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Objective. With prolonged life expectancy, the incidence of memory deficits, especially in Alzheimer's disease (AD), has increased. Although multiple treatments have been evaluated, no promising treatment has been found to date. Deep brain stimulation (DBS) of the fornix area was explored as a possible treatment because the fornix is intimately connected to memory-related areas that are vulnerable in AD; however, a proper imaging biomarker for assessing the therapeutic efficiency of forniceal DBS in AD has not been established. Approach. This study assessed the efficacy and safety of DBS by estimating the optimal intersection volume between the volume of tissue activated and the fornix. Utilizing a gold-electroplating process, the microelectrode's surface area on the neural probe was increased, enhancing charge transfer performance within potential water window limits. Bilateral fornix implantation was conducted in triple-transgenic AD mice (3 × Tg-AD) and wild-type mice (strain: B6129SF1/J), with forniceal DBS administered exclusively to 3 × Tg-AD mice in the DBS-on group. Behavioral tasks, diffusion tensor imaging (DTI), and immunohistochemistry (IHC) were performed in all mice to assess the therapeutic efficacy of forniceal DBS. Main results. The results illustrated that memory deficits and increased anxiety-like behavior in 3 × Tg-AD mice were rescued by forniceal DBS. Furthermore, forniceal DBS positively altered DTI indices, such as increasing fractional anisotropy (FA) and decreasing mean diffusivity (MD), together with reducing microglial cell and astrocyte counts, suggesting a potential causal relationship between revised FA/MD and reduced cell counts in the anterior cingulate cortex, hippocampus, fornix, amygdala, and entorhinal cortex of 3 × Tg-AD mice following forniceal DBS. Significance. The efficacy of forniceal DBS in AD can be indicated by alterations in DTI-based biomarkers reflecting the decreased activation of glial cells, suggesting reduced neural inflammation as evidenced by improvements in memory and anxiety-like behavior., (Creative Commons Attribution license.)

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.

Long-term aluminum (Al) exposure increases the risk of mild cognitive impairment (MCI). The aim of the present study was to investigate the neural mechanisms of Al-induced MCI. In our study, a total of 52 individuals with occupational Al exposure >10 years were enrolled and divided into two groups: MCI (Al-MCI) and healthy controls (Al-HC). Plasma Al concentrations and Montreal Cognitive Assessment (MoCA) score were collected for all participants. And diffusion tensor imaging and resting-state functional magnetic resonance imaging were used to examine changes of white matter (WM) and functional connectivity (FC). There was a negative correlation between MoCA score and plasma Al concentration. Compared with the Al-HC, fractional anisotropy value for the right fornix (cres)/stria terminalis (FX/ST) was higher in the Al-MCI. Furthermore, there was a difference in FC between participants with and without MCI under Al exposure. We defined the regions with differing FC as a "pathway," specifically the connectivity from the right temporal pole to the right FX/ST, then to the right sagittal stratum, and further to the right anterior cingulate and paracingulate gyri and right inferior frontal gyrus, orbital part. In summary, we believe that the observed differences in WM integrity and FC in the right FX/ST between participants with and without MCI under long-term Al exposure may represent the neural mechanisms underlying MCI induced by Al exposure., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Zhang (张菲菲) et al.)

Prior studies have reported inconsistent results regarding the relationships between the integrity of the fornix and parahippocampal cingulum and both memory performance and longitudinal change in performance. In the present study, we examined associations in a sample of cognitively healthy older adults between free water-corrected fractional anisotropy (FA) metrics derived from the fornix and cingulum, baseline memory performance, and 3-year memory change. Neither fornix nor cingulum FA correlated with memory performance at baseline. By contrast, FA of each tract was predictive of memory change, such that greater FA was associated with less longitudinal decline. These associations remained significant after controlling for FA of other white matter tracts and for performance in other cognitive domains. Furthermore, fornix and cingulum FA explained unique variance in memory change. These results suggest that free water-corrected measures of fornix and parahippocampal cingulum integrity are reliable predictors of future memory change in cognitively healthy older adults. The findings for the fornix in particular highlight the utility of correcting for free water when estimating diffusion tensor imaging metrics of white matter integrity., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: 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., Methods: 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., Results: 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%., Conclusions: 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., Competing Interests: Conflict of interest The authors declare no commercial or financial conflict of interest., (Copyright © 2024 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Isolated fornix anterior column infarction has rarely been described and is difficult to assess accurately using conventional magnetic resonance imaging (MRI). We report the case of a 75-year-old female who experienced acute anterograde amnesia. MRI performed within 24 h after amnesia onset showed an isolated infarction of the bilateral anterior columns of the fornix on diffusion-weighted imaging (DWI). Her symptoms persisted for up to 50 days, and diffusion tensor imaging (DTI) showed disruption of the fiber tracts of the fornix. when acute amnesia syndrome onset, fornix anterior column infarction should be considered, and optimized DWI and DTI methods are needed to study the fornix in vivo in future research.

In March 2020, C.T., a kind, bright, and friendly young woman underwent surgery for a midline tumor involving her septum pellucidum and extending down into her fornices bilaterally. Following tumor diagnosis and surgery, C.T. experienced significant memory deficits: C.T.'s family reported that she could remember things throughout the day, but when she woke up in the morning or following a nap, she would expect to be in the hospital, forgetting all the information that she had learned before sleep. The current study aimed to empirically validate C.T.'s pattern of memory loss and explore its neurological underpinnings. On two successive days, C.T. and age-matched controls watched an episode of a TV show and took a nap or stayed awake before completing a memory test. Although C.T. performed numerically worse than controls in both conditions, sleep profoundly exacerbated her memory impairment, such that she could not recall any details following a nap. This effect was replicated in a second testing session. High-resolution MRI scans showed evidence of the trans-callosal surgical approach's impact on the mid-anterior corpus callosum, indicated that C.T. had perturbed white matter particularly in the right fornix column, and demonstrated that C.T.'s hippocampal volumes did not differ from controls. These findings suggest that the fornix is important for processing episodic memories during sleep. As a key output pathway of the hippocampus, the fornix may ensure that specific memories are replayed during sleep, maintain the balance of sleep stages, or allow for the retrieval of memories following sleep., (© 2023 Massachusetts Institute of Technology.)

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., (© 2023 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

The fornix, the limbic system's white matter tract connecting the extended hippocampal system to subcortical structures of the medial diencephalon, is strongly associated with learning and memory in humans and nonhuman primates (NHPs). Here, we sought to investigate alterations in structural connectivity across key cortical and subcortical regions after fornix transection in NHPs. We collected diffusion-weighted MRI (dMRI) data from three macaque monkeys that underwent bilateral fornix transection during neurosurgery and from four age- and cohort-matched control macaques that underwent surgery to implant a head-post but remained neurologically intact. dMRI data were collected from both groups at two time points, before and after the surgeries, and scans took place at around the same time for the two groups. We used probabilistic tractography and employed the number of tracking streamlines to quantify connectivity across our regions of interest (ROIs), in all dMRI sessions. In the neurologically intact monkeys, we observed high connectivity across certain ROIs, including the CA3 hippocampal subfield with the retrosplenial cortex (RSC), the anterior thalamus with the RSC, and the RSC with the anterior cingulate cortex (ACC). However, we found that, compared to the control group, the fornix-transected monkeys showed marked, significant, connectivity changes including increases between the anterior thalamus and the ACC and between the CA3 and the ACC, as well as decreases between the CA3 and the RSC. Our results highlight cortical and subcortical network changes after fornix transection and identify candidate indirect connectivity routes that may support memory functions after damage and/or neurodegeneration., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Deep brain stimulation (DBS) to the fornix is an investigational treatment for patients with mild Alzheimer's Disease. Outcomes from randomized clinical trials have shown that cognitive function improved in some patients but deteriorated in others. This could be explained by variance in electrode placement leading to differential engagement of neural circuits. To investigate this, we performed a post-hoc analysis on a multi-center cohort of 46 patients with DBS to the fornix (NCT00658125, NCT01608061). Using normative structural and functional connectivity data, we found that stimulation of the circuit of Papez and stria terminalis robustly associated with cognitive improvement (R = 0.53, p < 0.001). On a local level, the optimal stimulation site resided at the direct interface between these structures (R = 0.48, p < 0.001). Finally, modulating specific distributed brain networks related to memory accounted for optimal outcomes (R = 0.48, p < 0.001). Findings were robust to multiple cross-validation designs and may define an optimal network target that could refine DBS surgery and programming., (© 2022. The Author(s).)

Episodic memory relies on the coordination of widespread brain regions that reconstruct spatiotemporal details of an episode. These topologically dispersed brain regions can rapidly communicate through structural pathways. Research in animal and human lesion studies implicate the fornix-the major output pathway of the hippocampus-in supporting various aspects of episodic memory. Because episodic memory undergoes marked changes in early childhood, we tested the link between the fornix and episodic memory in an age window of robust memory development (ages 4-8 years). Children were tested on the stories subtest from the Children's Memory Scale, a temporal order memory task, and a source memory task. Fornix streamlines were reconstructed using probabilistic tractography to estimate fornix microstructure. In addition, we measured fornix macrostructure and computed free water. To assess selectivity of our findings, we also reconstructed the uncinate fasciculus. Findings show that children's memory increases from ages 4 to 8 and that fornix micro- and macrostructure increases between ages 4 and 8. Children's memory performance across nearly every memory task correlated with individual differences in fornix, but not uncinate fasciculus, white matter. These findings suggest that the fornix plays an important role in supporting the development of episodic memory, and potentially semantic memory, in early childhood., (Published by Oxford University Press 2022.)

Background and Purpose: The fornix-fimbria complex is mainly involved in emotions and memory. In brain MR imaging studies of young children, we have occasionally noted DWI hyperintensity in this region. The significance of this finding remains unclear. This study evaluated the DWI signal in the fornix-fimbria complex of children 0-2 years of age, including the frequency of signal hyperintensity and clinical context., Materials and Methods: Brain MR imaging of 714 children 0-2 years of age (mean, 11 months), performed between September 2018 and May 2021, was reviewed and evaluated for DWI signal changes in the fornix-fimbria. All children with available MR imaging studies including DWI were included. Children with poor image quality, poor visualization of the fornix-fimbria region, and missing medical data were excluded. Additional imaging findings were also evaluated. Demographic data were retrieved from the medical files. We compared the ADC values of the fimbria and fornix between children with and without signal changes. The unpaired 2-tailed Student t test and χ 2 test were used for statistical analysis., Results: DWI signal hyperintensity of the Fornix-fimbria complex was noted in 53 (7.4%) children (mean age, 10 months). Their mean ADC values were significantly lower than those of the children with normal DWI findings ( P  < .05). About half of the children had otherwise normal MR imaging findings. When detected, the most common abnormality was parenchymal volume loss (15%). The most common indication for imaging was seizures (26.5%)., Conclusions: DWI hyperintensity in the fornix-fimbria complex was detected in 7.4% of children 0-2 years of age. The etiology is not entirely clear, possibly reflecting a transient phenomenon., (© 2022 by American Journal of Neuroradiology.)

Acute episodes of amnestic syndrome can be a challenging diagnostic problem. Except for nonvascular etiology, thalamic strokes or infarction involving several temporal lobe structures has been reported in earlier cases. The authors report a patient who suddenly developed memory loss without any other focal neurologic deficits. Brain magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) performed 1 day after onset revealed acute infarction involving the bilateral fornix column and the genu of corpus callosum. Because simple fornix infarcts often have no obvious positive neurological signs, most of the related manifestations were provided by family members, are easy to be diagnosed falsely, and missed in clinical areas, we suggest that bilateral fornix infarction should be considered in the diagnosis of an acute onset amnestic syndrome.

Purpose: Cerebral amyloid angiopathy (CAA) is a common neuropathological finding and clinical entity that occurs independently and with co-existent Alzheimer's disease (AD) and small vessel disease. We compared diffusion tensor imaging (DTI) metrics of the fornix, the primary efferent tract of the hippocampus between CAA, AD and Mild Cognitive Impairment (MCI) and healthy controls., Methods: Sixty-eight healthy controls, 32 CAA, 21 AD, and 26 MCI patients were recruited at two centers. Diffusion tensor images were acquired at 3 T with high spatial resolution and fluid-attenuated inversion recovery (FLAIR) to suppress cerebrospinal fluid (CSF) and minimize partial volume effects on the fornix. The fornix was delineated with deterministic tractography to yield mean diffusivity (MD), axial diffusivity (AXD), radial diffusivity (RD), fractional anisotropy (FA) and tract volume. Volumetric measurements of the hippocampus, thalamus, and lateral ventricles were obtained using T1-weighted MRI., Results: Diffusivity (MD, AXD, and RD) of the fornix was highest in AD followed by CAA compared to controls; the MCI group was not significantly different from controls. FA was similar between groups. Fornix tract volume was ∼ 30% lower for all three patient groups compared to controls, but not significantly different between the patient groups. Thalamic and hippocampal volumes were preserved in CAA, but lower in AD and MCI compared to controls. Lateral ventricular volumes were increased in CAA, AD and MCI. Global cognition, memory, and executive function all correlated negatively with fornix diffusivity across the combined clinical group., Conclusion: There were significant diffusion changes of the fornix in CAA, AD and MCI compared to controls, despite relatively intact thalamic and hippocampal volumes in CAA, suggesting the mechanisms for fornix diffusion abnormalities may differ in CAA compared to AD and MCI., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

A tool was developed to automatically segment several subcortical limbic structures (nucleus accumbens, basal forebrain, septal nuclei, hypothalamus without mammillary bodies, the mammillary bodies, and fornix) using only a T1-weighted MRI as input. This tool fills an unmet need as there are few, if any, publicly available tools to segment these clinically relevant structures. A U-Net with spatial, intensity, contrast, and noise augmentation was trained using 39 manually labeled MRI data sets. In general, the Dice scores, true positive rates, false discovery rates, and manual-automatic volume correlation were very good relative to comparable tools for other structures. A diverse data set of 698 subjects were segmented using the tool; evaluation of the resulting labelings showed that the tool failed in less than 1% of cases. Test-retest reliability of the tool was excellent. The automatically segmented volume of all structures except mammillary bodies showed effectiveness at detecting either clinical AD effects, age effects, or both. This tool will be publicly released with FreeSurfer (surfer.nmr.mgh.harvard.edu/fswiki/ScLimbic). Together with the other cortical and subcortical limbic segmentations, this tool will allow FreeSurfer to provide a comprehensive view of the limbic system in an automated way., (Copyright © 2021. Published by Elsevier Inc.)

Social interaction complexity makes humans unique. But in times of social deprivation, this strength risks exposure of important vulnerabilities. Human social neuroscience studies have placed a premium on the default network (DN). In contrast, hippocampus (HC) subfields have been intensely studied in rodents and monkeys. To bridge these two literatures, we here quantified how DN subregions systematically covary with specific HC subfields in the context of subjective social isolation (i.e., loneliness). By codecomposition using structural brain scans of ∼40,000 UK Biobank participants, loneliness was specially linked to midline subregions in the uncovered DN patterns. These association cortex patterns coincided with concomitant HC patterns implicating especially CA1 and molecular layer. These patterns also showed a strong affiliation with the fornix white matter tract and the nucleus accumbens. In addition, separable signatures of structural HC-DN covariation had distinct associations with the genetic predisposition for loneliness at the population level. NEW & NOTEWORTHY The hippocampus and default network have been implicated in rich social interaction. Yet, these allocortical and neocortical neural systems have been interrogated in mostly separate literatures. Here, we conjointly investigate the hippocampus and default network at a subregion level, by capitalizing structural brain scans from ∼40,000 participants. We thus reveal unique insights on the nature of the "lonely brain" by estimating the regimes of covariation between the hippocampus and default network at population scale.

We investigate the characteristics of injury of four portions of the Papez circuit in patients with diffuse axonal injury (DAI), using diffusion tensor tractography (DTT). Thirty-four consecutive patients with DAI and 30 normal control subjects were recruited. Four portions of the Papez circuit were reconstructed: the fornix, cingulum, thalamocingulate tract, and mammillothalamic tract. Analysis of DTT parameters [fractional anisotropy (FA) and tract volume (TV)] and configuration (narrowing, discontinuation, or non-reconstruction) was performed for each portion of the Papez circuit. The Memory Assessment Scale (MAS) was used for the estimation of cognitive function. In the group analysis, decreased fractional anisotropy and tract volume of the entire Papez circuit were observed in the patient group compared with the control group (p < 0.05). In the individual analysis, all four portions of the Papez circuit were injured in terms of DTT parameters or configuration. Positive correlation was observed between TV of the fornix and short-term memory on MAS r = 0.618, p < 0.05), and between FA of the fornix and total memory on MAS (r = 0.613, p < 0.05). We found that all four portions of the Papez circuit in the patient group were vulnerable to DAI, and among four portions of the Papez circuit, the fornix was the most vulnerable portion in terms of injury incidence and severity., (© 2020. Belgian Neurological Society.)

Background: Although the interforniceal approach with the preservation of the fornix is useful during the endoscopic approach for retroforaminal colloid cysts, it carries a significant risk of memory and cognitive difficulties. Because most reports have reported the endoscopic approach to colloid cysts through the foramen with little emphasis on retroforaminal cysts, the aim of this study was to investigate colloid cysts as a special entity with regard to their different characteristics and surgical approaches and outcomes., Methods: In this retrospective study, 12 patients with third ventricular colloid cysts with retroforaminal extensions were included. All patients underwent endoscopic transseptal interforniceal approach with tumor resection. The surgical technique was briefly described, and preoperative and postoperative data were evaluated., Results: Among the 12 patients included in this study, most of our patients were males. Average diameter of the colloid cyst was relatively large (average 22 mm). Gross total resection was achieved in 10 cases (83.3%). The stable images showed no local recurrence in the long-term follow-up period except in 1 case at the 28-month follow-up period., Conclusions: Retroforaminal colloid cyst represents a unique entity that requires special attention to its mode of growth. The endoscopic approach for retroforaminal colloid cysts is nearly the same as that for foraminal cysts. It has a lower incidence rate of postoperative memory changes, lower chances of total resection, and lower incidence rate of hard contents. Moreover, sufficient knowledge on morbid anatomy is important to avoid fornix injury., (Copyright © 2021 Elsevier Inc. All rights reserved.)

While stress may be a potential mechanism by which childhood threat and deprivation influence mental health, few studies have considered specific stress-related white matter pathways, such as the stria terminalis (ST) and medial forebrain bundle (MFB). Our goal was to examine the relationships between childhood adversity and ST and MFB structural integrity and whether these pathways may provide a link between childhood adversity and affective symptoms and disorders. Participants were young adults (n = 100) with a full distribution of maltreatment history and affective symptom severity. Threat was determined by measures of childhood abuse and repeated traumatic events. Socioeconomic deprivation (SED) was determined by a measure of childhood socioeconomic status (parental education). Participants underwent diffusion spectrum imaging. Human Connectome Project data was used to perform ST and MFB tractography; these tracts were used as ROIs to extract generalized fractional anisotropy (gFA) from each participant. Childhood threat was associated with ST gFA, such that greater threat was associated with less ST gFA. SED was also associated with ST gFA, however, conversely to threat, greater SED was associated with greater ST gFA. Additionally, threat was negatively associated with MFB gFA, and MFB gFA was negatively associated with post-traumatic stress symptoms. Our results suggest that childhood threat and deprivation have opposing influences on ST structural integrity, providing new evidence that the context of childhood adversity may have an important influence on its neurobiological effects, even on the same structure. Further, the MFB may provide a novel link between childhood threat and affective symptoms., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Purposes: The recently developed myelin imaging method, inhomogeneous magnetization transfer (ihMT), is a surrogate measure of myelin content. The goal of the current study was to investigate alterations in myelin integrity in patients with recurrent major depressive disorder (rMDD)., Methods: Fifty-two patients with rMDD (36 female and 16 male) and 42 healthy controls (HC, 29 female and 13 male) were included. Two ihMT indices, quantitative ihMT (qihMT) and quantitative MT (qMT), were estimated from the ihMT data. A 50 white matter atlas was used to extract the regional quantitative values for each subject. The differences in qihMT and qMT values between the rMDD and HC groups were compared by a general linear model. Pearson correlation analyses were conducted to investigate associations between the significantly altered ihMT indices and clinical measures (Hamilton Depression Rating Scale scores and disease duration) in rMDD group., Results: The rMDD group showed significantly lower qihMT values in the fornix, left anterior limb of internal capsule, and left sagittal stratum, and lower qMT values in the fornix and left anterior limb of internal capsule than those of the HC group (p < 0.05, false discovery rate corrected). Both the qihMT and qMT values in the fornix of patients with rMDD were negatively correlated with disease duration (qihMT: r = -0.478, p < 0.001, Bonferroni corrected; qMT: r = -0.433, p = 0.001, Bonferroni corrected)., Conclusion: Our findings suggested that rMDD is associated with myelin impairment in the fornix, left anterior limb of internal capsule, and left sagittal stratum. In addition, this disruption of myelin integrity in the fornix could be cumulative as the disease progresses., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The fornix is the primary efferent pathway of the hippocampus and plays a central role in memory circuitry. Diffusion tensor imaging has shown changes in the fornix with typical development and aging. Here, the fornix was investigated in 903 healthy young adult participants aged 22-36 years old from the high-spatial resolution 1.25 mm isotropic Human Connectome Project (HCP) diffusion dataset. Manual deterministic tractography was used to assess relationships between fornix diffusion parameters and age, sex, laterality, hippocampus volume, memory scores, and genetic effects in a subgroup of mono- and dizygotic twins. Fornix diffusion metrics were weakly correlated with age over the given age span. While significant hemispheric and sex differences were observed (greater fractional anisotropy (FA) and volume in the right hemisphere; greater FA and volume in females), there was great overlap between the groups. Hippocampus volume measurements showed greater volume in the right hemisphere, were found to be larger in males, and were weakly correlated with fornix FA and volume. Interestingly, all fornix diffusion measurements correlated strongly with fornix volume, suggesting the presence of partial volume effects despite the high-spatial resolution of the data. Both fornix diffusion parameters and hippocampal volumes were able to explain some variance (0.6-5.5%) in the memory tests evaluated. The fornix diffusion parameters were influenced by both genetic and shared environmental factors, displaying greater variability in dizygotic than in monozygotic twins. These findings provide a comprehensive depiction of the fornix in healthy, young individuals, upon which future typical development/aging and pathological studies could anchor.

Novelty facilitates memory formation and is detected by both the dorsal and ventral hippocampus. Although dentate granule cells (GCs) in the dorsal hippocampus are known to mediate the formation of novelty-induced contextual memories, the required pathways and mechanisms remain unclear. Here we demonstrate that a powerful excitatory pathway from mossy cells (MCs) in the ventral hippocampus to dorsal GCs is necessary and sufficient for driving dorsal GC activation in novel environment exploration. In vivo Ca 2+ imaging in freely moving mice indicated that this pathway relays environmental novelty. Furthermore, manipulation of ventral MC activity bidirectionally regulates novelty-induced contextual memory acquisition. Our results show that ventral MC activity gates contextual memory formation through an intra-hippocampal interaction activated by environmental novelty., Competing Interests: Declaration of interests All authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Tractography is an important tool for the in vivo analysis of brain connectivity based on diffusion MRI data, but it also has well-known limitations in false positives and negatives for the faithful reconstruction of neuroanatomy. These problems persist even in the presence of strong anatomical priors in the form of multiple region of interests (ROIs) to constrain the trajectories of fiber tractography. In this work, we propose a novel track filtering method by leveraging the groupwise consistency of fiber bundles that naturally exists across subjects. We first formalize our groupwise concept with a flexible definition that characterizes the consistency of a track with respect to other group members based on three important aspects: degree, affinity, and proximity. An iterative algorithm is then developed to dynamically update the localized consistency measure of all streamlines via message passing from a reference set, which then informs the pruning of outlier points from each streamline. In our experiments, we successfully applied our method to diffusion imaging data of varying resolutions from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Human Connectome Project (HCP) for the consistent reconstruction of three important fiber bundles in human brain: the fornix, locus coeruleus pathways, and corticospinal tract. Both qualitative evaluations and quantitative comparisons showed that our method achieved significant improvement in enhancing the anatomical fidelity of fiber bundles., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Schizophrenia (SCZ) is associated with an increased risk of violence compared to the general population. Previous studies have indicated smaller hippocampal and amygdala volumes in violent than non-violent psychotic patients . However, little is known about volumetric differences at the subdivision level of these structures. In the present study, hippocampal subfields and amygdala nuclei volumes were estimated with FreeSurfer from 3 T MRI of SCZ patients with (SCZ-V, n = 24) and without (SCZ-NV, n = 51) a history of severe violence and 90 healthy controls (HC). Volumetric differences between groups were explored with a general linear model covarying for confounders, in addition to follow-up analyses in patient groups controlling for clinical characteristics such as antipsychotic medication, duration of illness and illicit substance use. SCZ-V had smaller total hippocampal volume and smaller CA1, HATA, fimbria, and molecular layer of DG volumes compared to HC. Total amygdala volume together with basal nucleus, accessory basal nucleus, CTA, and paralaminar nucleus volumes were smaller in SCZ-V compared to HC. In SCZ-NV, compared to HC, the observed smaller volumes were limited to basal and paralaminar nucleus. There were no significant differences in hippocampal subfield and amygdala nuclei volumes between SCZ-V and SCZ-NV. Follow-up analyses showed that the results in patient groups were not affected by clinical characteristics. The results suggest that smaller hippocampal subfield and amygdala nuclei volumes may be relevant to violence risk in SCZ. However, the neurobiological signature of violence in SCZ should be further investigated in larger cohorts.

Objectives: The authors investigated the topography of cholinergic vulnerability in patients with dementia with Lewy bodies (DLB) using positron emission tomography (PET) imaging with the vesicular acetylcholine transporter (VAChT) [ 18 F]-fluoroethoxybenzovesamicol ([ 18 F]-FEOBV) radioligand., Methods: Five elderly participants with DLB (mean age, 77.8 years [SD=4.2]) and 21 elderly healthy control subjects (mean age, 73.62 years [SD=8.37]) underwent clinical assessment and [ 18 F]-FEOBV PET., Results: Compared with the healthy control group, reduced VAChT binding in patients with DLB demonstrated nondiffuse regionally distinct and prominent reductions in bilateral opercula and anterior cingulate to mid-cingulate cortices, bilateral insula, right (more than left) lateral geniculate nuclei, pulvinar, right proximal optic radiation, bilateral anterior and superior thalami, and posterior hippocampal fimbria and fornices., Conclusions: The topography of cholinergic vulnerability in DLB comprises key neural hubs involved in tonic alertness (cingulo-opercular), saliency (insula), visual attention (visual thalamus), and spatial navigation (fimbria/fornix) networks. The distinct denervation pattern suggests an important cholinergic role in specific clinical disease-defining features, such as cognitive fluctuations, visuoperceptual abnormalities causing visual hallucinations, visuospatial changes, and loss of balance caused by DLB.

Background: The fimbria/fornix fiber system is an essential part of the hippocampal-VTA loop, and therefore activities that are propagated through this fiber system control the activity of the mesolimbic dopamine system., Objectives/hypothesis: We hypothesized that stimulation of the fimbria/fornix with an increasing number of electrical pulses would cause increasing activity of the mesolimbic dopamine system, which coincides with concurrent changes in neuronal activities in target regions of the mesolimbic dopaminergic system., Methods: Right fimbria/fornix fibers were electrically stimulated with different pulse protocols. Stimulus-induced changes in neuronal activities were visualized with BOLD-fMRI, whereas stimulus-induced release of dopamine, as measured for the activity of the mesolimbic dopamine system, was determined in the nucleus accumbens with in vivo fast-scan cyclic voltammetry., Results: Dependent on the protocol, electrical fimbria/fornix stimulation caused BOLD responses in various targets of the mesolimbic dopamine system. Stimulation in the low theta frequency range (5 Hz) triggered significant BOLD responses mainly in the hippocampal formation, infralimbic cortex, and septum. Stimulation in the beta frequency range (20 Hz) caused additional activation in the medial prefrontal cortex (mPFC), nucleus accumbens, striatum, and VTA. Stimulation in the high-gamma frequency range (100 Hz) caused further activation in the hippocampus proper and mPFC. The strong activation in the mPFC during 100 Hz stimulations depended not only on the number of pulses but also on the frequency. Thus, short bursts of 5 or 20 high-frequency pulses caused stronger activation in the mPFC than continuous 5 or 20 Hz pulses. In contrast, high-frequency burst fimbria/fornix stimulation did not further activate the mesolimbic dopamine system when compared to continuous 5 or 20 Hz pulse stimulation., Conclusions: There exists a frequency-dependent dissociation between BOLD responses and activation of the dopaminergic system. Low frequencies were more efficient to activate the mesolimbic dopamine system, whereas high frequencies were more efficient to trigger BOLD responses in target regions of the mesolimbic dopamine system, particularly the mPFC., Competing Interests: Declaration of competing interest The authors confirm that there are no known conflicts of interest associated with this publication and there has been no financial support for this work that could have influenced its outcome., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Diffusion tensor imaging (DTI) has shown abnormalities of the fornix and other limbic white matter tracts in multiple sclerosis (MS), mainly focusing on relapsing-remitting MS., Methods: The goal here was to evaluate the fornix, cingulum, and uncinate fasciculus with DTI tractography at 1.7 mm isotropic resolution in three MS subgroups (11 relapsing-remitting (RRMS), nine secondary progressive (SPMS), eight primary progressive (PPMS)) versus 11 controls, and assess correlations with cognitive and clinical scores., Results: The MS group overall showed extensive diffusion abnormalities of the fornix with less volume, lower fractional anisotropy (FA), and higher mean and radial diffusivities, which were similarly affected in all three MS subgroups. The uncinate fasciculus had lower FA only in the secondary progressive subgroup, and the cingulum had no DTI differences in any MS subgroup. The FA and/or volumes of these tracts correlated negatively with larger total lesion volume. The only DTI-cognitive correlation was lower right cingulum FA and greater depression over the entire MS cohort., Conclusions: Diffusion tractography identified abnormalities in the fornix that appears to be affected early and consistently across all three primary MS phenotypes of RRMS, SPMS, and PPMS regardless of Expanded Disability Status Scale, time since diagnosis, or cognitive scores., (© 2019 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Advancing age is associated with both declines in episodic memory and degradation of medial temporal lobe (MTL) structure. The contribution of MTL to episodic memory is complex and depends upon the interplay among hippocampal subfields and surrounding structures that participate in anatomical connectivity to the cortex through inputs (parahippocampal and entorhinal cortices) and outputs (fornix). However, the differential contributions of MTL system components in mediating age effects on memory remain unclear. In a sample of 177 healthy individuals aged 20-94 we collected high-resolution T1-weighted, ultrahigh-resolution T2/PD, and diffusion tensor imaging (DTI) MRI sequences on a 3T Phillips Achieva scanner. Hippocampal subfield and entorhinal cortex (ERC) volumes were measured from T2/PD scans using a combination of manual tracings and training of a semiautomated pipeline. Parahippocampal gyrus volume was estimated using Freesurfer and DTI scans were used to obtain diffusion metrics from tractography of the fornix. Item and associative episodic memory constructs were formed from multiple tests. Competing structural equation models estimating differential association among these structural variables were specified and tested to investigate whether and how fornix diffusion and volume of parahippocampal gyrus, ERC, and hippocampal subfields mediate age effects on associative and/or item memory. The most parsimonious, best-fitting model included an anatomically based path through the MTL as well as a single hippocampal construct which combined all subfields. Results indicated that fornix microstructure independently mediated the effect of age on associative memory, but not item memory. Additionally, all regions and estimated paths (including fornix) combined to significantly mediate the age-associative memory relationship. These findings suggest that preservation of fornix connectivity and MTL structure with aging is important for maintenance of associative memory performance across the lifespan., (© 2019 Wiley Periodicals, Inc.)

Introduction : Aging is associated with heterogeneous cognitive trajectories. There is considerable interest in identifying risk factors for pathological aging, with recent studies demonstrating a link between surgical procedures and proximal cognitive decline; however, the role of lifetime exposure to surgical procedures and cognitive function has been relatively unexplored. This pilot study aimed to evaluate the association between total lifetime surgical procedures and memory function in older adults. Methods : A cohort of 62 older adults underwent a neuropsychological evaluation and health history assessment. Self-reported lifetime surgical history was categorized as "cardiac" or "non-cardiac." General linear models were fit with demographics as nuisance covariates, and the total number of non-cardiac surgeries as our predictor of interest. Total scores on measures of episodic memory, language, working memory, fluency, and visuospatial function were separate outcome variables. In a secondary analysis, vascular risk factors were included as covariates. Diffusion tensor imaging was obtained for exploratory analyses of selected regions of interest. Results : The mean age of participants was 70, and 0-13 lifetime non-cardiac surgical procedures were reported. Higher numbers of lifetime non-cardiac surgical procedures were associated with worse verbal learning and memory ( p = .04). The negative association between lifetime non-cardiac procedures and cognition was specific to memory. Exploratory analyses showed that higher number of lifetime non-cardiac procedures was related to lower FA in the fornix body ( p = .02). Conclusions : These results of this pilot study suggest that greater lifetime exposure to surgery may be associated with worse verbal learning and memory in healthy older adults. These findings add to a growing body of literature suggesting that cumulative medical events may be risk factors for negative cognitive outcomes.

Introduction: The earliest changes in the brain due to Alzheimer's disease are associated with the neural networks related to memory function. We investigated changes in functional and structural connectivity among regions that support memory function in prodromal Alzheimer's disease, i.e., during the mild cognitive impairment (MCI) stage., Methods: Twenty-three older healthy controls and 25 adults with MCI underwent multimodal MRI scanning. Limbic white matter tracts-the fornix, parahippocampal cingulum, retrosplenial cingulum, subgenual cingulum and uncinate fasciculus-were reconstructed in ExploreDTI using constrained spherical deconvolution-based tractography. Using a network-of-interest approach, resting-state functional connectivity time-series correlations among sub-parcellations of the default mode and limbic networks, the hippocampus and the thalamus were calculated in Conn., Analysis: Controlling for age, education, and gender between group linear regressions of five diffusion-weighted measures and of resting state connectivity measures were performed per hemisphere. FDR-corrections were performed within each class of measures. Correlations of within-network Fisher Z-transformed correlation coefficients and the mean diffusivity per tract were performed. Whole-brain graph theory measures of cluster coefficient and average path length were inspecting using the resting state data., Results & Conclusion: MCI-related changes in white matter structure were found in the fornix, left parahippocampal cingulum, left retrosplenial cingulum and left subgenual cingulum. Functional connectivity decreases were observed in the MCI group within the DMN-a sub-network, between the hippocampus and sub-areas -a and -c of the DMN, between DMN-c and DMN-a, and, in the right hemisphere only between DMN-c and both the thalamus and limbic-a. No relationships between white matter tract 'integrity' (mean diffusivity) and within sub-network functional connectivity were found. Graph theory revealed that changes in the MCI group was mostly restricted to diminished between-neighbour connections of the hippocampi and of nodes within DMN-a and DMN-b., Competing Interests: The authors have declared that no competing interests exist.

The fornix is the primary efferent white matter tract of the hippocampus and is implicated in episodic memory. In this study, we investigated whether baseline measures of altered fornix microstructure and elevated beta amyloid (Aβ) burden influence prospective cognitive decline. A secondary goal examined whether Aβ burden is negatively associated with fornix microstructure. 253 clinically normal older adults underwent diffusion-weighted imaging and Pittsburgh Compound B positron emission tomography at baseline. We applied a novel streamline tractography protocol to reconstruct a fornix bundle in native space. Cognition was measured annually in domains of episodic memory, executive function, and processing speed (median follow-up = 4.0 ± 1.4 years). After controlling for covariates, linear mixed-effects models demonstrated an interaction of fornix microstructure with Aβ burden on episodic memory, such that combined lower fornix microstructure and higher Aβ burden was associated with accelerated decline. By contrast, associations with executive function and processing speed were not significant. There was no cross-sectional association between Aβ burden and fornix microstructure. In conclusion, altered fornix microstructure may accelerate memory decline in preclinical Alzheimer's disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The fornix is a region of greatest neurosurgical interest in regards to its complex anatomy and surgical approaches to this area. The objective of this study was to evaluate the morphology of the triangular recess (TR) and its role in the growth pattern of the colloid cysts (CC) within the third ventricle and in the choice of the surgical approach for their removal. Furthermore, to compare the results of the dissections with measurements performed on a magnetic resonance imaging scan., Methods: In the anatomic study, 20 cadaveric specimens were dissected and analyzed. In the radiologic study, a magnetic resonance imaging scan was performed in 20 healthy volunteers. In the clinical study, a retrospective analysis of all the patients affected with CCs microsurgically removed at our institute between 2010 and 2018 was conducted., Results: In the anatomic study, the width, height, and the area of the TR were respectively 0.31 cm, 0.33cm, and 0.051 cm 2 . In the radiologic study, 3 different typologies of TR were identified: open recess in ventriculomegaly (7 patients); open recess in physiologic ventricular system (3 patients); closed or blind recess (10 patients). Three different growth patterns of CCs were identified: type 1) CCs localized at the foramen of Monro growing behind the fornix and below the third ventricular roof; type 2) CCs growing rostrally between the column of fornix; and type 3) CCs growing above the plane of the third ventricular roof., Conclusions: The anatomy of the TR influences the growth pattern of CC within the ventricular cavity and determines the surgical strategy for their removal., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The tumors in third ventricle are common intracranial tumors in children, characterized by various pathological types and difficult to be removed. The transcallosal interforniceal approach is often used for these tumors. The separation of bilateral fornix causes multiple surgical complications. In the past, complications could only be assessed by clinical feature and traditional imaging, lack of quantitative data to support. Resting-state functional magnetic resonance imaging (rs-fMRI) can assess brain functional connectivity between local regions and different regions in quiet state. The changes of ReHo, ALFF, fALFF and brain function connections (DMN and Hippocampus as ROI) can be used to evaluate the effects caused by operation., Objective: To evaluate the effects of brain function caused by operation., Methods: 9 children patients with tumors in third ventricle were randomly selected in Yuquan hospital, and scanned by rs-fMRI before and after operation. ReHo, ALFF, fALFF and function connections (DMN and Hippocampus as ROI) were chosen to analyze rs-fMRI data., Results: The results of ReHo, ALFF, fALFF and brain function connections (DMN and Hippocampus as ROI) showed that: (1) Compared with preoperative state, ReHo decreased in left superior frontal gyrus in 1 month after operation, while increased in right middle occipital gyrus, right middle temporal gyrus, and left posterior central gyrus. In 2 months after operation, ReHo decreased in left superior temporal gyrus and right precentral gyrus compared with that in 1 month after operation. (2) Compared with preoperative state, ALFF decreased in left middle frontal gyrus and increased in left superior temporal gyrus in 1 month after operation; ALFF decreased in right fusiform gyrus and right supramarginal gyrus, while increased in left parahippocampal gyrus and left caudate nucleus in 2 months after operation. When compared with these in 1 month after operation, ALFF decreased in right fusiform gyrus and left precentral gyrus in 2 months after operation. (3) Compared with preoperative state, fALFF decreased in left superior frontal gyrus in 1 month after operation, and decreased in left middle frontal gyrus in 2 months after surgery. (4) The connections of DMN showed that enhanced connections of bilateral middle frontal gyrus and other regions in 1 month after operation, which restored to preoperative state in 3 months after operation. (5) There were changes of connections between bilateral hippocampus and related brain regions without any interruption occurred. The effects of approach can disappear in 3 months after operation., Conclusions: The short-term effects of ReHo, ALFF and fALFF in brain regions of children patients can recover to preoperative state with time. The operation did not interrupt the connections between DMN and hippocampus related brain areas. The effects of surgery can restore to the preoperative state in 3 months after operation., (Copyright © 2019. Published by Elsevier Inc.)

Objective: White 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., Method: Fractional 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., Results: Memory 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., Conclusions: Memory and executive functions are associated with different patterns of WM diffusivity. Findings add insight into WM alterations underlying age- and disease-related cognitive decline.

Purpose: The objective of this review is to provide a structured approach to the main white matter commissures, their anatomic and radiological definition and disease implications., Methods: The Pubmed database and The JAMA Network were used for the literature review and the following terms were searched using Sort by: Best Match and Sort by: Most Recent: telencephalic commissure, forebrain commissure anatomy, fornix anatomy, commissure of fornix, posterior commissure, corpus callosum, commissural agenesis, Probst bundle, corpus callosum disorders review, corpus callosum diseases review, Marchiafava-Bignami, Alzheimer's disease and Forel commissure; 36 papers were selected, one excluded due to the language barrier., Results: The interhemispheric communication in the brain is achieved via the brain commissures, bundles of white matter linking the two cerebral hemispheres. Anterior white commissure (AWC)-related with olfactory and non-visual communication, hippocampal commissure-main efferent pathway of the hippocampus, connecting the hippocampal formation to structures beyond the temporal lobe, crucial in declarative memory formation and consolidation-and the corpus callosum (CC)-from the anterior commissure to the hippocampal commissure-are the main telencephalic commissures. Supramammilary commissure, posterior commissure, supraoptic commissure and habenular commissure are diencephalic commissures-unknown function, probably related to involuntary eye movements. Commissural agenesis (AWC is absent or impossible to recognize), Alzheimer's Disease (hippocampal commissure may contribute for disease dissemination) and agenesis of corpus callosum are some of the disturbances that involve the telenchephalic commissures., Conclusions: A comprehensive understanding of the clinic-anatomic correlation is pivotal to understand the pathology and therefore improve our diagnostic accuracy and treatment options, in the background of all patient management.

Objective: Diffusion magnetic resonance imaging (dMRI) enables non-invasive characterization of white matter (WM) structures in vivo. Prior studies suggest that certain WM tracts may be affected in major depressive disorder (MDD), however, hippocampal subfield-specific dMRI measures have not yet been explored in MDD. We use 7 Tesla dMRI to investigate differences in hippocampal subfield connectivity of MDD patients., Methods: Eighteen MDD patients and eighteen matched healthy volunteers underwent 7 Tesla MRI. The hippocampal formations were segmented by subfields and tractography was performed to determine streamline count (SC), fractional anisotropy (FA), and mean diffusivity (MD) in patients and controls. Significant subfield connectivity measures were also correlated with age at depression onset., Results: Compared with controls, MDD patients exhibited reduced SC in the molecular layer of the left dentate gyrus (p < 0.001). SC count in the left dentate gyrus was shown to positively correlate with age at disease onset (p < 0.05). Increased MD was observed in streamlines emanating from both the left (p = 0.0001) and right (p < 0.001) fimbriae in MDD patients., Conclusions: Increased MD of tracts in the fimbriae suggests compromised neuronal membranes in the major hippocampal output gate. Reduced SC of the dentate gyri indexes a disruption of normal cellular processes such as neurogenesis. These findings may have significant implications for identifying biomarkers of MDD and elucidating the neurobiological underpinnings of depression., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Midlife obesity is a risk factor of late onset Alzheimer's disease (LOAD) but why this is the case remains unknown. As systemic inflammation is involved in both conditions, obesity-related neuroinflammation may contribute to damage in limbic structures important in LOAD. Here, we investigated the hypothesis that systemic inflammation would mediate central obesity related effects on limbic tissue microstructure in 166 asymptomatic individuals (38-71 years old). We employed MRI indices sensitive to myelin and neuroinflammation [macromolecular proton fraction (MPF) and k f ] from quantitative magnetization transfer (qMT) together with indices from neurite orientation dispersion and density imaging (NODDI) to investigate the effects of central adiposity on the fornix, parahippocampal cingulum, uncinate fasciculus (compared with whole brain white matter and corticospinal tract) and the hippocampus. Central obesity was assessed with the Waist Hip Ratio (WHR) and abdominal visceral and subcutaneous fat area fractions (VFF, SFF), and systemic inflammation with blood plasma concentrations of leptin, adiponectin, C-reactive protein and interleukin 8. Men were significantly more centrally obese and had higher VFF than women. Individual differences in WHR and in VFF were negatively correlated with differences in fornix MPF and k f , but not with any differences in neurite microstructure. In women, age mediated the effects of VFF on fornix MPF and k f , whilst in men differences in the leptin and adiponectin ratio fully mediated the effect of WHR on fornix MPF. These results suggest that visceral fat related systemic inflammation may damage myelin-related properties of the fornix, a key limbic structure known to be involved in LOAD., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Aging leads to gray and white matter decline but their causation remains unclear. We explored two classes of models of age and dementia risk related brain changes. The first class of models emphasises the importance of gray matter: age and risk-related processes cause neurodegeneration and this causes damage in associated white matter tracts. The second class of models reverses the direction of causation: aging and risk factors cause white matter damage and this leads to gray matter damage. We compared these models with linear mediation analysis and quantitative MRI indices (from diffusion, quantitative magnetization transfer and relaxometry imaging) of tissue properties in two limbic structures implicated in age-related memory decline: the hippocampus and the fornix in 166 asymptomatic individuals (aged 38-71 years). Aging was associated with apparent glia but not neurite density damage in the fornix and the hippocampus. Mediation analysis supported white matter damage causing gray matter decline; controlling for fornix glia damage, the correlations between age and hippocampal damage disappear, but not vice versa. Fornix and hippocampal differences were both associated with reductions in episodic memory performance. These results suggest that fornix white matter glia damage may cause hippocampal gray matter damage during age-dependent limbic decline.

Objective: To investigate relationships between cognitive domains and white matter changes in different regions in patients with cognitive deficits after traumatic brain injury (TBI)., Methods: Databases including PubMed, Embase, Web of Science and CENTRAL were searched for studies published before 5 August 2017. Correlation coefficients between cognition and white matter integrity, measured by diffusion metrics, including fractional anisotropy (FA), were pooled from 49 studies including 1405 patients. The influence of demographic factors was assessed by meta-regression analysis., Results: Significant pooled FA-executive correlations (p<0.001) were found across various regions, including the corpus callosum (CC) (r=0.42, 95% CI 0.30 to 0.54), superior longitudinal fasciculus (r=0.50, 95% CI 0.41 to 0.59) and internal capsule (IC) (r=0.49, 95% CI 0.37 to 0.61). The fornix (r=0.62, 95% CI 0.45 to 0.78) and cingulum (r=0.57, 95% CI 0.34 to 0.81) particularly correlated with memory (p<0.001). The CC and IC also showed significant relationships with attention and processing speed (p<0.001). Demographic factors had no influence overall, except that studies with a greater proportion of males had stronger correlations between memory and white matter (p<0.05)., Conclusions: FA is the most sensitive metric for detecting post-TBI cognitive decline across various domains. Representative white matter regions, such as the CC and IC, perform better than whole-brain white matter for reflecting a wide range of cognitive domains, including memory, attention and executive functions. Moreover, the fornix and cingulum particularly reflect memory function. They yield insights into particular imaging indicators that have neuropsychological value., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: We investigated the relation between memory impairment and the fornix injury in patients with mild traumatic brain injury, using diffusion tensor tractography., Design: Eighty-six chronic patients with mild traumatic brain injury and 50 normal control subjects were recruited. Fractional anisotropy and fiber volume were measured for each reconstructed fornix. The patients were classified according to the following three types: type A (47 patients), intact integrity of both fornical crura; type B (27 patients), showed a discontinuation in either fornical crus; and type C (12 patients), discontinuations in both fornical crura. The Memory Assessment Scale was used for evaluation of memory function., Results: Fractional anisotropy and fiber volume showed weak positive correlations with global memory of Memory Assessment Scale, respectively (r = 0.303, P = 0.006; r = 0.271, P = 0.014). Significant difference in the global memory of Memory Assessment Scale was observed between type A and B and between type A and C without difference between type B and C (P < 0.05)., Conclusion: It seems that the diffusion tensor tractography parameters of the fornix and the integrity of fornical crus can be used as a biomarker for axonal injury of the fornix in patients with mild traumatic brain injury.

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., (Copyright © 2018. Published by Elsevier B.V.)

BACKGROUND The fornix is a white matter tract bundle that acts as the major output of the hippocampus and is an important component of the Papez circuit. We present an instructive imaging case of sudden onset of persistent amnesia due to selective ischemic damage of the anterior fornix. CASE REPORT A 54-year-old Japanese male came to our attention for a sudden onset of retrograde amnesia, associated with severe anterograde amnesia. The brain magnetic resonance imaging demonstrated a bright diffusion restriction, which was associated with swollen fornices bilaterally. His symptoms gradually improved, but episodic memory impairment still persisted after 1 month. The coronal T1-weighted MPRAGE (magnetization-prepared rapid acquisition with gradient echo) sequence clearly showed disruption of the left anterior fornix. Diffusion tensor tracking showed decrease in the density of entire fiber tracts on the Papez circuit as well as location of the left fornix. CONCLUSIONS When dealing with sudden, persistent amnesia associated with small fornix infarction, it is prudent to consider the possibility of tract damage along with limbic system damage using MPRAGE sequence.

Stroke is a devastating neurovascular disorder that results in damage to neurons and white matter tracts. It has been previously demonstrated that neuregulin-1 (NRG-1) protects neurons from ischemic injury following stroke. Here, diffusion tensor imaging (DTI) was utilized to characterize the effects of NRG-1 treatment on cererbral infarction and integrity of white matter after ischemic insult using a permanent middle celebral artery occlusion (pMCAo) rat model. In the present study, sixteen Sprague-Dawley rats underwent pMCAo surgery and received either a single intra-arterial bolus (20 μg/kg) dose of NRG-1 or saline immediately prior to pMCAo. MRI including T2-weighted imaging and DTI was performed in the first 3 h post stroke, and repeated 48 h later. It is found that the stroke infarction was significantly reduced in the NRG-1 treated group. Also, NRG-1 prevented the reduction of fractional anisotropy (FA) in white matter tracts of fornix and corpus callosum (CC), indicating its protection of CC and fornix white matter bundles from ischemia insult. As a conclusion, the present DTI results demonstrate that NRG-1 has significantly neuroprotective effects in both cerebral cortex and white matter including corpus callosum and fornix during acute stroke. In particular, NRG-1 is more effective on stroke lesion with mild ischemia. As CC and fornix white matter bundles play critical roles in transcallosal connectivity and hippocampal projections respectively in the central nervous system, the findings could provide complementary information for better understanding the biological mechanism of NRG-1's neuroprotection in ischemic tissues and neurobehavioral effects., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Mechanism-based treatments for schizophrenia are needed, and increasing evidence suggests that oxidative stress may be a target. Previous research has shown that N-acetylcysteine (NAC), an antioxidant and glutathione (GSH) precursor almost devoid of side effects, improved negative symptoms, decreased the side effects of antipsychotics, and improved mismatch negativity and local neural synchronization in chronic schizophrenia. In a recent double-blind randomized placebo-controlled trial by Conus et al., early psychosis patients received NAC add-on therapy (2700 mg/day) for 6 months. Compared with placebo-treated controls, NAC patients showed significant improvements in neurocognition (processing speed) and a reduction of positive symptoms among patients with high peripheral oxidative status. NAC also led to a 23% increase in GSH levels in the medial prefrontal cortex (GSH mPFC ) as measured by 1 H magnetic resonance spectroscopy. A subgroup of the patients in this study were also scanned with multimodal MR imaging (spectroscopy, diffusion, and structural) at baseline (prior to NAC/placebo) and after 6 months of add-on treatment. Based on prior translational research, we hypothesized that NAC would protect white matter integrity in the fornix. A group × time interaction indicated a difference in the 6-month evolution of white matter integrity (as measured by generalized fractional anisotropy, gFA) in favor of the NAC group, which showed an 11% increase. The increase in gFA correlated with an increase in GSH mPFC over the same 6-month period. In this secondary study, we suggest that NAC add-on treatment may be a safe and effective way to protect white matter integrity in early psychosis patients.