of MRI for cognitive aging in middle-age and older adults with ASD.
PubMed: 36437999
DOI: 10.3389/fnagi.2022.1029166