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The European Journal of Neuroscience Apr 2023Converging evidence from studies of human and nonhuman animals suggests that the hippocampus contributes to sequence learning by using temporal context to bind...
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, lateral septum 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 Free-Water Elimination 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 and 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 inter-regional communication within an extended hippocampal system.
Topics: Adult; Humans; Diffusion Tensor Imaging; Fornix, Brain; Hippocampus; Temporal Lobe; Diffusion Magnetic Resonance Imaging; White Matter
PubMed: 36808163
DOI: 10.1111/ejn.15940 -
Brain : a Journal of Neurology Jun 2022Spontaneous recovery of motor and cognitive function occurs in many individuals after stroke. The mechanisms are incompletely understood, but may involve...
Spontaneous recovery of motor and cognitive function occurs in many individuals after stroke. The mechanisms are incompletely understood, but may involve neurotransmitter systems that support neural plasticity, networks that are involved in learning and regions of the brain that are able to flexibly adapt to demand (such as the 'multiple-demand system'). Forty-two patients with first symptomatic ischaemic stroke were enrolled in a longitudinal cohort study of cognitive function after stroke. High-resolution volumetric, diffusion MRI and neuropsychological assessment were performed at a mean of 70 ± 18 days after stroke. Cognitive assessment was repeated 1 year after stroke, using parallel test versions to avoid learning effects, and change scores were computed for long-term episodic, short-term and working memory. Structural MRI features that predicted change in cognitive scores were identified by a two-stage analysis: a discovery phase used whole-brain approaches in a hypothesis-free unbiased way; and an independent focused phase, where measurements were derived from regions identified in the discovery phase, using targeted volumetric measurements or tractography. Evaluation of the cholinergic basal forebrain, based on a validated atlas-based approach, was included given prior evidence of a role in neural plasticity. The status of the fornix, cholinergic basal forebrain and a set of hippocampal subfields were found to predict improvement in long-term memory performance. In contrast to prior expectation, the same pattern was found for short-term and working memory, suggesting that these regions are part of a common infrastructure that supports recovery across cognitive domains. Associations between cholinergic basal forebrain volume and cognitive recovery were found primarily in subregions associated with the nucleus basalis of Meynert, suggesting that it is the cholinergic outflow to the neocortex that enables recovery. Support vector regression models derived from baseline measurements of fornix, cholinergic basal forebrain and hippocampal subfields were able to explain 62% of change in long-term episodic and 41% of change in working memory performance over the subsequent 9 months. The results suggest that the cholinergic system and extended hippocampal network play key roles in cognitive recovery after stroke. Evaluation of these systems early after stroke may inform personalized therapeutic strategies to enhance recovery.
Topics: Basal Forebrain; Brain Ischemia; Cholinergic Agents; Cognition; Hippocampus; Humans; Longitudinal Studies; Stroke
PubMed: 35188545
DOI: 10.1093/brain/awac070 -
NeuroImage. Clinical 2023Impairments of memory, attention, and executive functioning are frequently reported after acute onset brain injury. MRI markers hold potential to contribute to... (Meta-Analysis)
Meta-Analysis Review
Impairments of memory, attention, and executive functioning are frequently reported after acute onset brain injury. MRI markers hold potential to contribute to identification of patients at risk for cognitive impairments and clarification of mechanisms. The aim of this systematic review was to summarize and value the evidence on MRI markers of memory, attention, and executive functioning after acute onset brain injury. We included ninety-eight studies, on six classes of MRI factors (location and severity of damage (n = 15), volume/atrophy (n = 36), signs of small vessel disease (n = 15), diffusion-weighted imaging measures (n = 36), resting-state functional MRI measures (n = 13), and arterial spin labeling measures (n = 1)). Three measures showed consistent results regarding their association with cognition. Smaller hippocampal volume was associated with worse memory in fourteen studies (pooled correlation 0.58 [95% CI: 0.46-0.68] for whole, 0.11 [95% CI: 0.04-0.19] for left, and 0.34 [95% CI: 0.17-0.49] for right hippocampus). Lower fractional anisotropy in cingulum and fornix was associated with worse memory in six and five studies (pooled correlation 0.20 [95% CI: 0.08-0.32] and 0.29 [95% CI: 0.20-0.37], respectively). Lower functional connectivity within the default-mode network was associated with worse cognition in four studies. In conclusion, hippocampal volume, fractional anisotropy in cingulum and fornix, and functional connectivity within the default-mode network showed consistent associations with cognitive performance in all types of acute onset brain injury. External validation and cut off values for predicting cognitive impairments are needed for clinical implementation.
Topics: Humans; Magnetic Resonance Imaging; Cognition; Cognitive Dysfunction; Brain Injuries; Diffusion Magnetic Resonance Imaging; Memory Disorders
PubMed: 37119695
DOI: 10.1016/j.nicl.2023.103415 -
Psychosomatic Medicine Sep 2017The fornix is a white matter tract carrying the fibers connecting the hippocampus and the hypothalamus, two essential stress-regulatory structures of the brain. We...
OBJECTIVE
The fornix is a white matter tract carrying the fibers connecting the hippocampus and the hypothalamus, two essential stress-regulatory structures of the brain. We tested the hypothesis that allostatic load (AL), derived from a battery of peripheral biomarkers indexing the cumulative effects of stress, is associated with abnormalities in brain white matter microstructure, especially the fornix, and that higher AL may help explain the white matter abnormalities in schizophrenia.
METHODS
Using 13 predefined biomarkers, we tested AL in 44 schizophrenic patients and 33 healthy controls. Diffusion tensor imaging was used to obtain fractional anisotropy (FA) values of the fornix and other white matter tracts.
RESULTS
AL scores were significantly elevated in patients compared with controls (F(3,77) = 7.87, p = .006). AL was significantly and inversely correlated with FA of fornix in both controls (r = -.58, p = .001) and patients (r = -.36, p = .023). Several nominally significant (p < .05 but did not survive Bonferroni correction for multiple comparison) correlations were also observed between AL and FA of other white matter tracts in schizophrenic patients. However, the fornix was the only tract exhibiting a correlation with AL in both groups.
CONCLUSIONS
These results provide initial evidence that allostatic processes are linked to fornix microstructure in clinical participants.
Topics: Adult; Allostasis; Biomarkers; Diffusion Tensor Imaging; Female; Fornix, Brain; Humans; Male; Middle Aged; Schizophrenia; Stress, Psychological
PubMed: 28498274
DOI: 10.1097/PSY.0000000000000487 -
Frontiers in Aging Neuroscience 2014The limbic system mediates memory, behavior, and emotional output in the human brain, and is implicated in the pathology of Alzheimer's disease and a wide spectrum of... (Review)
Review
The limbic system mediates memory, behavior, and emotional output in the human brain, and is implicated in the pathology of Alzheimer's disease and a wide spectrum of related neurological disorders. In vivo magnetic resonance imaging (MRI) of structural components comprising the limbic system and their interconnections via white matter pathways in the human brain has helped define current understanding of the limbic model based on the classical circuit proposed by Papez. MRI techniques, including diffusion MR imaging, provide a non-invasive method to characterize white matter tracts of the limbic system, and investigate pathological changes that affect these pathways in clinical settings. This review focuses on delineation of the anatomy of major limbic tracts in the human brain, namely, the cingulum, the fornix and fimbria, and the stria terminalis, based on in vivo MRI contrasts. The detailed morphology and intricate trajectories of these pathways that can be identified using relaxometry-based and diffusion-weighted MRI provide an important anatomical reference for evaluation of clinical disorders commonly associated with limbic pathology.
PubMed: 25505883
DOI: 10.3389/fnagi.2014.00321 -
Frontiers in Medicine 2022Glaucoma is hypothesized to originate in the brain but manifests as an eye disease as it possesses the common features of neurodegeneration diseases. But there is no...
BACKGROUND
Glaucoma is hypothesized to originate in the brain but manifests as an eye disease as it possesses the common features of neurodegeneration diseases. But there is no evidence to demonstrate the primary brain changes in glaucoma patients. In the present study, we have used Mendelian randomization (MR) to understand the causal effect of brain alterations on glaucoma.
METHODS
Our MR study was carried out using summary statistics from genome-wide associations for 110 diffusion tensor imaging (DTI) measurements of white matter (WM) tracts (17,706 individuals), 101 brain region-of-interest (ROI) volumes (19,629 individuals), and glaucoma (8,591 cases, 210,201 control subjects). The causal relationship was evaluated by multiplicative random effects inverse variance weighted (IVW) method and verified by two other MR methods, including MR Egger, weighted median, and extensive sensitivity analyses.
RESULTS
Genetic liability to fornix fractional anisotropy (FX.FA) (OR = 0.71, 95%CI = 0.56-0.88, = 2.44 × 10), and uncinate fasciculus UNC.FA (OR = 0.65, 95%CI = 0.48-0.88, = 5.57 × 10) was associated with a low risk of glaucoma. Besides, the right ventral diencephalon (OR = 1.72, 95%CI = 1.17-2.52, = 5.64 × 10) and brain stem (OR = 1.35, 95%CI = 1.08-1.69, = 8.94 × 10) were associated with the increased risk of glaucoma. No heterogeneity and pleiotropy were detected.
CONCLUSION
Our study suggests that the fornix and uncinate fasciculus degenerations and injures of the right ventral diencephalon and brain stem potentially increase the occurrence of glaucoma and reveal the existence of the brain-eye axis.
PubMed: 35847794
DOI: 10.3389/fmed.2022.956339 -
The Journal of Clinical Endocrinology... Oct 2021Gray matter morphology in the prefrontal cortex and subcortical regions, including the hippocampus and amygdala, are affected in youth with classical congenital adrenal...
CONTEXT
Gray matter morphology in the prefrontal cortex and subcortical regions, including the hippocampus and amygdala, are affected in youth with classical congenital adrenal hyperplasia (CAH). It remains unclear if white matter connecting these aforementioned brain regions is compromised in youth with CAH.
OBJECTIVE
To examine brain white matter microstructure in youth with CAH compared to controls.
DESIGN
A cross-sectional sample of 23 youths with CAH due to 21-hydroxylase deficiency (12.9 ± 3.5 year; 61% female) and 33 healthy controls (13.1 ± 2.8 year; 61% female) with 3T multishell diffusion-weighted magnetic resonance brain scans.
MAIN OUTCOME MEASURES
Complementary modeling approaches, including diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI), to examine in vivo white matter microstructure in six white matter tracts that innervate the prefrontal and subcortical regions.
RESULTS
DTI showed CAH youth had lower fractional anisotropy in both the fornix and stria terminalis and higher mean diffusivity in the fornix compared to controls. NODDI modeling revealed that CAH youth have a significantly higher orientation dispersion index in the stria terminalis compared to controls. White matter microstructural integrity was associated with smaller hippocampal and amygdala volumes in CAH youth.
CONCLUSIONS
These patterns of microstructure reflect less restricted water diffusion likely due to less coherency in oriented microstructure. These results suggest that white matter microstructural integrity in the fornix and stria terminalis is compromised and may be an additional related brain phenotype alongside affected hippocampus and amygdala neurocircuitry in individuals with CAH.
Topics: Adolescent; Adrenal Hyperplasia, Congenital; Case-Control Studies; Cross-Sectional Studies; Diffusion Magnetic Resonance Imaging; Female; Follow-Up Studies; Gray Matter; Humans; Male; Neuroimaging; Prognosis; White Matter
PubMed: 34272858
DOI: 10.1210/clinem/dgab520 -
Proceedings of the National Academy of... Sep 2021Brain microstructure plays a key role in driving the transport of drug molecules directly administered to the brain tissue, as in Convection-Enhanced Delivery...
Brain microstructure plays a key role in driving the transport of drug molecules directly administered to the brain tissue, as in Convection-Enhanced Delivery procedures. The proposed research analyzes the hydraulic permeability of two white matter (WM) areas (corpus callosum and fornix) whose three-dimensional microstructure was reconstructed starting from the acquisition of electron microscopy images. We cut the two volumes with 20 equally spaced planes distributed along two perpendicular directions, and, on each plane, we computed the corresponding permeability vector. Then, we considered that the WM structure is mainly composed of elongated and parallel axons, and, using a principal component analysis, we defined two principal directions, parallel and perpendicular, with respect to the axons' main direction. The latter were used to define a reference frame onto which the permeability vectors were projected to finally obtain the permeability along the parallel and perpendicular directions. The results show a statistically significant difference between parallel and perpendicular permeability, with a ratio of about two in both the WM structures analyzed, thus demonstrating their anisotropic behavior. Moreover, we find a significant difference between permeability in corpus callosum and fornix, which suggests that the WM heterogeneity should also be considered when modeling drug transport in the brain. Our findings, which demonstrate and quantify the anisotropic and heterogeneous character of the WM, represent a fundamental contribution not only for drug-delivery modeling, but also for shedding light on the interstitial transport mechanisms in the extracellular space.
Topics: Humans; Microscopy, Electron; Permeability; White Matter
PubMed: 34480003
DOI: 10.1073/pnas.2105328118 -
ELife Dec 2021Neurodevelopmental axonal pathfinding plays a central role in correct brain wiring and subsequent cognitive abilities. Within the growth cone, various intracellular...
Neurodevelopmental axonal pathfinding plays a central role in correct brain wiring and subsequent cognitive abilities. Within the growth cone, various intracellular effectors transduce axonal guidance signals by remodeling the cytoskeleton. Semaphorin-3E (Sema3E) is a guidance cue implicated in development of the fornix, a neuronal tract connecting the hippocampus to the hypothalamus. Microtubule-associated protein 6 (MAP6) has been shown to be involved in the Sema3E growth-promoting signaling pathway. In this study, we identified the collapsin response mediator protein 4 (CRMP4) as a MAP6 partner and a crucial effector in Sema3E growth-promoting activity. CRMP4-KO mice displayed abnormal fornix development reminiscent of that observed in Sema3E-KO mice. CRMP4 was shown to interact with the Sema3E tripartite receptor complex within detergent- membrane (DRM) domains, and DRM domain integrity was required to transduce Sema3E signaling through the Akt/GSK3 pathway. Finally, we showed that the cytoskeleton-binding domain of CRMP4 is required for Sema3E's growth-promoting activity, suggesting that CRMP4 plays a role at the interface between Sema3E receptors, located in DRM domains, and the cytoskeleton network. As the fornix is affected in many psychiatric diseases, such as schizophrenia, our results provide new insights to better understand the neurodevelopmental components of these diseases.
Topics: Animals; Female; Fornix, Brain; Male; Mice; Nerve Tissue Proteins; Semaphorins; Signal Transduction
PubMed: 34860155
DOI: 10.7554/eLife.70361 -
Alzheimer's & Dementia : the Journal of... 2012The fornix is the predominant outflow tract of the hippocampus, a brain region known to be affected early in the course of Alzheimer's disease (AD). The aims of the...
BACKGROUND
The fornix is the predominant outflow tract of the hippocampus, a brain region known to be affected early in the course of Alzheimer's disease (AD). The aims of the present study were to: (1) examine the cross-sectional relationship between fornix diffusion tensor imaging (DTI) measurements (fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity, and radial diffusivity), hippocampal volume, and memory performance, and (2) compare fornix DTI measures with hippocampal volumes as predictors of progression and transition from amnestic mild cognitive impairment to AD dementia.
METHODS
Twenty-three mild cognitive impairment participants for whom hippocampal volumetry and DTI were conducted at baseline received detailed evaluations at baseline; 3, 6, and 12 months; and 2.5 years. Six participants converted to AD over the follow-up period. Fornix and posterior cingulum DTI measurements and hippocampal volumes were ascertained using manual measures. Random effects models assessed each of the neuroimaging measures as predictors of decline on the Mini-Mental State Examination, Clinical Dementia Rating-sum of boxes, and memory z scores; receiver operating characteristic analyses examined the predictive value for conversion to AD.
RESULTS
There was a significant correlation between fornix FA and hippocampal volumes. However, only the fornix measurements (FA, MD, radial diffusivity, and axial diffusivity) were cross-sectionally correlated with memory z scores. Both fornix FA and hippocampal volumes were predictive of memory decline. Individually, fornix FA and MD and hippocampal volumes were very good predictors of progression, with likelihood ratios >83, and better than 90% accuracy.
CONCLUSION
Fornix FA both cross-sectionally correlated with and longitudinally predicted memory decline and progression to AD. Manually drawn region of interest within the fornix shows promise comparable with hippocampal volume as a predictive biomarker of progression, and this finding warrants replication in a larger study.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cross-Sectional Studies; Diffusion Magnetic Resonance Imaging; Disease Progression; Female; Frontal Lobe; Hippocampus; Humans; Longitudinal Studies; Male; Memory Disorders; Neuropsychological Tests; Predictive Value of Tests; Psychiatric Status Rating Scales; ROC Curve
PubMed: 22404852
DOI: 10.1016/j.jalz.2011.05.2416