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Drawing is a powerful tool to enhance memory in healthy participants and patients with probable dementia. Here, we investigated whether the drawing effect could extend to patient CT, a young woman with severe anterograde amnesia. Following surgery for a midline tumor involving her septum pellucidium and extending down into her fornices bilaterally, CT experienced a severe case of sleep-related amnesia. She can remember information encountered throughout the day, but when waking up in the morning or following a nap she forgets information learned prior to sleep. Here, we tested CT and 21 age-matched controls in a 3-day within-subjects design, during which participants encoded words by either drawing or writing them down. Memory for encoded words was tested in two conditions that each followed a 12-h delay, once after a night of sleep, and once after 12 h of wake. Despite her severe memory impairment, CT showed a drawing effect that was comparable to controls in both sleep and wake conditions. Whereas CT's memory for written words was consistently impaired relative to controls, her memory for drawn words was at the lower control range following a waking delay and above chance following a sleep delay. We suggest that amnesic patients may benefit from the drawing effect due to the recruitment of brain regions outside of the hippocampal system for encoding and consolidation. Furthermore, in control participants, sleep benefited memory for written words, but not for drawn words, suggesting that sleep preferentially consolidates memories that are more dependent on the hippocampal system. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder that primarily affects elderly individuals. Mild cognitive impairment (MCI) represents an intermediate stage between normal cognitive functioning and the onset of AD. During this transition state, various subanatomic structures of the brain, including fornix, undergo pathological changes. In this study, an attempt has been made to analyse the structural variations in the fornix region of MCI and AD using invariant moments. For this purpose, T1- weighted brain structural magnetic resonance (sMR) images are obtained from a public database. The pre-processing of the raw images is conducted in FreeSurfer, and the fornix region is segmented using the reaction-diffusion level set (RDLS) method. Further, seven Hu's invariant moments are extracted from the segmented fornix region, and statistical analysis is carried out using student t-test and Wilcoxon's rank sum test to identify the significant features that could differentiate between the MCI and AD conditions. The results demonstrate that the combination of FreeSurfer and RDLS technique effectively pre-processes the brain sMR images and accurately delineates the fornix region. Statistical results revealed that six out of seven invariant moments are significant (p<0.001). It is observed that the mean values of all the moments in MCI are lower than AD, suggesting a higher degree of structural variation in AD compared to MCI. Considering the potential of fornix alterations in predicting the early stages of AD, the proposed approach holds considerable clinical relevance for further investigation. [ABSTRACT FROM AUTHOR]

Objective: Recognition memory is widely accepted as a dual process-based model, namely familiarity and recollection. However, the location of their specific neurobiological substrates remains unclear. Similar to hippocampal damage, fornix damage has been associated with recollection memory but not familiarity memory deficits. To understand the neural basis of recognition memory, determining the importance of the fornix and its hippocampal connections is essential. Methods: Recognition memory was examined in a 45-year-old male who underwent a complete bilateral fornix section following the removal of a third ventricle colloid cyst. The application of familiarity and recollection for recognition memory decisions was investigated via an immediate and delayed associative recognition test and an immediate and delayed forced-choice task in the patient and a control group (N = 15) over a two-year follow-up period. Complete demographic, neuropsychological, neuropsychiatric, and neuroradiological characterizations of this patient were performed. Results: Persistent immediate and delayed verbal recollection memory deficits were observed in the patient. Moreover, delayed familiarity-based recognition memory declined gradually over the follow-up period, immediate familiarity-based recognition memory was unaffected, and reduced non-verbal memory improved. Conclusion: The present findings support models that the extended hippocampal system, including the fornices, does not appear to play a role in familiarity memory but is particularly important for recollection memory. Moreover, our study suggests that bilateral fornix transection may be associated with relatively functional recovery of non-verbal memory. [ABSTRACT FROM AUTHOR]

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.

High-intensity magnetic resonance-guided focused ultrasound (MRgFUS) is a non-invasive therapy to lesion brain tissue, used clinically in patients and pre-clinically in several animal models. Challenges with focused ablation in rodent brains can include skull and near-field heating and accurately targeting small and deep brain structures. We overcame these challenges by creating a novel method consisting of a craniectomy skull preparation, a high-frequency transducer (3 MHz) with a small ultrasound focal spot, a transducer positioning system with an added manual adjustment of ∼0.1 mm targeting accuracy, and MR acoustic radiation force imaging for confirmation of focal spot placement. The study consisted of two main parts. First, two skull preparation approaches were compared. A skull thinning approach (n = 7 lesions) was compared to a craniectomy approach (n = 22 lesions), which confirmed a craniectomy was necessary to decrease skull and near-field heating. Second, the two transducer positioning systems were compared with the fornix chosen as a subcortical ablation target. We evaluated the accuracy of targeting using histologic methods from a high-frequency transducer with a small ultrasound focal spot and MR acoustic radiation force imaging. Comparing a motorized adjustment system (∼1 mm precision, n = 17 lesions) to the motorized system with an added micromanipulator (∼0.1 mm precision, n = 14 lesions), we saw an increase in the accuracy of targeting the fornix by 133%. The described work allows for repeatable and accurate targeting of small and deep structures in the rodent brain, such as the fornix, enabling the investigation of neurological disorders in chronic disease models. [ABSTRACT FROM AUTHOR]

A substantial fraction of those who had Alzheimer's Disease (AD) pathology on autopsy did not have dementia in life. While biomarkers for AD pathology are well-developed, biomarkers specific to cognitive domains affected by early AD are lagging. Diffusion MRI (dMRI) of the fornix is a candidate biomarker for early AD-related cognitive changes but is susceptible to bias due to partial volume averaging (PVA) with cerebrospinal fluid. The purpose of this work is to leverage multi-shell dMRI to correct for PVA and to evaluate PVA-corrected dMRI measures in fornix as a biomarker for cognition in AD. Thirty-three participants in the Cleveland Alzheimer's Disease Research Center (CADRC) (19 with normal cognition (NC), 10 with mild cognitive impairment (MCI), 4 with dementia due to AD) were enrolled in this study. Multi-shell dMRI was acquired, and voxelwise fits were performed with two models: 1) diffusion tensor imaging (DTI) that was corrected for PVA and 2) neurite orientation dispersion and density imaging (NODDI). Values of tissue integrity in fornix were correlated with neuropsychological scores taken from the Uniform Data Set (UDS), including the UDS Global Composite 5 score (UDSGC5). Statistically significant correlations were found between the UDSGC5 and PVA-corrected measure of mean diffusivity (MDc, r = −0.35, p < 0.05) from DTI and the intracelluar volume fraction (ficvf, r = 0.37, p < 0.04) from NODDI. A sensitivity analysis showed that the relationship to MDc was driven by episodic memory, which is often affected early in AD, and language. This cross-sectional study suggests that multi-shell dMRI of the fornix that has been corrected for PVA is a potential biomarker for early cognitive domain changes in AD. A longitudinal study will be necessary to determine if the imaging measure can predict cognitive decline. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The effect of juvenile stress on brain morphology, and especially white matter, is poorly understood. The present study aimed to evaluate the effects of two models of stress, physical and psychological, in the juvenile phase of male rats and their long-term impact on the integrity of the brain white matter. Morphological analysis was based on two major pathways of brain connection and myelin concentration, corpus callosum (CC) and fornix. Animals were randomly assigned to three groups: Control (C), Immobilization Stress (IS), and Predator Exposure Stress (PES). The stress procedures occurred for three consecutive days from d95 of postnatal life (P25 to P27). For long-term evaluation, in adulthood (P90-P95), the brains were collected, fixed, and processed by the Klüver-Barrera technique. The collected material was evaluated using image capture and analysis in the ImageJ Software. Both models of stress studied produced no changes in body and brain weight, and all regions analyzed (genu, body, and splenium of the corpus callosum and the fornix) showed no changes in optical integrity. Thus, this study suggests that short-term juvenile stress does not cause lasting morphological effects on white matter structure, and this adaptation, in which neither reductive nor protective changes occurred, can be considered a positive adaptation.

BACKGROUND: Recently recognized as a distinct entity, a myxoid glioneuronal tumor (MGNT) is a rare, low-grade central nervous system tumor. MGNTs are commonly located at the septum pellucidum or in the third ventricle, increasing the likelihood of tumor or treatment-related damage to adjacent structures critical for memory, such as the fornix. Though there have been a handful of case reports of neurosurgical and oncological outcomes of MGNTs, memory outcomes following resection of MGNTs adjacent to the fornix have not been previously reported. METHODS: We present a case of a high functioning female for whom an MRI revealed an incidental finding of an intraventricular tumor adjacent to the fornix bilaterally. The patient underwent resection of the tumor followed by MRI surveillance without additional oncologic intervention. Due to reported cognitive problems, the patient was referred for serial neuropsychological evaluations. RESULTS: Post-operative MRI following resection revealed cytotoxic edema followed by selective, progressive atrophy of the bilateral anterior fornices. Post-surgically, the patient developed an isolated verbal memory impairment, which persisted one-year post resection with minimal improvement. The memory impairment impacted the patients everyday functioning, including the ability to work in a cognitively demanding job. CONCLUSION: This unique case demonstrates the critical role of the bilateral fornix in verbal memory and underscores the importance of a careful risk/benefit analysis when considering neurosurgical intervention to MGNTs and other intracranial lesions adjacent to this structure during neurosurgical planning.

Background: Rett syndrome (RTT), caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2), severely impairs learning and memory. We previously showed that forniceal deep brain stimulation (DBS) stimulates hippocampal neurogenesis with concomitant improvements in hippocampal-dependent learning and memory in a mouse model of RTT. Objectives: To determine the duration of DBS benefits; characterize DBS effects on hippocampal neurogenesis; and determine whether DBS influences MECP2 genotype and survival of newborn dentate granular cells (DGCs) in RTT mice. Methods: Chronic DBS was delivered through an electrode implanted in the fimbria-fornix. We tested separate cohorts of mice in contextual and cued fear memory at different time points after DBS. We then examined neurogenesis, DGC apoptosis, and the expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) after DBS by immunohistochemistry. Results: After two weeks of forniceal DBS, memory improvements lasted between 6 and 9 weeks. Repeating DBS every 6 weeks was sufficient to maintain the improvement. Forniceal DBS stimulated the birth of more MeCP2-positive than MeCP2-negative DGCs and had no effect on DGC survival. It also increased the expression of BDNF but not VEGF in the RTT mouse dentate gyrus. Conclusion: Improvements in learning and memory from forniceal DBS in RTT mice extends well beyond the treatment period and can be maintained by repeated DBS. Stimulation of BDNF expression correlates with improvements in hippocampal neurogenesis and memory benefits.

Introduction: Acute amnestic syndrome is an uncommon clinical presentation of neurological disease. Differential diagnosis encompasses several syndromes including Wernicke-Korsakoff and transient global amnesia (TGA). Structural lesions of the fornix account for a minority of cases of acute amnestic syndromes. Etiology varies from iatrogenic injury to ischemic, inflammatory, or neoplastic lesions. A prompt diagnosis of the underlying pathology is essential but challenging. The aim of this review is to systematically review the existing literature regarding cases of acute amnestic syndrome associated with noniatrogenic lesions of the fornix. Methods: We performed a systematic literature search on PubMed, Scopus, and Web of Science up to September 2023 to identify case reports and case series of patients with amnestic syndrome due to fornix lesions. The systematic review was conducted according to PRISMA guidelines. The research was limited to articles written in English. Cases of fornix damage directly ascribable to a surgical procedure were excluded. Results: A total of 52 publications reporting 55 cases were included in the review. Focusing on acute/subacute onset, vascular etiology was highly prevalent, being responsible for 78% of cases, 40/55 (74%) of which were due to acute ischemic stroke. The amnestic syndrome was characterized by anterograde amnesia in all patients, associated with retrograde amnesia in 27% of cases. Amnesia was an isolated presentation in most cases. Up to two thirds of patients had persistent memory deficits of any severity at follow-up. Discussion: Acute amnestic syndrome can be rarely caused by fornix lesions. In most cases of acute/subacute presentation, the etiology is ischemic stroke, mainly caused by strokes involving the subcallosal artery territory. The differential diagnosis is challenging and a distinction from common mimics is often difficult on a clinical basis. A high index of suspicion should be maintained to avoid misdiagnosis and provide adequate acute treatment to patients with timedependent disease, also employing advanced neuroimaging. More research is needed to better understand the outcome and identify prognostic factors in patients with amnestic syndrome due to fornix lesions. [ABSTRACT FROM AUTHOR]

This investigation explores memory performance using the California Verbal Learning Test in relation to morphometric and connectivity measures of the memory network in severe traumatic brain injury. Twenty-two adolescents with severe traumatic brain injury were recruited for multimodal MRI scanning 1–2 years post-injury at 13 participating sites. Analyses included hippocampal volume derived from anatomical T1-weighted imaging, fornix white matter microstructure from diffusion tensor imaging, and hippocampal resting-state functional magnetic resonance imaging connectivity as well as diffusion-based structural connectivity. A typically developing control cohort of forty-nine age-matched children also underwent scanning and neurocognitive assessment. Results showed hippocampus volume was decreased in traumatic brain injury with respect to controls. Further, hippocampal volume loss was associated with worse performance on memory and learning in traumatic brain injury subjects. Similarly, hippocampal fornix fractional anisotropy was reduced in traumatic brain injury with respect to controls, while decreased fractional anisotropy in the hippocampal fornix also was associated with worse performance on memory and learning in traumatic brain injury subjects. Additionally, reduced structural connectivity of left hippocampus to thalamus and calcarine sulcus was associated with memory and learning in traumatic brain injury subjects. Functional connectivity in the left hippocampal network was also associated with memory and learning in traumatic brain injury subjects. These regional findings from a multi-modal neuroimaging approach should not only be useful for gaining valuable insight into traumatic brain injury induced memory and learning disfunction, but may also be informative for monitoring injury progression, recovery, and for developing rehabilitation as well as therapy strategies. [ABSTRACT FROM AUTHOR]

Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder of genetic etiology, characterized by paternal deletion of genes located at chromosome 15 in 70% of cases. Two distinct genetic subtypes of PWS deletions are characterized, where type I (PWS T1) carries four extra haploinsufficient genes compared to type II (PWS T2). PWS T1 individuals display more pronounced physiological and cognitive abnormalities than PWS T2, yet the exact neuropathological mechanisms behind these differences remain unclear. Our study employed postmortem hypothalamic tissues from PWS T1 and T2 individuals, conducting transcriptomic analyses and cell-specific protein profiling in white matter, neurons, and glial cells to unravel the cellular and molecular basis of phenotypic severity in PWS sub-genotypes. In PWS T1, key pathways for cell structure, integrity, and neuronal communication are notably diminished, while glymphatic system activity is heightened compared to PWS T2. The microglial defect in PWS T1 appears to stem from gene haploinsufficiency, as global and myeloid-specific Cyfip1 haploinsufficiency in murine models demonstrated. Our findings emphasize microglial phagolysosome dysfunction and altered neural communication as crucial contributors to the severity of PWS T1’s phenotype. [ABSTRACT FROM AUTHOR]

Purpose: Surgery, radiotherapy (RT), and chemotherapy have prolonged the survival of patients with anaplastic oligodendroglioma. However, whether RT induces long-term toxicity remains unknown. We analyzed the relationship between the RT dose to the fornix and symptomatic radiation necrosis (SRN). Materials and Methods: A total of 67 patients treated between 2009 and 2019 were analyzed. SRN was defined according to the following three criteria: 1) radiographic findings, 2) symptoms attributable to the lesion, and 3) treatment resulting in symptom improvement. Various contours, including the fornix, were delineated. Univariate and multivariate analyses of the relationship between RT dose and SRN, as well as receiver operating characteristic curve analysis for cut-off values, were performed. Results: The most common location was the frontal lobe (n=40, 60%). Gross total resection was performed in 38 patients (57%), and 42 patients (63%) received procarbazine, lomustine, and vincristine chemotherapy. With a median follow-up of 42 months, the median overall and progression-free survival was 74 months. Sixteen patients (24%) developed SRN. In multivariate analysis, age and maximum dose to the fornix were associated with the development of SRN. The cut-off values for the maximum dose to the fornix and age were 59 Gy (equivalent dose delivered in 2 Gy fractions) and 46 years, respectively. The rate of SRN was higher in patients whose maximum dose to the fornix was >59 Gy (13% vs. 43%, p=0.005). Conclusion: The maximum dose to the fornix was a significant factor for SRN development. While fornix sparing may help maintain neurocognitive function, additional studies are needed. [ABSTRACT FROM AUTHOR]

The effect of juvenile stress on brain morphology, and especially white matter, is poorly understood. The present study aimed to evaluate the effects of two models of stress, physical and psychological, in the juvenile phase of male rats and their long-term impact on the integrity of the brain white matter. Morphological analysis was based on two major pathways of brain connection and myelin concentration, corpus callosum (CC) and fornix. Animals were randomly assigned to three groups: Control (C), Immobilization Stress (IS), and Predator Exposure Stress (PES). The stress procedures occurred for three consecutive days from d95 of postnatal life (P25 to P27). For long-term evaluation, in adulthood (P90-P95), the brains were collected, fixed, and processed by the Klüver-Barrera technique. The collected material was evaluated using image capture and analysis in the ImageJ Software. Both models of stress studied produced no changes in body and brain weight, and all regions analyzed (genu, body, and splenium of the corpus callosum and the fornix) showed no changes in optical integrity. Thus, this study suggests that short-term juvenile stress does not cause lasting morphological effects on white matter structure, and this adaptation, in which neither reductive nor protective changes occurred, can be considered a positive adaptation. [ABSTRACT FROM AUTHOR]

Abstract Introduction Alcohol dependence is characterized by a gradual reduction in cognitive control and inflexibility to contingency changes. The neuroadaptations underlying this aberrant behavior are poorly understood. Using an animal model of alcohol use disorders (AUD) and complementing diffusion-weighted (dw)-MRI with quantitative immunohistochemistry and electrophysiological recordings, we provide causal evidence that chronic intermittent alcohol exposure affects the microstructural integrity of the fimbria/fornix, decreasing myelin basic protein content, and reducing the effective communication from the hippocampus (HC) to the prefrontal cortex (PFC). Using a simple quantitative neural network model, we show how disturbed HC-PFC communication may impede the extinction of maladaptive memories, decreasing flexibility. Finally, combining dw-MRI and psychometric data in AUD patients, we discovered an association between the magnitude of microstructural alteration in the fimbria/fornix and the reduction in cognitive flexibility. Overall, these findings highlight the vulnerability of the fimbria/fornix microstructure in AUD and its potential contribution to alcohol pathophysiology. Summary Fimbria vulnerability to alcohol underlies hippocampal-prefrontal cortex dysfunction and correlates with cognitive impairment.

IntroductionAcute amnestic syndrome is an uncommon clinical presentation of neurological disease. Differential diagnosis encompasses several syndromes including Wernicke-Korsakoff and transient global amnesia (TGA). Structural lesions of the fornix account for a minority of cases of acute amnestic syndromes. Etiology varies from iatrogenic injury to ischemic, inflammatory, or neoplastic lesions. A prompt diagnosis of the underlying pathology is essential but challenging. The aim of this review is to systematically review the existing literature regarding cases of acute amnestic syndrome associated with non-iatrogenic lesions of the fornix.MethodsWe performed a systematic literature search on PubMed, Scopus, and Web of Science up to September 2023 to identify case reports and case series of patients with amnestic syndrome due to fornix lesions. The systematic review was conducted according to PRISMA guidelines. The research was limited to articles written in English. Cases of fornix damage directly ascribable to a surgical procedure were excluded.ResultsA total of 52 publications reporting 55 cases were included in the review. Focusing on acute/subacute onset, vascular etiology was highly prevalent, being responsible for 78% of cases, 40/55 (74%) of which were due to acute ischemic stroke. The amnestic syndrome was characterized by anterograde amnesia in all patients, associated with retrograde amnesia in 27% of cases. Amnesia was an isolated presentation in most cases. Up to two thirds of patients had persistent memory deficits of any severity at follow-up.DiscussionAcute amnestic syndrome can be rarely caused by fornix lesions. In most cases of acute/subacute presentation, the etiology is ischemic stroke, mainly caused by strokes involving the subcallosal artery territory. The differential diagnosis is challenging and a distinction from common mimics is often difficult on a clinical basis. A high index of suspicion should be maintained to avoid misdiagnosis and provide adequate acute treatment to patients with time-dependent disease, also employing advanced neuroimaging. More research is needed to better understand the outcome and identify prognostic factors in patients with amnestic syndrome due to fornix lesions.

Aging leads to response slowing but the underpinning cognitive and neural mechanisms remain elusive. We modelled older and younger adults’ response times (RT) from a flanker task with a diffusion drift model (DDM) and employed diffusion-weighted magnetic resonance imaging and spectroscopy to study neurobiological predictors of DDM components (drift-rate, boundary separation, non-decision time). Microstructural indices were derived from white matter pathways involved in visuo-perceptual and attention processing [optic radiation, inferior and superior longitudinal fasciculi (ILF, SLF), fornix]. Estimates of metabolite concentrations [N-acetyl aspartate (NAA), glutamate (Glx), and γ-aminobutyric acid (GABA), creatine (Cr), choline (Cho), myoinositol (mI)] were measured from occipital (OCC), anterior cingulate (ACC) and posterior parietal cortices (PPC). Age-related increases in RT, boundary separation, and non-decision time were observed with response conservatism acounting for RT slowing. Aging was associated with reductions in white matter microstructure (lower fractional anisotropy and restricted signal fraction, larger diffusivities) and in metabolites (NAA in ACC and PPC, Glx in ACC). Regression analyses identified brain regions involved in top-down (fornix, SLF, ACC, PPC) and bottom-up (ILF, optic radiation OCC) processing as predictors for DDM parameters and RT. Fornix FA was the strongest predictor for increases in boundary separation (beta = −0.8) and mediated the effects of age on RT. These findings demonstrate that response slowing in visual discrimination is driven by the adoption of a more conservative response strategy. Age-related fornix decline may result in noisier communication of contextual information from the hippocampus to anterior decision-making regions and thus contribute to the conservative response strategy shift.

Up to 45% of the elderly population suffer from chronic tinnitus - the phantom perception of sound that is often perceived as ringing, whistling, or hissing “in the ear” without external stimulation. Previous research investigated white matter changes in tinnitus patients using diffusion-weighted magnetic resonance imaging (DWI) to assess measures such as fractional anisotropy (a measure of microstructural integrity of fiber tracts) or mean diffusivity (a measure for general water diffusion). However, findings overlap only minimally and are sometimes even contradictory. We here present the first study encompassing higher diffusion data that allow to focus on changes in tissue microstructure, such as number of axons (fiber density) and macroscopic alterations, including axon diameter, and a combination of both. In order to deal with the crossing-fibers problem, we applied a fixel-based analysis using a constrained spherical deconvolution signal modeling approach. We investigated differences between tinnitus patients and control participants as well as how cognitive abilities and tinnitus distress are related to changes in white matter morphology in chronic tinnitus. For that aim, 20 tinnitus patients and 20 control participants, matched in age, sex and whether they had hearing loss or not, underwent DWI, audiometric and cognitive assessments, and filled in questionnaires targeting anxiety and depression. Our results showed increased fiber density in the fornix in tinnitus patients compared to control participants. The observed changes might, reflect compensatory structural alterations related to the processing of negative emotions or maladaptive changes related to the reinforced learning of the chronic tinnitus sensation. Due to the low sample size, the study should be seen as a pilot study that motivates further research to investigate underlying white matter morphology alterations in tinnitus.

Rett syndrome (RTT), caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2), severely impairs learning and memory. We previously showed that forniceal deep brain stimulation (DBS) stimulates hippocampal neurogenesis with concomitant improvements in hippocampal-dependent learning and memory in a mouse model of RTT. To determine the duration of DBS benefits; characterize DBS effects on hippocampal neurogenesis; and determine whether DBS influences MECP2 genotype and survival of newborn dentate granular cells (DGCs) in RTT mice. Chronic DBS was delivered through an electrode implanted in the fimbria-fornix. We tested separate cohorts of mice in contextual and cued fear memory at different time points after DBS. We then examined neurogenesis, DGC apoptosis, and the expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) after DBS by immunohistochemistry. After two weeks of forniceal DBS, memory improvements lasted between 6 and 9 weeks. Repeating DBS every 6 weeks was sufficient to maintain the improvement. Forniceal DBS stimulated the birth of more MeCP2-positive than MeCP2-negative DGCs and had no effect on DGC survival. It also increased the expression of BDNF but not VEGF in the RTT mouse dentate gyrus. Improvements in learning and memory from forniceal DBS in RTT mice extends well beyond the treatment period and can be maintained by repeated DBS. Stimulation of BDNF expression correlates with improvements in hippocampal neurogenesis and memory benefits. • Memory enhancement persists weeks after forniceal DBS treatment • Repeated DBS treatment maintains memory benefit • DBS skews neurogenesis toward MeCP2-positive cells • DBS stimulates BDNF expression in the hippocampus [ABSTRACT FROM AUTHOR]

Experiments on rodents have demonstrated that transecting the white matter fibre pathway linking the hippocampus with an array of cortical and subcortical structures - the fornix - impairs flexible navigational learning in the Morris Water Maze (MWM), as well as similar spatial learning tasks. While diffusion magnetic resonance imaging (dMRI) studies in humans have linked inter-individual differences in fornix microstructure to episodic memory abilities, its role in human spatial learning is currently unknown. We used high-angular resolution diffusion MRI combined with constrained spherical deconvolution-based tractography, to ask whether inter-individual differences in fornix microstructure in healthy young adults would be associated with spatial learning in a virtual reality navigation task. To efficiently capture individual learning across trials, we adopted a novel curve fitting approach to estimate a single index of learning rate. We found a statistically significant correlation between learning rate and the microstructure (mean diffusivity) of the fornix, but not that of a comparison tract linking occipital and anterior temporal cortices (the inferior longitudinal fasciculus, ILF). Further, this correlation remained significant when controlling for both hippocampal volume and participant gender. These findings extend previous animal studies by demonstrating the functional relevance of the fornix for human spatial learning in a virtual reality environment, and highlight the importance of a distributed neuroanatomical network, underpinned by key white matter pathways, such as the fornix, in complex spatial behaviour.

Germinoma is a rare CNS germ cell tumor preferentially affecting children and young adults. Intracranial germinomas arise typically in the neurohypophysis and pineal region and occasionally in the basal ganglia and thalamus. Germinomas in the basal ganglia and thalamus are characterized by the ipsilateral cerebral and brainstem hemiatrophy with slowly progressive neurological deficits, which is due to tumor infiltration into the thalamocortical and corticospinal tract and induction of anterograde and retrograde Wallerian degeneration. We report an 11-year-old boy with a mass located in the fornix incidentally discovered on the first work-up of his minor head injury. Imaging findings revealed the ipsilateral atrophy of the mammillary body and the fornix. Stereotactic brain biopsy was performed and the final diagnosis was germinoma. The ipsilateral atrophy of the mammillary body and the fornix implied the transsynaptic degeneration via the Papez circuit. We discuss the unique nature of germinomas and underlying pathological mechanisms.

To observe the surgical outcome of “Tenon Excision with Fibrin Glue-Assisted Reattachment of Conjunctiva Flap” (T.E.F.A.R.C.) for the treatment of symptomatic conjunctivochalasis (CCH). This is a retrospective case series of CCH patients undergoing T.E.F.A.R.C. from January 2017 to December 2020 were reviewed. Seven patients (14 eyes) with symptomatic CCH received T.E.F.A.R.C. in both eyes. The symptoms before and after the procedures were compared and surgical complication was evaluated. The mean follow-up time was 13.7 ± 2.14 months. After the operation, resolution of the symptoms was reported in 12 eyes (86%). The grade of CCH decreased from 3 to 0 in all 14 eyes, and the restoration of inferior conjunctival surface and fornix within 1 day was also observed in all eyes. Most patients had localized injection and mild chemosis after the operation, which mostly recovered within 3 weeks. No complication or recurrence of CCH was reported after 1 year of follow-up. In conclusion, T.E.F.A.R.C. is a simple and effective treatment option for CCH with less surgical complication. Future larger studies are needed to confirm its clinical applicability.

White matter commissural fibers are a special type of fibers that connect similar areas of the cortex of opposite hemispheres. Telencephalic commissures have a direct impact on cognitive function. Diencephalic commissures connect the structures of the midbrain, diencephalon, and forebrain. The pathways they form are involved in the proliferation of white matter diseases. The review provides updated information on the morphology, functions, impairments of development and blood supply of brain commissures and their functional relationship with neurological diseases such as Alzheimer's disease, Parino's syndrome, agenesis of the corpus callosum, and autism spectrum disorders.

Alzheimer's disease (AD) is one of the most common progressive neurodegenerative diseases associated with the degradation of memory and cognitive ability. Current pharmacotherapies show little therapeutic effect in AD treatment and still cannot prevent the pathological progression of AD. Deep brain stimulation (DBS) has shown to enhance memory in morbid obese, epilepsy and traumatic brain injury patients, and cognition in Parkinson's disease (PD) patients deteriorates during DBS off. Some relevant animal studies and clinical trials have been carried out to discuss the DBS treatment for AD. Reviewing the fornix trials, no unified conclusion has been reached about the clinical benefits of DBS in AD, and the dementia ratings scale has not been effectively improved in the long term. However, some patients have presented promising results, such as improved glucose metabolism, increased connectivity in cognition‐related brain regions and even elevated cognitive function rating scale scores. The fornix plays an important regulatory role in memory, attention, and emotion through its complex fibre projection to cognition‐related structures, making it a promising target for DBS for AD treatment. Moreover, the current stereotaxic technique and various evaluation methods have provided references for the operator to select accurate stimulation points. Related adverse events and relatively higher costs in DBS have been emphasized. In this article, we summarize and update the research progression on fornix DBS in AD and seek to provide a reliable reference for subsequent experimental studies on DBS treatment of AD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Alcohol dependence is characterized by a gradual reduction in cognitive control and inflexibility to contingency changes. The neuroadaptations underlying this aberrant behavior are poorly understood. Using an animal model of alcohol use disorders (AUD) and complementing diffusion-weighted (dw)-MRI with quantitative immunohistochemistry and electrophysiological recordings, we provide causal evidence that chronic intermittent alcohol exposure affects the microstructural integrity of the fimbria/fornix, decreasing myelin basic protein content, and reducing the effective communication from the hippocampus (HC) to the prefrontal cortex (PFC). Using a simple quantitative neural network model, we show how disturbed HC-PFC communication may impede the extinction of maladaptive memories, decreasing flexibility. Finally, combining dw-MRI and psychometric data in AUD patients, we discovered an association between the magnitude of microstructural alteration in the fimbria/fornix and the reduction in cognitive flexibility. Overall, these findings highlight the vulnerability of the fimbria/fornix microstructure in AUD and its potential contribution to alcohol pathophysiology. Summary: Fimbria vulnerability to alcohol underlies hippocampal-prefrontal cortex dysfunction and correlates with cognitive impairment. [ABSTRACT FROM AUTHOR]

BackgroundRecently recognized as a distinct entity, a myxoid glioneuronal tumor (MGNT) is a rare, low-grade central nervous system tumor. MGNTs are commonly located at the septum pellucidum or in the third ventricle, increasing the likelihood of tumor or treatment-related damage to adjacent structures critical for memory, such as the fornix. Though there have been a handful of case reports of neurosurgical and oncological outcomes of MGNTs, memory outcomes following resection of MGNTs adjacent to the fornix have not been previously reported.MethodsWe present a case of a high functioning female for whom an MRI revealed an incidental finding of an intraventricular tumor adjacent to the fornix bilaterally. The patient underwent resection of the tumor followed by MRI surveillance without additional oncologic intervention. Due to reported cognitive problems, the patient was referred for serial neuropsychological evaluations.ResultsPost-operative MRI following resection revealed cytotoxic edema followed by selective, progressive atrophy of the bilateral anterior fornices. Post-surgically, the patient developed an isolated verbal memory impairment, which persisted one-year post resection with minimal improvement. The memory impairment impacted the patient’s everyday functioning, including the ability to work in a cognitively demanding job.ConclusionThis unique case demonstrates the critical role of the bilateral fornix in verbal memory and underscores the importance of a careful risk/benefit analysis when considering neurosurgical intervention to MGNTs and other intracranial lesions adjacent to this structure during neurosurgical planning.

Aging, even in the absence of clear pathology of dementia, is associated with cognitive decline. Neuroimaging, especially diffusion-weighted imaging, has been highly valuable in understanding some of these changes in live humans, non-invasively. Traditional tensor techniques have revealed that the integrity of the fornix and other white matter tracts significantly deteriorates with age, and that this deterioration is highly correlated with worsening cognitive performance. However, traditional tensor techniques are still not specific enough to indict explicit microstructural features that may be responsible for age-related cognitive decline and cannot be used to effectively study gray matter properties. Here, we sought to determine whether recent advances in diffusion-weighted imaging, including Neurite Orientation Dispersion and Density Imaging (NODDI) and Constrained Spherical Deconvolution, would provide more sensitive measures of age-related changes in the microstructure of the medial temporal lobe. We evaluated these measures in a group of young (ages 20-38 years old) and older (ages 59-84 years old) adults and assessed their relationships with performance on tests of cognition. We found that the fiber density (FD) of the fornix and the neurite density index (NDI) of the fornix, hippocampal subfields (DG/CA3, CA1, and subiculum), and parahippocampal cortex, varied as a function of age in a cross-sectional cohort. Moreover, in the fornix, DG/CA3, and CA1, these changes correlated with memory performance on the Rey Auditory Verbal Learning Test (RAVLT), even after regressing out the effect of age, suggesting that they were capturing neurobiological properties directly related to performance in this task. These measures provide more details regarding age-related neurobiological properties. For example, a change in fiber density could mean a reduction in axonal packing density or myelination, and the increase in NDI observed might be explained by changes in dendritic complexity or even sprouting. These results provide a far more comprehensive view than previously determined on the possible system-wide processes that may be occurring because of healthy aging and demonstrate that advanced diffusion-weighted imaging is evolving into a powerful tool to study more than just white matter properties.

ObjectiveWhite matter (WM) microstructural changes are increasingly recognized as a mechanism of age-related cognitive differences. This study examined the associations between patterns of WM microstructure and cognitive performance on the University of California, San Francisco (UCSF) Brain Health Assessment (BHA) subtests of memory (Favorites), executive functions and speed (Match), and visuospatial skills (Line Orientation) within a sample of older adults.MethodFractional anisotropy (FA) in WM tracts and BHA performance were examined in 84 older adults diagnosed as neurologically healthy (47), with mild cognitive impairment (19), or with dementia (18). The relationships between FA and subtest performances were evaluated using regression analyses. We then explored whether regional WM predicted performance after accounting for variance explained by global FA.ResultsMemory performance was associated with FA of the fornix and the superior cerebellar peduncle; and executive functions and speed, with the body of the corpus callosum. The fornix-memory association and the corpus callosum-executive association remained significant after accounting for global FA. Neither tract-based nor global FA was associated with visuospatial performance.ConclusionsMemory and executive functions are associated with different patterns of WM diffusivity. Findings add insight into WM alterations underlying age- and disease-related cognitive decline.

To understand multifactorial conditions such as Alzheimer's disease (AD) we need brain signatures that predict the impact of multiple pathologies and their interactions. To help uncover the relationships between pathology affected brain circuits and cognitive markers we have used mouse models that represent, at least in part, the complex interactions altered in AD, while being raised in uniform environments and with known genotype alterations. In particular, we aimed to understand the relationship between vulnerable brain circuits and memory deficits measured in the Morris water maze, and we tested several predictive modeling approaches. We used in vivo manganese enhanced MRI traditional voxel based analyses to reveal regional differences in volume (morphometry), signal intensity (activity), and magnetic susceptibility (iron deposition, demyelination). These regions included hippocampus, olfactory areas, entorhinal cortex and cerebellum, as well as the frontal association area. The properties of these regions, extracted from each of the imaging markers, were used to predict spatial memory. We next used eigenanatomy, which reduces dimensionality to produce sets of regions that explain the variance in the data. For each imaging marker, eigenanatomy revealed networks underpinning a range of cognitive functions including memory, motor function, and associative learning, allowing the detection of associations between context, location, and responses. Finally, the integration of multivariate markers in a supervised sparse canonical correlation approach outperformed single predictor models and had significant correlates to spatial memory. Among a priori selected regions, expected to play a role in memory dysfunction, the fornix also provided good predictors, raising the possibility of investigating how disease propagation within brain networks leads to cognitive deterioration. Our cross-sectional results support that modeling approaches integrating multivariate imaging markers provide sensitive predictors of AD-like behaviors. Such strategies for mapping brain circuits responsible for behaviors may help in the future predict disease progression, or response to interventions.

Objective To investigate whether there is a link between cognitive function and motor reserve (i.e., individual capacity to cope with nigrostriatal dopamine depletion) in patients with newly diagnosed Parkinson’s disease (PD). Methods A total of 163 patients with drug-naïve PD who underwent 18F-FP-CIT PET, brain MRI, and a detailed neuropsychological test were enrolled. We estimated individual motor reserve based on initial motor deficits and striatal dopamine depletion using a residual model. We performed correlation analyses between motor reserve estimates and cognitive composite scores. Diffusion connectometry analysis was performed to map the white matter fiber tracts, of which fractional anisotropy (FA) values were well correlated with motor reserve estimates. Additionally, Cox regression analysis was used to assess the effect of initial motor reserve on the risk of dementia conversion. Results The motor reserve estimate was positively correlated with the composite score of the verbal memory function domain (γ = 0.246) and with the years of education (γ = 0.251). Connectometry analysis showed that FA values in the left fornix were positively correlated with the motor reserve estimate, while no fiber tracts were negatively correlated with the motor reserve estimate. Cox regression analysis demonstrated that higher motor reserve estimates tended to be associated with a lower risk of dementia conversion (hazard ratio, 0.781; 95% confidence interval, 0.576–1.058). Conclusion The present study demonstrated that the motor reserve estimate was well correlated with verbal memory function and with white matter integrity in the left fornix, suggesting a possible link between cognition and motor reserve in patients with PD.

Cerebral infarction is an uncommon and unusual cause of acute amnesia. The fornix is a white matter tract bundle that plays an important function in memory. We present the case of a 60-year-old male presenting with altered mental status and acute onset amnesia with CT and MR imaging demonstrating an acute left fornix infarct. This case serves to further illuminate the findings associated with this uncommon clinical event. In addition, it highlights the importance for physicians across multiple subspecialities to maintain an index of suspicion for fornix infarct in the evaluation of acute onset amnesia.

Identification of neural correlates of relapse to alcohol after treatment is clinically important as it may inform better substance abuse treatment. Few studies have specifically analyzed the white matter microstructure in treatment seekers as it might relate to relapse risk versus long-term abstinence. Using 4 Tesla diffusion tensor imaging, we compared two groups of one-month-abstinent treatment-seekers, who were classified based on their drinking status between six and nine months after treatment initiation. We hypothesized that subsequent relapsers had greater white matter microstructural deficits in specific brain regions than long-term abstainers. At one month of abstinence, 37 future relapsers versus 25 future abstainers had lower fractional anisotropy (a measure of axonal organization and membrane integrity) in the corpus callosum and right stria terminalis/fornix, higher diffusivity in the genu of the corpus callosum, left and right stria terminalis/fornix, and lower diffusivity in left anterior corona radiata. These differences existed despite similar lifetime and recent drinking and smoking histories in the groups. Longer smoking duration in relapsers was associated with lower fractional anisotropy in right stria terminalis/fornix. The study identified specific microstructural biomarkers of alcohol relapse risk in adults, contributing to the definition of a neurobiological relapse risk profile in alcohol use disorder.