Sex difference in brain functional connectivity of hippocampus in Alzheimer's disease.

Alzheimer's disease (AD), affecting nearly 6.5 million people, is the fifth leading cause of death in individuals 65 years or older in the USA. Prior research has shown that AD disproportionality affects females; females have a greater incidence rate, perform worse on a variety of neuropsychological tasks, and have greater total brain atrophy. Recent research has linked these sex differences to neuroimaging markers of brain pathology, such as hippocampal volumes. Specifically, research from our lab found that functional connectivity from the hippocampus to the precuneus cortex and brain stem was significantly stronger in males than in females with mild cognitive impairment. The aim of this study was to extend our understanding to individuals with AD and to determine if these potential sex-specific functional connectivity biomarkers extend through different disease stages. The resting state fMRI and T2 MRI of cognitively normal individuals (n = 32, female = 16) and individuals with AD (n = 32, female = 16) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed using the Functional Connectivity Toolbox (CONN). Our results demonstrate that males had a significantly stronger interhemispheric functional connectivity between the left and right hippocampus compared to females. These results improve our current understanding of the role of the hippocampus in sex differences in AD. Understanding the contribution of impaired functional connectivity sex differences may aid in the development of sex-specific precision medicine for improved AD treatment.

Cortical Reorganization of Early Somatosensory Processing in Hemiparetic Stroke.

The cortical motor system can be reorganized following a stroke, with increased recruitment of the contralesional hemisphere. However, it is unknown whether a similar hemispheric shift occurs in the somatosensory system to adapt to this motor change, and whether this is related to movement impairments. This proof-of-concept study assessed somatosensory evoked potentials (SEPs), P50 and N100, in hemiparetic stroke participants and age-matched controls using high-density electroencephalograph (EEG) recordings during tactile finger stimulation. The laterality index was calculated to determine the hemispheric dominance of the SEP and re-confirmed with source localization. The study found that latencies of P50 and N100 were significantly delayed in stroke brains when stimulating the paretic hand. The amplitude of P50 in the contralateral (to stimulated hand) hemisphere was negatively correlated with the Fügl-Meyer upper extremity motor score in stroke. Bilateral cortical responses were detected in stroke, while only contralateral cortical responses were shown in controls, resulting in a significant difference in the laterality index. These results suggested that somatosensory reorganization after stroke involves increased recruitment of ipsilateral cortical regions, especially for the N100 SEP component. This reorganization delays the latency of somatosensory processing after a stroke. This research provided new insights related to the somatosensory reorganization after stroke, which could enrich future hypothesis-driven therapeutic rehabilitation strategies from a sensory or sensory-motor perspective.

Sex differences in brain functional connectivity of hippocampus in mild cognitive impairment.

Mild cognitive impairment (MCI) is the prodromal stage of Alzheimer's Disease (AD). Prior research shows that females are more impacted by MCI than males. On average females have a greater incidence rate of any dementia and current evidence suggests that they suffer greater cognitive deterioration than males in the same disease stage. Recent research has linked these sex differences to neuroimaging markers of brain pathology, such as hippocampal volumes. Specifically, the rate of hippocampal atrophy affects the progression of AD in females more than males. This study was designed to extend our understanding of the sex-related differences in the brain of participants with MCI. Specifically, we investigated the difference in the hippocampal connectivity to different areas of the brain. The Resting State fMRI and T2 MRI of cognitively normal individuals (n = 40, female = 20) and individuals with MCI (n = 40, female = 20) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed using the Functional Connectivity Toolbox (CONN). Our results demonstrate that connectivity of hippocampus to the precuneus cortex and brain stem was significantly stronger in males than in females. These results improve our current understanding of the role of hippocampus-precuneus cortex and hippocampus-brainstem connectivity in sex differences in MCI. Understanding the contribution of impaired functional connectivity sex differences may aid in the development of sex specific precision medicine to manipulate hippocampal-precuneus cortex and hippocampal-brainstem connectivity to decrease the progression of MCI to AD.

Impact of beam-hardening corrections on proton relative stopping power estimates from single- and dual-energy CT.

A major contributing factor to proton range uncertainty is the conversion of computed tomography (CT) Hounsfield units (HU) to proton relative stopping power (RSP). This uncertainty is heightened in the presence of X-ray beam-hardening artifact (BHA), which has two manifestations: cupping and streaking, especially in and near bone tissue. This uncertainty can affect the accuracy of proton RSP calculation for treatment planning in proton radiotherapy. Dual-energy CT (DECT) and iterative beam-hardening correction (iBHC) both show promise in mitigating CT BHA. This present work attempts to analyze the relative robustness of iBHC and DECT techniques on both manifestations of BHA. The stoichiometric method for HU to RSP conversion was used for single-energy CT (SECT) and DECT-based monochromatic techniques using a tissue substitute phantom. Cupping BHA was simulated by measuring the HU of a bone substitute plug in wax/3D-printed phantoms of increasing size. Streaking BHA was simulated by placing a solid water plug between two bone plugs in a wax phantom. Finally, the effect of varying calibration phantom size on RSP was calculated in an anthropomorphic head phantom. The RSP decreased -0.002 cm-1 as phantom size increased for SECT but remained largely constant when iBHC applied or with DECT techniques. The RSP varied a maximum of 2.60% in the presence of streaking BHA in SECT but was reduced to 1.40% with iBHC. For DECT techniques, the maximum difference was 2.40%, reduced to 0.6% with iBHC. Comparing calibration phantoms of 20- and 33-cm diameter, maximum voxel differences of 5 mm in the water-equivalent thickness were observed in the skull but reduced to 1.3 mm with iBHC. The DECT techniques excelled in mitigating cupping BHA, but streaking BHA still could be observed. The use of iBHC reduced RSP variation with BHA in both SECT and DECT techniques.

Augmented Efficacy of Uttroside B over Sorafenib in a Murine Model of Human Hepatocellular Carcinoma.

We previously reported the remarkable potency of uttroside B (Utt-B), saponin-isolated and characterized in our lab from Solanum nigrum Linn, against HCC. Recently, the U.S. FDA approved Utt-B as an 'orphan drug' against HCC. The current study validates the superior anti-HCC efficacy of Utt-B over sorafenib, the first-line treatment option against HCC. The therapeutic efficacies of Utt-B vs. sorafenib against HCC were compared in vitro, using various liver cancer cell lines and in vivo, utilizing NOD.CB17-Prkdcscid/J mice bearing human HCC xenografts. Our data indicate that Utt-B holds an augmented anti-HCC efficacy over sorafenib. Our previous report demonstrated the pharmacological safety of Utt-B in Chang Liver, the normal immortalized hepatocytes, and in the acute and chronic toxicity murine models even at elevated Utt-B concentrations. Here, we show that higher concentrations of sorafenib induce severe toxicity, in Chang Liver, as well as in acute and chronic in vivo models, indicating that, apart from the superior therapeutic benefit over sorafenib, Utt-B is a pharmacologically safer molecule, and the drug-induced undesirable effects can, thus, be substantially alleviated in the context of HCC chemotherapy. Clinical studies in HCC patients utilizing Utt-B, is a contiguous key step to promote this drug to the clinic.

Urinary Biomarkers of Oxidative Stress in Aging: Implications for Prediction of Accelerated Biological Age in Prospective Cohort Studies.

Background: Aging is a major risk factor for a range of chronic diseases. Oxidative stress theory of aging has been previously proposed as one of the mechanisms responsible for the age-related decline in organ/tissue function and the development of age-related diseases. Urine contains rich biological information on the health status of every major organ system and can be an important noninvasive source for biomarkers of systemic oxidative stress in aging. Aims: The objective of this cross-sectional study was to validate a novel panel of urinary oxidative stress biomarkers. Methods: Nucleic acid oxidation adducts and oxidative damage markers of lipids and proteins were assessed in urine samples from nondiabetic and currently nonsmoking subjects (n = 198) across different ages (20 to 89 years old). Urinary parameters and chronological age were correlated then the biological age of enrolled individuals was determined from the urinary oxidative stress markers using the algorithm of Klemera and Doubal. Results: Our findings showed that 8-oxo-7,8-deoxyguanosine (8-oxoG), 8-oxo-7,8-dihydroguanosine (8-OHdG), and dityrosine (DTyr) positively correlated with chronological age, while the level of an F2-isoprostane (iPF2 α-VI) correlated negatively with age. We found that 8-oxoG, DTyr, and iPF2 α-VI were significantly higher among accelerated agers compared to nonaccelerated agers and that a decision tree model could successfully identify accelerated agers with an accuracy of >92%. Discussion. Our results indicate that 8-oxoG and iPF2 α-VI levels in the urine reveal biological aging. Conclusion: Assessing urinary biomarkers of oxidative stress may be an important approach for the evaluation of biological age by identifying individuals at accelerated risk for the development of age-related diseases.

Physical Forces in Glioblastoma Migration: A Systematic Review.

The invasive capabilities of glioblastoma (GBM) define the cancer's aggressiveness, treatment resistance, and overall mortality. The tumor microenvironment influences the molecular behavior of cells, both epigenetically and genetically. Current forces being studied include properties of the extracellular matrix (ECM), such as stiffness and "sensing" capabilities. There is currently limited data on the physical forces in GBM-both relating to how they influence their environment and how their environment influences them. This review outlines the advances that have been made in the field. It is our hope that further investigation of the physical forces involved in GBM will highlight new therapeutic options and increase patient survival. A search of the PubMed database was conducted through to 23 March 2022 with the following search terms: (glioblastoma) AND (physical forces OR pressure OR shear forces OR compression OR tension OR torsion) AND (migration OR invasion). Our review yielded 11 external/applied/mechanical forces and 2 tumor microenvironment (TME) forces that affect the ability of GBM to locally migrate and invade. Both external forces and forces within the tumor microenvironment have been implicated in GBM migration, invasion, and treatment resistance. We endorse further research in this area to target the physical forces affecting the migration and invasion of GBM.

Multi-Phase Locking Value: A Generalized Method for Determining Instantaneous Multi-Frequency Phase Coupling.

BACKGROUND: Many physical, biological and neural systems behave as coupled oscillators, with characteristic phase coupling across different frequencies. Methods such as n : m phase locking value (where two coupling frequencies are linked as: mf 1 = nf 2) and bi-phase locking value have previously been proposed to quantify phase coupling between two resonant frequencies (e.g. f, 2f/3) and across three frequencies (e.g. f 1, f 2, f 1 + f 2), respectively. However, the existing phase coupling metrics have their limitations and limited applications. They cannot be used to detect or quantify phase coupling across multiple frequencies (e.g. f 1, f 2, f 3, f 4, f 1 + f 2 + f 3 - f 4), or coupling that involves non-integer multiples of the frequencies (e.g. f 1, f 2, 2f 1/3 + f 2/3). NEW METHODS: To address the gap, this paper proposes a generalized approach, named multi-phase locking value (M-PLV), for the quantification of various types of instantaneous multi-frequency phase coupling. Different from most instantaneous phase coupling metrics that measure the simultaneous phase coupling, the proposed M-PLV method also allows the detection of delayed phase coupling and the associated time lag between coupled oscillators. RESULTS: The M-PLV has been tested on cases where synthetic coupled signals are generated using white Gaussian signals, and a system comprised of multiple coupled Rössler oscillators, as well as a human subject dataset. Results indicate that the M-PLV can provide a reliable estimation of the time window and frequency combination where the phase coupling is significant, as well as a precise determination of time lag in the case of delayed coupling. This method has the potential to become a powerful new tool for exploring phase coupling in complex nonlinear dynamic systems.

Accuracy of proton stopping power estimation of silicone breast implants with single and dual-energy CT calibration techniques.

A major contributing factor to proton range uncertainty is the conversion of computed tomography (CT) Hounsfield Units (HU) to proton relative stopping power (RSP). This uncertainty is elevated with implanted devices, such as silicone breast implants when computed with single energy CT (SECT). In recent years, manufacturers have introduced implants with variations in gel cohesivity. Deriving the RSP for these implants from dual-energy CT (DECT) can result in a marked reduction of the error associated with SECT. In this study, we investigate the validity of DECT calibration of HU to RSP on silicone breast implants of varying cohesivity levels. A DECT capable scanner was calibrated using the stoichiometric method of Bourque et al for SECT and DECT using a tissue substitute phantom. Three silicone breast implants of increasing gel cohesivity were measured in a proton beam of clinical energy to determine ground-truth RSP and water equivalent thickness (WET). These were compared to SECT-derived RSP at three CT spectrum energies and DECT with two energy pairs (80/140 kVp and 100/140 kVp) as obtained from scans with and without an anthropomorphic phantom. The RSP derived from parameters estimates from CT vendor-specific software (syngo.via) was compared. The WET estimates from SECT deviated from MLIC ground truth approximately +11%-19%, which would result in overpenetration if used clinically. Both the Bourque calibration and syngo.via WET estimates from DECT yielded error ≤0.5% from ground truth; no significant difference was found between models of varying gel cohesivity levels. WET estimates without the anthropomorphic phantom were significantly different than ground truth for the Bourque calibration. From these results, gel cohesivity had no effect on proton RSP. User-generated DECT calibration can yield comparably accurate RSP estimates for silicone breast implants to vendor software methods. However, care must be taken to account for beam hardening effects.

Proton Exchange Magnetic Resonance Imaging: Current and Future Applications in Psychiatric Research.

Proton exchange provides a powerful contrast mechanism for magnetic resonance imaging (MRI). MRI techniques sensitive to proton exchange provide new opportunities to map, with high spatial and temporal resolution, compounds important for brain metabolism and function. Two such techniques, chemical exchange saturation transfer (CEST) and T1 relaxation in the rotating frame (T1ρ), are emerging as promising tools in the study of neurological and psychiatric illnesses to study brain metabolism. This review describes proton exchange for non-experts, highlights the current status of proton-exchange MRI, and presents advantages and drawbacks of these techniques compared to more traditional methods of imaging brain metabolism, including positron emission tomography (PET) and MR spectroscopy (MRS). Finally, this review highlights new frontiers for the use of CEST and T1ρ in brain research.

Machine learning paradigm for dynamic contrast-enhanced MRI evaluation of expanding bladder.

Delineation of the bladder under a dynamic contrast enhanced (DCE)-MRI protocol requires robust segmentation. However, this method is subject to errors due to variations in the content of fluid within the bladder, as well as presence of air and similarity of signal intensity in adjacent organs. Introduction of the contrast media into the bladder also causes signal errors due to alterations in the shape of the bladder. To circumvent such errors, and to improve the accuracy, we adapted a machine learning paradigm that utilizes the global bladder shape. The ML system first uses the combination of low level image processing tools such as filtering, and mathematical morphology as preprocessing step. We use neural network for training the network using extracted features and application of trained model on test slices to compute the delineated bladder shapes. This ML-based integrated system has an accuracy of 90.73% and time reduction of 65.2% in over manual delineation and can be used in clinical settings for IC/BPS patient care. Finally, we apply Jaccard Similarity Measure which we report to have a mean score of 0.933 (95% Confidence Interval 0.923, 0.944).

Low-cost preventive screening using carotid ultrasound in patients with diabetes.

Diabetes and atherosclerosis are the predominant causes of stroke and cardiovascular disease (CVD) both in low- and high-income countries. This is due to the lack of appropriate medical care or high medical costs. Low-cost 10-year preventive screening can be used for deciding an effective therapy to reduce the effects of atherosclerosis in diabetes patients. American College of Cardiology (ACC)/American Heart Association (AHA) recommended the use of 10-year risk calculators, before advising therapy. Conventional risk calculators are suboptimal in certain groups of patients because their stratification depends on (a) current blood biomarkers and (b) clinical phenotypes, such as age, hypertension, ethnicity, and sex. The focus of this review is on risk assessment using innovative composite risk scores that use conventional blood biomarkers combined with vascular image-based phenotypes. AtheroEdge™ tool is beneficial for low-moderate to high-moderate and low-risk to high-risk patients for the current and 10-year risk assessment that outperforms conventional risk calculators. The preventive screening tool that combines the image-based phenotypes with conventional risk factors can improve the 10-year cardiovascular/stroke risk assessment.

Modern Neonatal Transport: Sound and Vibration Levels and Their Impact on Physiological Stability.

OBJECTIVE: To measure sound and vibration in rotary wing air transport (RWAT) and ground ambulance transport (GAT), comparing them to current recommendations, and correlating them with physiological stability measures in transported neonates. STUDY DESIGN: This is a prospective cohort observational study including infants ≤ 7 days of age transported over an 8-month period. Infants with neurologic conditions were excluded. Sound and vibration was continuously measured during transport. Transport Risk Index of Physiologic Stability (TRIPS) scores were calculated from vital signs as a proxy for physiological stability. RESULTS: In total, 118 newborns were enrolled, of whom 109 were analyzed: 67 in RWAT and 42 in GAT. Peak sound levels ranged from 80.4 to 86.4 dBA in RWAT and from 70.3 to 71.6 dBA in GAT. Whole-body vibration ranged from 1.68 to 5.09 m/s2 in RWAT and from 1.82 to 3.96 m/s2 in GAT. Interval TRIPS scores for each infant were not significantly different despite excessive sound and vibration. CONCLUSION: Noise levels during neonatal transport exceed published recommendations for both RWAT and GAT and are higher in RWAT. Transported infants are exposed to vibration levels exceeding acceptable adult standards. Despite excessive noise and vibration, levels of physiological stability remained stable after transport in both RWAT and GAT groups.

Radiological Estimation of Intracranial Blood Volume and Occurrence of Hydrocephalus Determines Stress-Induced Hyperglycemia After Aneurysmal Subarachnoid Hemorrhage.

Acute phase after aneurysmal subarachnoid hemorrhage (aSAH) is associated with several metabolic derangements including stress-induced hyperglycemia (SIH). The present study is designed to identify objective radiological determinants for SIH to better understand its contributory role in clinical outcomes after aSAH. A computer-aided detection tool was used to segment admission computed tomography (CT) images of aSAH patients to estimate intracranial blood and cerebrospinal fluid volumes. Modified Graeb score (mGS) was used as a semi-quantitative measure to estimate degree of hydrocephalus. The relationship between glycemic gap (GG) determined SIH, mGS, and estimated intracranial blood and cerebrospinal fluid volumes were evaluated using linear regression. Ninety-four [94/187 (50.3%)] among the study cohort had SIH (defined as GG > 26.7 mg/dl). Patients with SIH had 14.3 ml/1000 ml more intracranial blood volume as compared to those without SIH [39.6 ml (95% confidence interval, CI, 33.6 to 45.5) vs. 25.3 ml (95% CI 20.6 to 29.9), p = 0.0002]. Linear regression analysis of mGS with GG showed each unit increase in mGS resulted in 1.2 mg/dl increase in GG [p = 0.002]. Patients with SIH had higher mGS [median 4.0, interquartile range, IQR 2.0-7.0] as compared to those without SIH [median 2.0, IQR 0.0-6.0], p = 0.002. Patients with third ventricular blood on admission CT scan were more likely to develop SIH [67/118 (56.8%) vs. 27/69 (39.1%), p = 0.023]. Hence, the present study, using unbiased SIH definition and objective CT scan parameters, reports "dose-dependent" radiological features resulting in SIH. Such findings allude to a brain injury-stress response-neuroendocrine axis in etiopathogenesis of SIH.

The crossed frontal aslant tract: A possible pathway involved in the recovery of supplementary motor area syndrome.

Introduction: Supplementary motor area (SMA) syndrome is a constellation of temporary symptoms that may occur following tumors of the frontal lobe. Affected patients develop akinesia and mutism but often recover within weeks to months. With our own case examples and with correlations to fiber tracking validated by gross anatomical dissection as ground truth, we describe a white matter pathway through which recovery may occur. Methods: Diffusion spectrum imaging from the Human Connectome Project was used for tractography analysis. SMA outflow tracts were mapped in both hemispheres using a predefined seeding region. Postmortem dissections of 10 cadaveric brains were performed using a modified Klingler technique to verify the tractography results. Results: Two cases were identified in our clinical records in which patients sustained permanent SMA syndrome after complete disconnection of the SMA and corpus callosum (CC). After investigating the postoperative anatomy of these resections, we identified a pattern of nonhomologous connections through the CC connecting the premotor area to the contralateral premotor and SMAs. The transcallosal fibers have projections from the previously described frontal aslant tract (FAT) and thus, we have termed this path the "crossed FAT." Conclusions: We hypothesize that this newly described tract may facilitate recovery from SMA syndrome by maintaining interhemispheric connectivity through the supplementary motor and premotor areas.

Anatomy and white matter connections of the orbitofrontal gyrus.

OBJECTIVE The orbitofrontal cortex (OFC) is understood to have a role in outcome evaluation and risk assessment and is commonly involved with infiltrative tumors. A detailed understanding of the exact location and nature of associated white matter tracts could significantly improve postoperative morbidity related to declining capacity. Through diffusion tensor imaging-based fiber tracking validated by gross anatomical dissection as ground truth, the authors have characterized these connections based on relationships to other well-known structures. METHODS Diffusion imaging from the Human Connectome Project for 10 healthy adult controls was used for tractography analysis. The OFC was evaluated as a whole based on connectivity with other regions. All OFC tracts were mapped in both hemispheres, and a lateralization index was calculated with resultant tract volumes. Ten postmortem dissections were then performed using a modified Klingler technique to demonstrate the location of major tracts. RESULTS The authors identified 3 major connections of the OFC: a bundle to the thalamus and anterior cingulate gyrus, passing inferior to the caudate and medial to the vertical fibers of the thalamic projections; a bundle to the brainstem, traveling lateral to the caudate and medial to the internal capsule; and radiations to the parietal and occipital lobes traveling with the inferior fronto-occipital fasciculus. CONCLUSIONS The OFC is an important center for processing visual, spatial, and emotional information. Subtle differences in executive functioning following surgery for frontal lobe tumors may be better understood in the context of the fiber-bundle anatomy highlighted by this study.

Comparison of computed tomography shielding design methods using RadShield.

PURPOSE: To comprehensively compare four computed tomography (CT) scanner shielding design methods using RadShield, a Java-based graphical user interface (GUI). METHODS: RadShield, a floor plan based GUI, was extended to calculate air kerma and barrier thickness using accepted methods from the National Council on Radiation Protection and Measurements (NCRP), the British Institute of Radiology, and a method using isodose maps, for spatially distributed points beyond user defined barriers. For a stationary CT scanner, the overall shielding recommendations found using RadShield were also compared to those found by American Board of Radiology certified diagnostic medical physicists using the conventional NCRP dose length product method and the isodose map method. RESULTS: The results between methods differed significantly for calculation point locations beyond the gantry and to the rear of the gantry. Overall shielding design recommendations across the four methods yielded similar average air kerma and thickness values for the barriers. CONCLUSIONS: RadShield was extended to perform CT shielding design and proved reliable using four methods.

White matter connections of the inferior parietal lobule: A study of surgical anatomy.

INTRODUCTION: Interest in the function of the inferior parietal lobule (IPL) has resulted in increased understanding of its involvement in visuospatial and cognitive functioning, and its role in semantic networks. A basic understanding of the nuanced white-matter anatomy in this region may be useful in improving outcomes when operating in this region of the brain. We sought to derive the surgical relationship between the IPL and underlying major white-matter bundles by characterizing macroscopic connectivity. METHODS: Data of 10 healthy adult controls from the Human Connectome Project were used for tractography analysis. All IPL connections were mapped in both hemispheres, and distances were recorded between cortical landmarks and major tracts. Ten postmortem dissections were then performed using a modified Klingler technique to serve as ground truth. RESULTS: We identified three major types of connections of the IPL. (1) Short association fibers connect the supramarginal and angular gyri, and connect both of these gyri to the superior parietal lobule. (2) Fiber bundles from the IPL connect to the frontal lobe by joining the superior longitudinal fasciculus near the termination of the Sylvian fissure. (3) Fiber bundles from the IPL connect to the temporal lobe by joining the middle longitudinal fasciculus just inferior to the margin of the superior temporal sulcus. CONCLUSIONS: We present a summary of the relevant anatomy of the IPL as part of a larger effort to understand the anatomic connections of related networks. This study highlights the principle white-matter pathways and highlights key underlying connections.