Regulation of THI and PDC genes by Pdc2 in Nakaseomyces glabratus (Candida glabrata) is complex.

Thiamine (vitamin B1) is essential for glucose catabolism. In the yeast species Nakaseomyces glabratus (formerly Candida glabrata) and Saccharomyces cerevisiae, the transcription factor Pdc2 (with Thi3 and Thi2) upregulates pyruvate decarboxylase (PDC) genes and thiamine biosynthetic and acquisition (THI) genes during starvation. There have not been genome-wide analyses of Pdc2 binding. Previously, we identified small regions of Pdc2 regulated genes sufficient to confer thiamine regulation. Here, we performed deletion analyses on these regions. We observed that when the S. cerevisiae PDC5 promoter is introduced into N. glabratus, it is thiamine starvation inducible but does not require the Thi3 coregulator. The ScPDC5 promoter contains a 22 bp duplication with an AT-rich spacer between the two repeats, which are important for regulation. Loss of the first 22 bp element does not eliminate regulation, but the promoter becomes Thi3-dependent, suggesting cis architecture can generate a Thi3-independent, thiamine starvation inducible response. Whereas many THI promoters only have one copy of this element, addition of the first 22 bp element to a Thi3-dependent promoter confers Thi3-independence. Finally, we performed fluorescence anisotropy and ChIP-seq. Pdc2 and Thi3 bind to regions that share similarity to the 22 bp element in the ScPDC5 promoter and previously identified cis elements in N. glabratus promoters. Also, while Pdc2 binds to THI and PDC promoters, neither Pdc2 nor Thi3 appear to bind the evolutionarily new NgPMU3 promoter that is regulated by Pdc2. Further study is warranted because PMU3 is required for cells to acquire thiamine from environments where thiamine is phosphorylated, such as in the human bloodstream.

Focal motor weakness and recovery following chronic subdural hematoma evacuation.

OBJECTIVE: The incidence of chronic subdural hematomas (cSDHs) is expected to climb precipitously in the coming decades because of the aging populous. Neurological weakness is one of the most common presenting neurological symptoms of cSDH. Yet, the recovery rates of motor strength recovery are seldom documented, as neurological outcomes have predominantly focused on broader functional assessment scores or mortality. In this study, the authors performed one of the first detailed analyses on functional motor weakness and recovery in patients who underwent cSDH evacuation. METHODS: Patients who underwent evacuation of a cSDH at a tertiary academic medical center between November 2013 and December 2021 were retrospectively identified using ICD-9 and ICD-10 billing codes. The presence of focal motor weakness was subcategorized by location as upper extremity (UE) or lower extremity (LE). Postoperative improvement, worsening, or resolution of weakness was recorded at the time of discharge. Statistical analysis included univariate and backward stepwise multivariable logistic regression modeling. RESULTS: A total of 311 patients were included in the analysis. Patients were significantly more likely to experience UE weakness than LE weakness (29% vs 18%, p < 0.001). Forty-one percent (43/104) had both UE and LE weakness present. Risk factors for the development of focal motor weakness at the time of presentation were older age (OR 1.02, p = 0.03), increased cSDH size (OR 1.04, p = 0.02), and the presence of a unilateral cSDH (OR 2.32, p = 0.008). The majority of patients (68%, 71/104) experienced motor strength improvement following cSDH evacuation, with 58% (60/104) having complete resolution of weakness. Multivariable logistic regression analysis revealed that longer symptom duration was associated with lower rates of improvement (OR 0.96, p = 0.024). Older age was also associated with reduced resolution of weakness (OR 0.96, p = 0.02). CONCLUSIONS: This study represents one of the first in-depth analyses investigating the rates of motor strength weakness and recovery following cSDH evacuation. Nearly two-thirds of all patients had complete resolution of their weakness by the time of discharge, and more than three-quarters had partial improvement. Risk factors for impaired neurological recovery were longer symptom duration prior to treatment and older age.

A proposed stratification system to address the heterogeneity of Subdural Hematoma Outcome reporting in the literature.

A major challenge within the academic literature on SDHs has been inconsistent outcomes reported across studies. Historically, patients have been categorized by the blood-product age identified on imaging (i.e., acute, subacute, or chronic). However, this schematic has likely played a central role in producing the heterogeneity encountered in the literature. In this investigation, a total of 494 patients that underwent SDH evacuation at a tertiary medical center between November 2013-December 2021 were retrospectively identified. Mechanism of injury was reviewed by the authors and categorized as either positive or negative for a high-velocity impact (HVI) injury. Any head strike injury leading to the formation of a SDH while traveling at a velocity beyond that of normal locomotion or daily activities was categorized as an HVI. Patients were subsequently stratified by those with an acute SDHs after a high-velocity impact (aSDHHVI), those with an acute SDH without a high-velocity impact injury (aSDHWO), and those with any combination of subacute or chronic blood products (mixed-SDH [mSDH]). Nine percent (n = 44) of patients experienced an aSDHHVI, 23% (n = 113) aSDHWO, and 68% (n = 337) mSDH. Between these groups, highly distinct patient populations were identified using several metrics for comparison. Most notably, aSDHHVI had a significantly worse neurological status at discharge (50% vs. 23% aSDHWO vs. 8% mSDH; p < 0.001) and mortality (25% vs. 8% aSDHWO vs. 4% mSDH; p < 0.001). Controlling for gender, midline shift (mm), and anticoagulation use in the acute SDH population, multivariable logistic regression revealed a 6.85x odds ratio (p < 0.001) for poor outcomes in those with a positive history for a high-velocity impact injury. As such, the distribution of patients that suffer an HVI related acute SDH versus those that do not can significantly affect the outcomes reported. Adoption of this stratification system will help address the heterogeneity of SDH reporting in the literature while still closely aligning with conventional reporting.

Optic Nerve Sheath MR Imaging Measurements in Patients with Orthostatic Headaches and Normal Findings on Conventional Imaging Predict the Presence of an Underlying CSF-Venous Fistula.

BACKGROUND AND PURPOSE: Spontaneous spinal CSF leaks typically cause orthostatic headache, but their detection may require specialized and invasive spinal imaging. We undertook a study to determine the value of simple optic nerve sheath MR imaging measurements in predicting the likelihood of finding a CSF-venous fistula, a type of leak that cannot be detected with routine spine MR imaging or CT myelography, among patients with orthostatic headache and normal conventional brain and spine imaging findings. MATERIALS AND METHODS: This cohort study included a consecutive group of patients with orthostatic headache and normal conventional brain and spine imaging findings who underwent digital subtraction myelography under general anesthesia to look for spinal CSF-venous fistulas. RESULTS: The study group consisted of 93 patients (71 women and 22 men; mean age, 47.5 years; range, 17-84 years). Digital subtraction myelography demonstrated a CSF-venous fistula in 15 patients. The mean age of these 8 women and 7 men was 56 years (range, 23-83 years). The mean optic nerve sheath diameter was 4.0 mm, and the mean perioptic subarachnoid space was 0.5 mm in patients with a CSF-venous fistula compared with 4.9 and 1.2 mm, respectively, in patients without a fistula (P < .001). Optimal cutoff values were found at 4.4 mm for optic nerve sheath diameter and 1.0 mm for the perioptic subarachnoid space. Fistulas were detected in about 50% of patients with optic nerve sheath diameter or perioptic subarachnoid space measurements below these cutoff values compared with <2% of patients with optic nerve sheath diameter or perioptic subarachnoid space measurements above these cutoff values. Following surgical ligation of the fistula, optic nerve sheath diameter increased from 4.0 to 5.3 mm and the perioptic subarachnoid space increased from 0.5 to 1.2 mm (P < .001). CONCLUSIONS: Concerns about a spinal CSF leak should not be dismissed in patients with orthostatic headache when conventional imaging findings are normal, and simple optic nerve sheath MR imaging measurements can help decide if more imaging needs to be performed in this patient population.

Extreme-aged patients (≥ 85 years) experience similar outcomes as younger geriatric patients following chronic subdural hematoma evacuation: a matched cohort study.

Subdural hematoma (SDH) evacuation represents one of the most frequently performed neurosurgical procedures. Several reports cite a rise in both the age and number of patient's requiring treatment, due in part to an aging population and expanded anticoagulation use. However, limited data and conflicting conclusions exist on extreme-aged geriatric patients (≥ 85 years of age) after undergoing surgery. Patients undergoing SDH evacuation at a tertiary academic medical center between November 2013-December 2021 were retrospectively identified. The study group consisted of patients ≥ 85 years (Group 1) diagnosed with a chronic SDH surgically evacuated. A control group was created matching patients by 70-84 years of age, gender, and anticoagulation use (Group 2). Multiple metrics were evaluated between the two including length-of hospital-stay, tracheostomy/PEG placement, reoperation rate, complications, discharge location, neurological outcome at the time of discharge, and survival. A total of 130 patients were included; 65 in Group 1 and 65 in Group 2. Patient demographics, medical comorbidities, SDH characteristics, international normalized ratio, partial thromboplastin time, and use of blood thinning agents were similar between the two groups. Kaplan Meier survival analysis at one-year was 80% for Group 1 and 76% for Group 2. No significant difference was identified using the log-rank test for equality of survivor functions (p = 0.26). All measured outcomes including GCS at time of discharge, length of stay, rate of reoperations, and neurological outcome were statistically similar between the two groups. Backwards stepwise conditional logistic regression revealed no significant association between poor outcomes at the time of discharge and age. Alternatively, anticoagulation use was found to be associated with poor outcomes (OR 3.55, 95% CI 1.08-11.60; p = 0.036). Several outcome metrics and statistical analyses were used to compare patients ≥ 85 years of age to younger geriatric patients (70-84 years) in a matched cohort study. Adjusting for age group, gender, and anticoagulation use, no significant difference was found between the two groups including neurological outcome at discharge, reoperation rate, and survival.

Evolution of two-pore domain potassium channels and their gene expression in zebrafish embryos.

BACKGROUND: The two-pore domain potassium (K2P) channels are a major type of potassium channels that maintain the cell membrane potential by conducting passive potassium leak currents independent of voltage change. They play prominent roles in multiple physiological processes, including neuromodulation, perception of pain, breathing and mood control, and response to volatile anesthetics. Mutations in K2P channels have been linked to many human diseases, such as neuronal and cardiovascular disorders and cancers. Significant progress has been made to understand their protein structures, physiological functions, and pharmacological modifiers. However, their expression and function during embryonic development remain largely unknown. RESULTS: We employed the zebrafish model and identified 23 k2p genes using BLAST search and gene cloning. We first analyzed vertebrate K2P channel evolution by phylogenetic and syntenic analyses. Our data revealed that the six subtypes of the K2P genes have already evolved in invertebrates long before the emergence of vertebrates. Moreover, the vertebrate K2P gene number increased, most likely due to two whole-genome duplications. Furthermore, we examined zebrafish k2p gene expression during early embryogenesis by in situ hybridization. Each subgroup's genes showed similar but distinct gene expression domains with some exceptions. Most of them were expressed in neural tissues consistent with their known function of neural excitability regulation. However, a few k2p genes were expressed temporarily in specific tissues or organs, suggesting that these K2P channels may be needed for embryonic development. CONCLUSIONS: Our phylogenetic and developmental analyses of K2P channels shed light on their evolutionary history and potential roles during embryogenesis related to their physiological functions and human channelopathies.

Arachnoid Cyst of the Cerebellopontine Angle: A Systematic Literature Review.

OBJECTIVE: The role of surgical management of arachnoid cyst (AC) of the cerebellopontine angle (CPA) is uncertain. This topic has remained controversial with varying contradictory recommendations in the literature, which is limited to mostly case reports. We aimed to provide a comprehensive summary and analysis of symptoms, operative techniques, outcomes, and recurrence of all available surgical cases of AC of the CPA to date. METHODS: A systematic literature search was performed in May 2022 querying several scientific databases. Inclusion criteria specified all studies and case reports of patients with AC located at the CPA for which any relevant surgical procedures were performed. RESULTS: A total of 55 patients from the literature and 5 treated at our institution were included. Mean patient age was 29 years (range, 0.08-79 years), with nearly twice (1.7×) as many female as male patients (37 female, 22 male). Headaches (35%), hearing loss (30%), vertigo (22%), and ataxia (22%) were the most common presentations. Following surgery, 95% experienced symptom improvement, with complete resolution in 64%. Of patients with hearing loss, 44% reported a return to normal. The rate of mortality was 1.69%, and 10% of tumors recurred (mean follow-up 2.3 years [range, 0-15 years]. CONCLUSIONS: Symptomatic AC of the CPA is rare. It exhibits a proclivity for females and commonly manifests with headache, hearing loss, vertigo, and ataxia. While careful selection for surgical candidacy is needed and intervention should be reserved for patients with severe symptoms, surgical decompression is an effective tool for symptom alleviation and recovery.

Endoscopic endonasal transclival clipping of a cerebellar arteriovenous malformation feeding vessel and associated aneurysm; a 2D operative video.

Positioned along the ventral surface of the pons, proximal superior cerebellar artery (SCA) aneurysms account for only 1.7% of all intracranial aneurysms [1]. Unlike more commonly encountered basilar artery aneurysms, patients often experience good outcomes when treated via endovascular coiling or surgical clipping [1,2]. These lesions frequently have a lateral projection and paucity of perforator arteries [2]. With further development of endoscopic endonasal techniques, access to this region is possible via a direct frontal exposure to the ventral brainstem, basilar artery and branching vessels. To date, there are only a limited number of reports describing an endoscopic endonasal transclival (EETC) approach for surgical clipping [3-5]. In this operative video, we detail the surgical clipping of a cerebellar arteriovenous malformation feeding vessel and an associated aneurysm using the EETC approach in a 59-year-old woman who presented with sudden onset of a severe headache. The feeding vessel and aneurysm's midline location, just below the take-off of the SCA made it a good candidate for this surgery. Major steps included in this video include 1) transsphenoidal exposure of and subsequent drilling of the clivus, 2) dural opening into the pre-pontine cistern and dissection of the aneurysm, 3) clipping of the aneurysm, and 4) multi-layered closure of the skull base defect. Overall, the patient tolerated the procedure well and was found to have no residual filling of the aneurysm or the AVM feeding vessel at 2-year follow-up. EETC is a viable surgical option for the treatment of aneurysm located along the midline of the pre-pontine cistern.

Tandem cranial and spinal cerebrospinal fluid leaks presenting with otogenic tension pneumocephalus: illustrative case.

BACKGROUND: Cranial and spinal cerebrospinal fluid (CSF) leaks are associated with opposite CSF fluid dynamics. The differing pathophysiology between spontaneous cranial and spinal CSF leaks are, therefore, mutually exclusive in theory. OBSERVATIONS: A 66-year-old female presented with tension pneumocephalus. The patient underwent computed tomography (CT) scanning, which demonstrated left-sided tension pneumocephalus, with an expanding volume of air directly above a bony defect of the tegmen tympani and mastoideum. The patient underwent a left middle fossa craniotomy for repair of the tegmen CSF leak. In the week after discharge, she developed a recurrence of positional headaches and underwent head CT. Further magnetic resonance imaging of the brain and thoracic spine showed bilateral subdural hematomas and multiple meningeal diverticula. LESSONS: Cranial CSF leaks are caused by intracranial hypertension and are not associated with subdural hematomas. Clinicians should maintain a high index of suspicion for intracranial hypotension due to spinal CSF leak whenever "otogenic" pneumocephalus is found. Close postoperative follow-up and clinical monitoring for symptoms of intracranial hypotension in any patients who undergo repair of a tegmen defect for otogenic pneumocephalus is recommended.

Vascular determinants of hippocampal viscoelastic properties in healthy adults across the lifespan.

Arterial stiffness and cerebrovascular pulsatility are non-traditional risk factors of Alzheimer's disease. However, there is a gap in understanding the earliest mechanisms that link these vascular determinants to brain aging. Changes to mechanical tissue properties of the hippocampus (HC), a brain structure essential for memory encoding, may reflect the impact of vascular dysfunction on brain aging. We tested the hypothesis that arterial stiffness and cerebrovascular pulsatility are related to HC tissue properties in healthy adults across the lifespan. Twenty-five adults underwent measurements of brachial blood pressure (BP), large elastic artery stiffness, middle cerebral artery pulsatility index (MCAv PI), and magnetic resonance elastography (MRE), a sensitive measure of HC viscoelasticity. Individuals with higher carotid pulse pressure (PP) exhibited lower HC stiffness (ß = -0.39, r = -0.41, p = 0.05), independent of age and sex. Collectively, carotid PP and MCAv PI significantly explained a large portion of the total variance in HC stiffness (adjusted R2 = 0.41, p = 0.005) in the absence of associations with HC volumes. These cross-sectional findings suggest that the earliest reductions in HC tissue properties are associated with alterations in vascular function.

Pyruvate decarboxylase and thiamine biosynthetic genes are regulated differently by Pdc2 in S. cerevisiae and C. glabrata.

Understanding metabolism in the pathogen Candida glabrata is key to identifying new targets for antifungals. The thiamine biosynthetic (THI) pathway is partially defective in C. glabrata, but the transcription factor CgPdc2 upregulates some thiamine biosynthetic and transport genes. One of these genes encodes a recently evolved thiamine pyrophosphatase (CgPMU3) that is critical for accessing external thiamine. Here, we demonstrate that CgPdc2 primarily regulates THI genes. In Saccharomyces cerevisiae, Pdc2 regulates both THI and pyruvate decarboxylase (PDC) genes, with PDC proteins being a major thiamine sink. Deletion of PDC2 is lethal in S. cerevisiae in standard growth conditions, but not in C. glabrata. We uncover cryptic cis elements in C. glabrata PDC promoters that still allow for regulation by ScPdc2, even when that regulation is not apparent in C. glabrata. C. glabrata lacks Thi2, and it is likely that inclusion of Thi2 into transcriptional regulation in S. cerevisiae allows for a more complex regulation pattern and regulation of THI and PDC genes. We present evidence that Pdc2 functions independent of Thi2 and Thi3 in both species. The C-terminal activation domain of Pdc2 is intrinsically disordered and critical for species differences. Truncation of the disordered domains leads to a gradual loss of activity. Through a series of cross species complementation assays of transcription, we suggest that there are multiple Pdc2-containing complexes, and C. glabrata appears to have the simplest requirement set for THI genes, except for CgPMU3. CgPMU3 has different cis requirements, but still requires Pdc2 and Thi3 to be upregulated by thiamine starvation. We identify the minimal region sufficient for thiamine regulation in CgTHI20, CgPMU3, and ScPDC5 promoters. Defining the cis and trans requirements for THI promoters should lead to an understanding of how to interrupt their upregulation and provide targets in metabolism for antifungals.

Influence of mild cognitive impairment and body mass index on white matter integrity assessed by diffusion tensor imaging.

Mild cognitive impairment (MCI), a prodromal stage of Alzheimer's disease, is characterized by decreased memory and cognition, which are linked to degenerative changes in the brain. To assess whether white matter (WM) integrity is compromised in MCI, we collected diffusion-weighted images from 60 healthy older adults (OA) (69.16 ± 0.7) and 20 older adults with amnestic MCI (72.45 ± 1.9). WM integrity differences were examined using Tract-Based Spatial Statistics (TBSS). We hypothesized that those with MCI would have diminished WM integrity relative to OA. In a whole-brain comparison, those with MCI showed higher axial diffusivity in the splenium (SCC) and body of the corpus callosum (BCC), superior corona radiata (SCR), and the retrolenticular part of the internal capsule (RLIC) (p's < .05 TFCE-corrected). Additionally, significant between-group connectivity differences were observed using probabilistic tractography between the SCC, chosen from the TBSS results, and forceps major and minor (p-value's < .05). To further relate a physical health indicator to WM alterations, linear regression showed significant interactions between cognitive status and body mass index (BMI) on diffusivity outcome measures from probabilistic tractography (p-value-'s < .05). Additionally, we examined the association between relational memory, BMI, and WM integrity. WM integrity was positively associated with relational memory performance. These findings suggest that these regions may be more sensitive to early markers of neurodegenerative disease and health behaviors, suggesting that modifiable lifestyle factors may affect white matter integrity.

Heritability of Childhood Music Engagement and Associations with Language and Executive Function: Insights from the Adolescent Brain Cognitive Development (ABCD) Study.

Music engagement is a powerful, influential experience that often begins early in life. Music engagement is moderately heritable in adults (~ 41-69%), but fewer studies have examined genetic influences on childhood music engagement, including their association with language and executive functions. Here we explored genetic and environmental influences on music listening and instrument playing (including singing) in the baseline assessment of the Adolescent Brain Cognitive Development study. Parents reported on their 9-10-year-old children's music experiences (N = 11,876 children; N = 1543 from twin pairs). Both music measures were explained primarily by shared environmental influences. Instrument exposure (but not frequency of instrument engagement) was associated with language skills (r = .27) and executive functions (r = .15-0.17), and these associations with instrument engagement were stronger than those for music listening, visual art, or soccer engagement. These findings highlight the role of shared environmental influences between early music experiences, language, and executive function, during a formative time in development.

Hippocampal subfield viscoelasticity in amnestic mild cognitive impairment evaluated with MR elastography.

Hippocampal subfields (HCsf) are brain regions important for memory function that are vulnerable to decline with amnestic mild cognitive impairment (aMCI), which is often a preclinical stage of Alzheimer's disease. Studies in aMCI patients often assess HCsf tissue integrity using measures of volume, which has little specificity to microstructure and pathology. We use magnetic resonance elastography (MRE) to examine the viscoelastic mechanical properties of HCsf tissue, which is related to structural integrity, and sensitively detect differences in older adults with aMCI compared to an age-matched control group. Group comparisons revealed HCsf viscoelasticity is differentially affected in aMCI, with CA1-CA2 and DG-CA3 exhibiting lower stiffness and CA1-CA2 exhibiting higher damping ratio, both indicating poorer tissue integrity in aMCI. Including HCsf stiffness in a logistic regression improves classification of aMCI beyond measures of volume alone. Additionally, lower DG-CA3 stiffness predicted aMCI status regardless of DG-CA3 volume. These findings showcase the benefit of using MRE in detecting subtle pathological tissue changes in individuals with aMCI via the HCsf particularly affected in the disease.

Exploring the genetics of rhythmic perception and musical engagement in the Vanderbilt Online Musicality Study.

Uncovering the genetic underpinnings of musical ability and engagement is a foundational step for exploring their wide-ranging associations with cognition, health, and neurodevelopment. Prior studies have focused on using twin and family designs, demonstrating moderate heritability of musical phenotypes. The current study used genome-wide complex trait analysis and polygenic score (PGS) approaches utilizing genotype data to examine genetic influences on two musicality traits (rhythmic perception and music engagement) in N = 1792 unrelated adults in the Vanderbilt Online Musicality Study. Meta-analyzed heritability estimates (including a replication sample of Swedish individuals) were 31% for rhythmic perception and 12% for self-reported music engagement. A PGS derived from a recent study on beat synchronization ability predicted both rhythmic perception (ß = 0.11) and music engagement (ß = 0.19) in our sample, suggesting that genetic influences underlying self-reported beat synchronization ability also influence individuals' rhythmic discrimination aptitude and the degree to which they engage in music. Cross-trait analyses revealed a modest contribution of PGSs from several nonmusical traits (from the cognitive, personality, and circadian chronotype domains) to individual differences in musicality (ß = -0.06 to 0.07). This work sheds light on the complex relationship between the genetic architecture of musical rhythm processing, beat synchronization, music engagement, and other nonmusical traits.

Structure-Function Dissociations of Human Hippocampal Subfield Stiffness and Memory Performance.

Aging and neurodegenerative diseases lead to decline in thinking and memory ability. The subfields of the hippocampus (HCsf) play important roles in memory formation and recall. Imaging techniques sensitive to the underlying HCsf tissue microstructure can reveal unique structure-function associations and their vulnerability in aging and disease. The goal of this study was to use magnetic resonance elastography (MRE), a noninvasive MR imaging-based technique that can quantitatively image the viscoelastic mechanical properties of tissue to determine the associations of HCsf stiffness with different cognitive domains across the lifespan. Eighty-eight adult participants completed the study (age 23-81 years, male/female 36/51), in which we aimed to determine which HCsf regions most strongly correlated with different memory performance outcomes and if viscoelasticity of specific HCsf regions mediated the relationship between age and performance. Our results revealed that both interference cost on a verbal memory task and relational memory task performance were significantly related to cornu ammonis 1-2 (CA1-CA2) stiffness (p = 0.018 and p = 0.011, respectively), with CA1-CA2 stiffness significantly mediating the relationship between age and interference cost performance (p = 0.031). There were also significant associations between delayed free verbal recall performance and stiffness of both the dentate gyrus-cornu ammonis 3 (DG-CA3; p = 0.016) and subiculum (SUB; p = 0.032) regions. This further exemplifies the functional specialization of HCsf in declarative memory and the potential use of MRE measures as clinical biomarkers in assessing brain health in aging and disease.SIGNIFICANCE STATEMENT Hippocampal subfields are cytoarchitecturally unique structures involved in distinct aspects of memory processing. Magnetic resonance elastography is a technique that can noninvasively image tissue viscoelastic mechanical properties, potentially serving as sensitive biomarkers of aging and neurodegeneration related to functional outcomes. High-resolution in vivo imaging has invigorated interest in determining subfield functional specialization and their differential vulnerability in aging and disease. Applying MRE to probe subfield-specific cognitive correlates will indicate that measures of subfield stiffness can determine the integrity of structures supporting specific domains of memory performance. These findings will further validate our high-resolution MRE method and support the potential use of subfield stiffness measures as clinical biomarkers in classifying aging and disease states.

Combined Transcranial and Endoscopic Endonasal Approach for Resection of a Complex Sinonasal Squamous Cell Carcinoma: Two-Dimensional Operative Video.

Sinonasal squamous cell carcinoma (SCC) is a rare head-and-neck neoplasm that has a propensity to locally invade vital structures. Currently, the combination of surgical resection and radiation remains the optimal treatment. 1 However, the extent of disease burden and involvement of surrounding anatomy may make these inoperable. Here, we demonstrate the successful application of multidisciplinary approach for surgical resection of a large, complex SCC lesion centered at the superior nasal cavity with extension into the eye orbits and brain. A two-step approach was performed; transcribiform, endoscopic piecemeal resection with reconstruction of the skull base, followed by a bifrontal craniotomy. Reconstruction was achieved using an inlay of DuraMatrix allograft (Stryker Inc., Kalamzoo, Michigan, United States) followed by an inlay of AlloDerm (Allergan Inc., Irvine, California, United States), anchored anteriorly and posteriorly with wide wings placed over the respective orbital roofs. Major steps include (1) a summary of the patient presentation and preoperative imaging, (2) resection of the tumor endonasally, (3) resection of the tumor intracranially from a bifrontal craniotomy, and (4) a review of the postoperative imaging. The patient tolerated the procedure ( Fig. 1 ) well, returned to his baseline with no new neurologic deficits, and was placed on 6-week antibiotics regimen for osteomyelitis discovered during the operation. Approximately, 2 months after discharge, the patient unfortunately returned with altered mental status, was found to have sepsis, and expired shortly thereafter. This operative video illustrates the technical steps and capabilities of surgical treatment, achieving near-complete gross total resection of a complex SCC lesion using a multidisciplinary approach. The link to the video can be found at: https://youtu.be/8ffckKIuBzM .

The Musical Abilities, Pleiotropy, Language, and Environment (MAPLE) Framework for Understanding Musicality-Language Links Across the Lifespan.

Using individual differences approaches, a growing body of literature finds positive associations between musicality and language-related abilities, complementing prior findings of links between musical training and language skills. Despite these associations, musicality has been often overlooked in mainstream models of individual differences in language acquisition and development. To better understand the biological basis of these individual differences, we propose the Musical Abilities, Pleiotropy, Language, and Environment (MAPLE) framework. This novel integrative framework posits that musical and language-related abilities likely share some common genetic architecture (i.e., genetic pleiotropy) in addition to some degree of overlapping neural endophenotypes, and genetic influences on musically and linguistically enriched environments. Drawing upon recent advances in genomic methodologies for unraveling pleiotropy, we outline testable predictions for future research on language development and how its underlying neurobiological substrates may be supported by genetic pleiotropy with musicality. In support of the MAPLE framework, we review and discuss findings from over seventy behavioral and neural studies, highlighting that musicality is robustly associated with individual differences in a range of speech-language skills required for communication and development. These include speech perception-in-noise, prosodic perception, morphosyntactic skills, phonological skills, reading skills, and aspects of second/foreign language learning. Overall, the current work provides a clear agenda and framework for studying musicality-language links using individual differences approaches, with an emphasis on leveraging advances in the genomics of complex musicality and language traits.

Mental health and music engagement: review, framework, and guidelines for future studies.

Is engaging with music good for your mental health? This question has long been the topic of empirical clinical and nonclinical investigations, with studies indicating positive associations between music engagement and quality of life, reduced depression or anxiety symptoms, and less frequent substance use. However, many earlier investigations were limited by small populations and methodological limitations, and it has also been suggested that aspects of music engagement may even be associated with worse mental health outcomes. The purpose of this scoping review is first to summarize the existing state of music engagement and mental health studies, identifying their strengths and weaknesses. We focus on broad domains of mental health diagnoses including internalizing psychopathology (e.g., depression and anxiety symptoms and diagnoses), externalizing psychopathology (e.g., substance use), and thought disorders (e.g., schizophrenia). Second, we propose a theoretical model to inform future work that describes the importance of simultaneously considering music-mental health associations at the levels of (1) correlated genetic and/or environmental influences vs. (bi)directional associations, (2) interactions with genetic risk factors, (3) treatment efficacy, and (4) mediation through brain structure and function. Finally, we describe how recent advances in large-scale data collection, including genetic, neuroimaging, and electronic health record studies, allow for a more rigorous examination of these associations that can also elucidate their neurobiological substrates.

IL-6 Inhibition Reduces Neuronal Injury in a Murine Model of Ventilator-induced Lung Injury.

Mechanical ventilation is a known risk factor for delirium, a cognitive impairment characterized by dysfunction of the frontal cortex and hippocampus. Although IL-6 is upregulated in mechanical ventilation-induced lung injury (VILI) and may contribute to delirium, it is not known whether the inhibition of systemic IL-6 mitigates delirium-relevant neuropathology. To histologically define neuropathological effects of IL-6 inhibition in an experimental VILI model, VILI was simulated in anesthetized adult mice using a 35 cc/kg tidal volume mechanical ventilation model. There were two control groups, as follow: 1) spontaneously breathing or 2) anesthetized and mechanically ventilated with 10 cc/kg tidal volume to distinguish effects of anesthesia from VILI. Two hours before inducing VILI, mice were treated with either anti-IL-6 antibody, anti-IL-6 receptor antibody, or saline. Neuronal injury, stress, and inflammation were assessed using immunohistochemistry. CC3 (cleaved caspase-3), a neuronal apoptosis marker, was significantly increased in the frontal (P < 0.001) and hippocampal (P < 0.0001) brain regions and accompanied by significant increases in c-Fos and heat shock protein-90 in the frontal cortices of VILI mice compared with control mice (P < 0.001). These findings were not related to cerebral hypoxia, and there was no evidence of irreversible neuronal death. Frontal and hippocampal neuronal CC3 were significantly reduced with anti-IL-6 antibody (P < 0.01 and P < 0.0001, respectively) and anti-IL-6 receptor antibody (P < 0.05 and P < 0.0001, respectively) compared with saline VILI mice. In summary, VILI induces potentially reversible neuronal injury and inflammation in the frontal cortex and hippocampus, which is mitigated with systemic IL-6 inhibition. These data suggest a potentially novel neuroprotective role of systemic IL-6 inhibition that justifies further investigation.