Structural interhemispheric connectivity defects in mouse models of BBSOAS: Insights from high spatial resolution 3D white matter tractography.

White matter (WM) tract formation and axonal pathfinding are major processes in brain development allowing to establish precise connections between targeted structures. Disruptions in axon pathfinding and connectivity impairments will lead to neural circuitry abnormalities, often associated with various neurodevelopmental disorders (NDDs). Among several neuroimaging methodologies, Diffusion Tensor Imaging (DTI) is a magnetic resonance imaging (MRI) technique that has the advantage of visualizing in 3D the WM tractography of the whole brain non-invasively. DTI is particularly valuable in unpinning structural tract connectivity defects of neural networks in NDDs. In this study, we used 3D DTI to unveil brain-specific tract defects in two mouse models lacking the Nr2f1 gene, which mutations in patients have been proven to cause an emerging NDD, called Bosch-Boonstra-Schaaf Optic Atrophy (BBSOAS). We aimed to investigate the impact of the lack of cortical Nr2f1 function on WM morphometry and tract microstructure quantifications. We found in both mutant mice partial loss of fibers and severe misrouting of the two major cortical commissural tracts, the corpus callosum, and the anterior commissure, as well as the two major hippocampal efferent tracts, the post-commissural fornix, and the ventral hippocampal commissure. DTI tract malformations were supported by 2D histology, 3D fluorescent imaging, and behavioral analyses. We propose that these interhemispheric connectivity impairments are consistent in explaining some cognitive defects described in BBSOAS patients, particularly altered information processing between the two brain hemispheres. Finally, our results highlight 3DDTI as a relevant neuroimaging modality that can provide appropriate morphometric biomarkers for further diagnosis of BBSOAS patients.

Microglial phagolysosome dysfunction and altered neural communication amplify phenotypic severity in Prader-Willi Syndrome with larger deletion.

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.

A Hypothesis for Anatomical Pathways of Chronic Pelvic Pain of "Unknown Origin".

BACKGROUND: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a disabling bladder condition. ESSIC, the IC/BPS society defines two types of IC/BPS: with Hunner's lesion (HL) and without. Pathogenesis is stated as unknown, with no cure possible. Scheffler in 2021 reported cystoscopically validated cure of HL IC/BPS by repair of uterosacral ligaments (USLs) and in 2022, Goeschen reported non-HL IC/BPS cure in 198 women following USL repair. Both Scheffler and Goeschen hypothesized IC/BPS may be a phenotype of the Integral Theory's Posterior Fornix Syndrome "PFS" (chronic pelvic pain, OAB, and emptying dysfunctions) and therefore potentially curable. SUMMARY: The hypothesis explores whether visceral plexuses (VPs), due to weakened USLs support, serve as a primary source of pelvic pain impulses, leading to development of an inflammatory condition - for example, IC/BPS, a chronic inflammatory condition, which shares similarities with vulvodynia and complex regional pain syndrome (CRPS). According to our hypothesis, such conditions involve axon reflexes. Stimuli such as gravity applied to unsupported nerve branches within the visceral pelvic plexus, trigger centrally propagating impulses, which then progress antidromally to influence innervated tissues through cytokine release and nociceptor stimulation, perpetuating inflammatory processes at the end organs, and pain perception. KEY MESSAGES: The hypothesis raises the question, "are IC/BPS, vulvodynia, other pain sites, even nonbacterial "chronic prostatitis" in the male, different phenotypes of the chronic pelvic pain syndrome which includes PFS. If so, the hypothesis opens several new research directions and would predict inflammatory findings in tender end organ pain sites.

Altered fornix integrity is associated with sleep apnea-related hypoxemia in mild cognitive impairment.

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.

Isolated bilateral fornix anterior columns infarction with acute amnesia and fiber tracts damage, a case report.

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.

Acute amnestic syndrome in fornix lesions: a systematic review of reported cases with a focus on differential diagnosis.

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 non-iatrogenic 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 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.

Metastases and Primary Brain Tumors Affecting the Fornix of the Brain.

Background The aim of this study is to evaluate the clinical and radiological findings of metastatic tumors and primary brain tumors affecting the fornix. Methods  Between January 2015 and March 2023, we retrospectively evaluated 1087 patients of both sexes who underwent cranial magnetic resonance imaging (MRI) for a preliminary diagnosis of intracranial malignancy in the radiology department of our hospital. Two radiologists with six and 10 years of experience in MRI examination assessed the relationship between primary and metastatic tumors and the fornix. Results  Involvement of the fornix was diagnosed in 29 of the 1087 patients (2.66%), of which fornix was affected by metastatic lesions in 14 patients (48.2%) and primary tumors in 15 patients (51.7%). The majority of metastatic lesions were from lung and breast cancers, with other tumor types including osteosarcoma, renal cell carcinoma, pancreatic adenocarcinoma, pleomorphic sarcoma, and diffuse large B-cell lymphoma. Among all primary tumors, glioblastoma was the most common primary brain tumor invading the fornix, with other diagnoses including diffuse astrocytoma, medulloblastoma, and anaplastic oligodendroglioma. Metastatic and primary brain tumors affecting the fornix were detected over a broad timeline, from the time of diagnosis up to 120 months after diagnosis. A retrospective evaluation of medical records revealed memory deficits in four patients. Conclusion The fornix can be affected by both metastatic and primary brain tumors. It is crucial to understand the relevant neuroanatomical relationships when evaluating lesions that affect the fornix.

High Radiation Dose to the Fornix Causes Symptomatic Radiation Necrosis in Patients with Anaplastic Oligodendroglioma.

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.

Impoverished details with preserved gist in remote and recent spatial memory following hippocampal and fornix lesions.

INTRODUCTION: Cognitive Map Theory predicts that the hippocampus (HPC) plays a specialized, time-invariant role in supporting allocentric spatial memory, while Standard Consolidation Theory makes the competing prediction that the HPC plays a time-limited role, with more remote memories gaining independence of HPC function. These theories, however, are largely informed by the results of laboratory-based tests that are unlikely to simulate the demands of representing real-world environments in humans. Validation of these theories is further limited by an overall focus on spatial memory of newly encountered environments and on individuals with extensive lesions to the HPC and to surrounding medial temporal lobe (MTL) regions. The current study incorporates naturalistic tests of spatial memory based on recently and remotely encountered environments navigated by individuals with lesions to the HPC/MTL or that are limited to the HPC's major output, the fornix. METHODS: Four participants with bilateral HPC/MTL and/or fornix lesions drew sketch maps of recently and remotely experienced neighbourhoods and houses. Tests of the appearance, distances, and routes between landmarks from the same real-world environments were also administered. Performance on the tasks was compared to that of control participants closely matched in terms of exposure to the same neighbourhoods and home environments as well as to actual maps. RESULTS: The performance of individuals with fornix/MTL lesions was found to be largely comparable to that of controls on objective tests of spatial memory, other than one case who was impaired on remote and recent conditions for several tasks. The nature of deficits in recent and remote spatial memory were further revealed on house floorplan drawings, which contained spatial distortions, room/structure transpositions, and omissions, and on neighbourhood sketch maps, which were intact in terms of overall layout but sparse in details such as landmarks. CONCLUSION: Lab-based tests of spatial memory of newly learned environments are unlikely to fully capture patterns of spared and impaired representations of real-world environments (e.g., peripheral features, configurations). Naturalistic tasks, including generative drawing tasks, indicate that contrary to Cognitive Map Theory, neither HPC nor MTL are critical for allocentric gross representations of large-scale environments. Conversely, the HPC appears critical for representing detailed spatial information of local naturalistic environments and environmental objects regardless of the age of the memory, contrary to Standard Consolidation Theory.

Targeting papez circuit for cognitive dysfunction- insights into deep brain stimulation for Alzheimer's disease.

Hippocampus is the most widely studied brain area coupled with impairment of memory in a variety of neurological diseases and Alzheimer's disease (AD). The limbic structures within the Papez circuit have been linked to various aspects of cognition. Unfortunately, the brain regions that include this memory circuit are often ignored in terms of understanding cognitive decline in these diseases. To properly comprehend where cognition problems originate, it is crucial to clarify any aberrant contributions from all components of a specific circuit -on both a local and a global level. The pharmacological treatments currently available are not long lasting. Deep Brain Stimulation (DBS) emerged as a new powerful therapeutic approach for alleviation of the cognitive dysfunctions. Metabolic, functional, electrophysiological, and imaging studies helped to find out the crucial nodes that can be accessible for DBS. Targeting these nodes within the memory circuit produced significant improvement in learning and memory by disrupting abnormal circuit activity and restoring the physiological network. Here, we provide an overview of the neuroanatomy of the circuit of Papez along with the mechanisms and various deep brain stimulation targets of the circuit structures which could be significant for improving cognitive dysfunctions in AD.

Superior rectus/levator complex in acquired anophthalmic socket repaired with spheric implant-a computed tomography scan and topographic study.

AIM: To determine whether the levator palpebrae superioris (LPS)/superior rectus (SR) muscle complex, can influence the position of the upper lid and fornix in acquired anophthalmic sockets. METHODS: This comparative non-randomized and non-interventional study included retrospective data of 21 patients with unilateral acquired anophthalmic sockets repaired with spheric implants. High-resolution computed tomography (CT) measurements of the LPM/SR muscle complex and clinical topographic position of the upper lid, superior and inferior fornix depth in primary gaze position were evaluated. Demographic data were presented as frequency and percentage proportions and quantitative variables comparing the socket measurements with the normal contralateral orbit was statistically analyzed using non-parametric tests considering P<0.05. RESULTS: The anophthalmic orbits had a significantly shorter LPS length (P=0.01) and significantly thicker SR (P=0.02) than the normal orbit. Lagophthalmos was present in anophthalmic sockets but not in normal orbits (P=0.002), while levator function was normal in both (P>0.05, all comparisons). The superior fornix depth was similar in the anophthalmic socket and the contralateral normal orbit (P=0.192) as well the inferior fornix depth (P=0.351). CONCLUSION: Acquired anophthalmic sockets repaired with spheric implants have shorter LPS, thicker SR, and more lagophthalmos than normal orbits. The relationship of the LPS and SR with other orbital structures, associated with passive or active forces acting in the final position of the lids and external ocular prosthesis should be further investigated.

Multi-shell diffusion MRI of the fornix as a biomarker for cognition in Alzheimer's disease.

BACKGROUND AND PURPOSE: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Development of an MR-Guided Focused Ultrasound (MRgFUS) Lesioning Approach for the Fornix in the Rat Brain.

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.

Interstitial cystitis/bladder pain syndrome: when part of the posterior fornix syndrome is potentially curable surgically.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is defined as chronic pelvic pain plus a bladder symptom, usually urge. Evidence is offered to show IC/BPS forms part of the posterior fornix syndrome (PFS), which was defined in 1993 as: chronic pelvic pain (CPP), urge, frequency, nocturia, abnormal emptying, post-void residual urine, caused by uterosacral ligament (USL) laxity and cured or improved by USL repair. The IC/BPS definition implies that the urge and pain of IC/BPS is from a single (as yet unknown) pathogenic origin. However, when urge and pain are viewed from the perspective of the PFS, though both have the same lax USL origin, the anatomical pathway from lax USL to symptom manifestation is very different manifestation. For CPP the anatomical pathway is the inability of loose USLs to support pelvic visceral plexuses (VPs); it is hypothesized that inability of weak USLs to mechanically supports VPs, the afferent nerve synapse from end organs may fire off autologous afferent impulses to the brain which interprets them as pain from end organs such as urothelium, vulva, lower abdomen. For urge, the anatomical pathway is very different: lax USLs weaken the directional pelvic muscle forces which stretch the vagina to support the urothelial stretch receptors. The receptors fire off afferent impulses to the cortex at a lower bladder volume, and these are interpreted as "urge to go". Mechanical support of USLs relieves both pain and urge, as does USL repair.

Pubourethral and uterosacral male analogues suggest parallel male/female pelvic anatomy and symptom pathogenesis.

The thesis that functional/dysfunctional male/female pelvic floor anatomy are parallel, originated from two studies: a successful retropubic perineal male sling for post-prostatectomy stress urinary incontinence (SUI) and discovery of a male uterosacral ligament (USL) analogue, we named "prostatosacral ligament" (PSL). In 25 out of the studied 27 males (92.6%), it starts on both sides of the median sulcus of the prostate the ligament passes lateral to the rectum being fused with the lateral margin of the mesorectum before leaving it as it thins out to be attached posteriorly similar to the USL. The ultrasound data during straining in men and women showed the same three oppositely acting muscle vectors contracting around analogous ligaments, puboprostatic ligament (PPL) (male), and pubourethral ligament (PUL) (female). Further parallels were pubovesical ligaments (PVLs) and arc of Gilvernet as part of the continence and micturition mechanisms. Impressive evidence for parallel anatomy came from the successful cure of 22 males with post-prostatectomy SUI using a perineal retropubic tissue fixation system (TFS) minisling applied to the PPL using a similar methodology to that used in the female for PUL midurethral sling repair for cure of SUI. Laparoscopic evidence confirmed the prostate as a male analogue of the cervix, and PSLs as analogues of USLs: PSL origin from the prostate attached laterally to the mesorectum and inserted into the sacrum. Histologically, PSLs had identical features with USLs: collagen, elastin, smooth muscle, blood vessels and nerves. Virtually identical symptoms for "chronic prostatitis" (CP) and "posterior fornix syndrome" (PFS), such as chronic pelvic pain, overactive bladder (OAB), abnormal emptying, gave birth to the hypothesis, of a common pathogenesis for "CP" and "PFS", USL (or PSL) laxity. If this could be proven by "simulated operations", "CP", at least in theory, may be potentially correctible by PSL repair.

Age-related fornix decline predicts conservative response strategy-based slowing in perceptual decision-making.

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.

A Critical Examination of Ligamentous Pathogenesis of Bladder Pain/Lower Urinary Tract Symptoms Using the UEDA Criteria.

To critically analyse the relationship of bladder pain syndrome (BPS/IC), as defined, to the posterior fornix syndrome, "PFS" predictably co-occurring bladder urgency, frequency, nocturia, chronic pelvic pain, emptying symptoms/retention, caused by uterosacral ligament (USL) laxity and cured by USL repair. The starting and end points of this paper are the questions, "Are there arguments that BPS/IC can, in some cases, be linked to PFS?" And if so, "To what extent?" We used the criteria required by Ueda for proper diagnosis: "understanding symptoms, detecting abnormal findings and verifying them as a cause of the symptoms." Literature, diagnostic and surgical, indicate that chronic pelvic pain "of unknown origin" can be caused by unsupported visceral pelvic plexuses because of weak USLs; these cause fire of afferent impulses, which the brain mistakenly interprets as coming from the end-organ itself (i.e., genitourinary pain, lower urinary tract symptoms). The same lax USLs can also weaken the pelvic muscles which contract to stretch the vagina to support the urothelial stretch receptors from below: these may prematurely fire off afferent impulses to activate micturition at lower bladder volumes, interpreted as urgency. A speculum placed in the vagina can relieve pain and urgency by mechanically supporting the vaginal wall and USLs, thus predicting an eventual cure by USL repair. There is need to evaluate what percentage of women with known BPS/IC also pass the criteria for PFS. Identifying a significant percentage of BPS/IC women with the causative relation between PFS pathogenesis and BPS/ IC may open a new way of diagnosing and treating BPS/IC in some women.

Cognitive and brain morphological deviations in middle-to-old aged autistic adults: A systematic review and meta-analysis.

Cognitive challenges and brain structure variations are common in autism spectrum disorder (ASD) but are rarely explored in middle-to-old aged autistic adults. Cognitive deficits that overlap between young autistic individuals and elderlies with dementia raise an important question: does compromised cognitive ability and brain structure during early development drive autistic adults to be more vulnerable to pathological aging conditions, or does it protect them from further decline? To answer this question, we have synthesized current theoretical models of aging in ASD and conducted a systematic literature review (Jan 1, 1980 - Feb 29, 2024) and meta-analysis to summarize empirical studies on cognitive and brain deviations in middle-to-old aged autistic adults. We explored findings that support different aging theories in ASD and addressed study limitations and future directions. This review sheds light on the poorly understood consequences of aging question raised by the autism community to pave the way for future studies to identify sensitive and reliable measures that best predict the onset, progression, and prognosis of pathological aging in ASD.

Increased fiber density of the fornix in patients with chronic tinnitus revealed by diffusion-weighted MRI.

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.

Sex moderates the association between age and myelin water fraction in the cingulum and fornix among older adults without dementia.

Background: Decreasing white matter integrity in limbic pathways including the fornix and cingulum have been reported in Alzheimer's disease (AD), although underlying mechanisms and potential sex differences remain understudied. We therefore sought to explore sex as a moderator of the effect of age on myelin water fraction (MWF), a measure of myelin content, in older adults without dementia (N = 52). Methods: Participants underwent neuropsychological evaluation and 3 T MRI at two research sites. Multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) quantified MWF in 3 a priori regions including the fornix, hippocampal cingulum (CgH), and cingulate cingulum (CgC). The California Verbal Learning Test-Second Edition assessed learning and delayed recall. Multiple linear regressions assessed for (1) interactions between age and sex on regional MWF and (2) associations of regional MWF and memory. Results: (1) There was a significant age by sex interaction on MWF of the fornix (p = 0.002) and CgC (p = 0.005), but not the CgH (p = 0.192); as age increased, MWF decreased in women but not men. (2) Fornix MWF was associated with both learning and recall (ps < 0.01), but MWF of the two cingulum regions were not (p > 0.05). Results were unchanged when adjusting for hippocampal volume. Conclusion: The current work adds to the literature by illuminating sex differences in age-related myelin decline using a measure sensitive to myelin and may help facilitate detection of AD risk for women.