Pulsatility analysis of the circle of Willis.

Purpose: To evaluate the phenomenological significance of cerebral blood pulsatility imaging in aging research. Methods: N = 38 subjects from 20 to 72 years of age (24 females) were imaged with ultrafast MRI with a sampling rate of 100 ms and simultaneous acquisition of pulse oximetry data. Of these, 28 subjects had acceptable MRI and pulse data, with 16 subjects between 20 and 28 years of age, and 12 subjects between 61 and 72 years of age. Pulse amplitude in the circle of Willis was assessed with the recently developed method of analytic phase projection to extract blood volume waveforms. Results: Arteries in the circle of Willis showed pulsatility in the MRI for both the young and old age groups. Pulse amplitude in the circle of Willis significantly increased with age (p = 0.01) but was independent of gender, heart rate, and head motion during MRI. Discussion and conclusion: Increased pulse wave amplitude in the circle of Willis in the elderly suggests a phenomenological significance of cerebral blood pulsatility imaging in aging research. The physiologic origin of increased pulse amplitude (increased pulse pressure vs. change in arterial morphology vs. re-shaping of pulse waveforms caused by the heart, and possible interaction with cerebrospinal fluid pulsatility) requires further investigation.

Etiologies and predictors of mortality in an all-comer population of patients with non-ischemic heart failure.

BACKGROUND: Despite progress in diagnosis and therapy of heart failure (HF), etiology and risk stratification remain elusive in many patients. METHODS: The My Biopsy HF Study (German clinical trials register number: DRKS22178) is a retrospective monocentric study investigating an all-comer population of patients with unexplained HF based on a thorough workup including endomyocardial biopsy (EMB). RESULTS: 655 patients (70.9% men, median age 55 [45/66] years) with non-ischemic, non-valvular HF were included in the analyses. 489 patients were diagnosed with HF with reduced ejection fraction (HFrEF), 52 patients with HF with mildly reduced ejection fraction (HFmrEF) and 114 patients with HF with preserved ejection fraction (HFpEF). After a median follow-up of 4.6 (2.5/6.6) years, 94 deaths were enumerated (HFrEF: 68; HFmrEF: 8; HFpEF: 18), equating to mortality rates of 3.3% and 11.6% for patients with HFrEF, 7.7% and 15.4% for patients with HFmrEF and 5.3% and 11.4% for patients with HFpEF after 1 and 5 years, respectively. In EMB, we detected a variety of putative etiologies of HF, including incidental cardiac amyloidosis (CA, 5.8%). In multivariate logistic regression analysis adjusting for age, sex and comorbidities only CA, age and NYHA functional class III + IV remained independently associated with all-cause mortality (CA: HRperui 3.13, 95% CI 1.5-6.51; p = 0.002). CONCLUSIONS: In an all-comer population of patients presenting with HF of unknown etiology, incidental finding of CA stands out to be independently associated with all-cause mortality. Our findings suggest that prospective trials would be helpful to test the added value of a systematic and holistic work-up of HF of unknown etiology.

Machine discovery of partial differential equations from spatiotemporal data: A sparse Bayesian learning framework.

This study presents a general framework, namely, Sparse Spatiotemporal System Discovery (S3d), for discovering dynamical models given by Partial Differential Equations (PDEs) from spatiotemporal data. S3d is built on the recent development of sparse Bayesian learning, which enforces sparsity in the estimated PDEs. This approach enables a balance between model complexity and fitting error with theoretical guarantees. The proposed framework integrates Bayesian inference and a sparse priori distribution with the sparse regression method. It also introduces a principled iterative re-weighted algorithm to select dominant features in PDEs and solve for the sparse coefficients. We have demonstrated the discovery of the complex Ginzburg-Landau equation from a traveling-wave convection experiment, as well as several other PDEs, including the important cases of Navier-Stokes and sine-Gordon equations, from simulated data.

SPRY4-dependent ERK negative feedback demarcates functional adult stem cells in the male mouse germline†.

Niche-derived growth factors support self-renewal of mouse spermatogonial stem and progenitor cells through ERK MAPK signaling and other pathways. At the same time, dysregulated growth factor-dependent signaling has been associated with loss of stem cell activity and aberrant differentiation. We hypothesized that growth factor signaling through the ERK MAPK pathway in spermatogonial stem cells is tightly regulated within a narrow range through distinct intracellular negative feedback regulators. Evaluation of candidate extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK)-responsive genes known to dampen downstream signaling revealed robust induction of specific negative feedback regulators, including Spry4, in cultured mouse spermatogonial stem cells in response to glial cell line-derived neurotrophic factor or fibroblast growth factor 2. Undifferentiated spermatogonia in vivo exhibited high levels of Spry4 mRNA. Quantitative single-cell analysis of ERK MAPK signaling in spermatogonial stem cell cultures revealed both dynamic signaling patterns in response to growth factors and disruption of such effects when Spry4 was ablated, due to dysregulation of ERK MAPK downstream of RAS. Whereas negative feedback regulator expression decreased during differentiation, loss of Spry4 shifted cell fate toward early differentiation with concomitant loss of stem cell activity. Finally, a mouse Spry4 reporter line revealed that the adult spermatogonial stem cell population in vivo is demarcated by strong Spry4 promoter activity. Collectively, our data suggest that negative feedback-dependent regulation of ERK MAPK is critical for preservation of spermatogonial stem cell fate within the mammalian testis.

Low-level language processing in brain-injured patients.

Assessing cognitive function-especially language processing-in severely brain-injured patients is critical for prognostication, care, and development of communication devices (e.g. brain-computer interfaces). In patients with diminished motor function, language processing has been probed using EEG measures of command-following in motor imagery tasks. While such tests eliminate the need for motor response, they require sustained attention. However, passive listening tasks, with an EEG response measure can reduce both motor and attentional demands. These considerations motivated the development of two assays of low-level language processing-identification of differential phoneme-class responses and tracking of the natural speech envelope. This cross-sectional study looks at a cohort of 26 severely brain-injured patient subjects and 10 healthy controls. Patients' level of function was assessed via the coma recovery scale-revised at the bedside. Patients were also tested for command-following via EEG and/or MRI assays of motor imagery. For the present investigation, EEG was recorded while presenting a 148 s audio clip of Alice in Wonderland. Time-locked EEG responses to phoneme classes were extracted and compared to determine a differential phoneme-class response. Tracking of the natural speech envelope was assessed from the same recordings by cross-correlating the EEG response with the speech envelope. In healthy controls, the dynamics of the two measures were temporally similar but spatially different: a central parieto-occipital component of differential phoneme-class response was absent in the natural speech envelope response. The differential phoneme-class response was present in all patient subjects, including the six classified as vegetative state/unresponsive wakefulness syndrome by behavioural assessment. However, patient subjects with evidence of language processing either by behavioural assessment or motor imagery tests had an early bilateral response in the first 50 ms that was lacking in patient subjects without any evidence of language processing. The natural speech envelope tracking response was also present in all patient subjects and responses in the first 100 ms distinguished patient subjects with evidence of language processing. Specifically, patient subjects with evidence of language processing had a more global response in the first 100 ms whereas those without evidence of language processing had a frontopolar response in that period. In summary, we developed two passive EEG-based methods to probe low-level language processing in severely brain-injured patients. In our cohort, both assays showed a difference between patient subjects with evidence of command-following and those with no evidence of command-following: a more prominent early bilateral response component.

Functional Diversity of Gram-Negative Permeability Barriers Reflected in Antibacterial Activities and Intracellular Accumulation of Antibiotics.

Gram-negative bacteria are notoriously more resistant to antibiotics than Gram-positive bacteria, primarily due to the presence of the outer membrane and a plethora of active efflux pumps. However, the potency of antibiotics also varies dramatically between different Gram-negative pathogens, suggesting major mechanistic differences in how antibiotics penetrate permeability barriers. Two approaches are used broadly to analyze how permeability barriers affect intracellular accumulation of antibiotics. One compares the antibacterial activities of compounds, while the other measures the total intracellular concentrations of compounds in nongrowing cells, with both approaches using strains harboring wild-type or genetically modified efflux systems and permeability barriers. Whether the two assays provide similar mechanistic insights remains unclear. In this study, we analyzed the intracellular accumulation and antibacterial activities of antibiotics representative of major clinical classes in three Gram-negative pathogens of high clinical importance, Pseudomonas aeruginosa, Escherichia coli, and Acinetobacter baumannii. We found that both assays are informative about properties of permeability barriers, but there is no quantitative agreement between the assays. Our results show that the three pathogens differ dramatically in their permeability barriers, with the outer membrane playing the dominant role in E. coli and P. aeruginosa but efflux dominating in A. baumannii. However, even compounds of the same chemotype may use different permeation pathways depending on small chemical modifications. Accordingly, a classification analysis revealed limited conservation of molecular properties that define compound penetration into the three bacteria.

Spontaneous Pituitary Neoplasm in Two Female Geriatric Southern Giant Pouched Rats (Cricetomys ansorgei).

Southern giant pouched rats (Cricetomys ansorgei) are a small muroid species native to the sub-Saharan Africa. Their exceptionally developed olfactory system, trainability, and relatively small size makes them useful working animals for various applications in humanitarian work. At our institution, a breeding colony of Southern giant pouched rats is maintained to study their physiology and utility as scent detectors. This case report describes the occurrence of spontaneous pituitary neoplasms with distinct clinical presentations in 2 geriatric (approximately 7.5 y old) wild-caught female Southern giant pouched rats. The first pouched rat displayed vestibular deficits, including left-sided head tilt, ataxia, disorientation, and circling. MRI revealed a large, focal heterogeneous mass arising from the pituitary fossa. The second pouched rat presented with polyuria, polydipsia, and hyperglycemia but no neurologic signs. Examination after euthanasia revealed a prolactin (PRL)-expressing pituitary carcinoma and adenoma in the first and second pouched rat, respectively, associated with mammary hyperplasia in both animals. This is the first report of spontaneous PRL-producing pituitary tumors in Southern giant pouched rats.

A pathway towards a two-dimensional, bore-mounted, volume body coil concept for ultra high-field magnetic resonance imaging.

Lack of a body-sized, bore-mounted, radiofrequency (RF) body coil for ultrahigh field (UHF) magnetic resonance imaging (MRI) is one of the major drawbacks of UHF, hampering the clinical potential of the technology. Transmit field (B1 ) nonuniformity and low specific absorption rate (SAR) efficiencies in UHF MRI are two challenges to be overcome. To address these problems, and ultimately provide a pathway for the full clinical potential of the modality, we have designed and simulated two-dimensional cylindrical high-pass ladder (2D c-HPL) architectures for clinical bore-size dimensions, and demonstrated a simplified proof of concept with a head-sized prototype at 7 T. A new dispersion relation has been derived and electromagnetic simulations were used to verify coil modes. The coefficient of variation (CV) for brain, cerebellum, heart, and prostate tissues after B1 + shimming in silico is reported and compared with previous works. Three prototypes were designed in simulation: a head-sized, body-sized, and long body-sized coil. The head-sized coil showed a CV of 12.3%, a B1 + efficiency of 1.33 µT/√W, and a SAR efficiency of 2.14 µT/√(W/kg) for brain simulations. The body-sized 2D c-HPL coil was compared with same-sized transverse electromagnetic (TEM) and birdcage coils in silico with a four-port circularly polarized mode excitation. Improved B1 + uniformity (26.9%) and SAR efficiency (16% and 50% better than birdcage and TEM coils, respectively) in spherical phantoms was observed. We achieved a CV of 12.3%, 4.9%, 16.7%, and 2.8% for the brain, cerebellum, heart, and prostate, respectively. Preliminary imaging results for the head-sized coil show good agreement between simulation and experiment. Extending the 1D birdcage coil concept to 2D c-HPLs provides improved B1 + uniformity and SAR efficiency.

Cognitive-Motor Dissociation Following Pediatric Brain Injury: What About the Children?

Background and Objectives: Following severe brain injury, up to 16% of adults showing no clinical signs of cognitive function nonetheless have preserved cognitive capacities detectable via neuroimaging and neurophysiology; this has been designated cognitive-motor dissociation (CMD). Pediatric medicine lacks both practice guidelines for identifying covert cognition and epidemiologic data regarding CMD prevalence. Methods: We applied a diverse battery of neuroimaging and neurophysiologic tests to evaluate 2 adolescents (aged 15 and 18 years) who had shown no clinical evidence of preserved cognitive function following brain injury at age 9 and 13 years, respectively. Clinical evaluations were consistent with minimally conscious state (minus) and vegetative state, respectively. Results: Both participants' EEG, and 1 participant's fMRI, provided evidence that they could understand commands and make consistent voluntary decisions to follow them. Both participants' EEG demonstrated larger-than-expected responses to auditory stimuli and intact semantic processing of words in context. Discussion: These converging lines of evidence lead us to conclude that both participants had preserved cognitive function dissociated from their motor output. Throughout the 5+ years since injury, communication attempts and therapy had remained uninformed by such objective evidence of their cognitive abilities. Proper diagnosis of CMD is an ethical imperative. Children with covert cognition reflect a vulnerable and isolated population; the methods outlined here provide a first step in identifying such persons to advance efforts to alleviate their condition.

Characterization of a Low-Profile, Flexible, and Acoustically Transparent Receive-Only MRI Coil Array for High Sensitivity MR-Guided Focused Ultrasound.

Magnetic resonance guided focused ultrasound (MRgFUS) is a non-invasive therapeutic modality for neurodegenerative diseases that employs real-time imaging and thermometry monitoring of targeted regions. MRI is used in guidance of ultrasound treatment; however, the MR image quality in current clinical applications is poor when using the vendor built-in body coil. We present an 8-channel, ultra-thin, flexible, and acoustically transparent receive-only head coil design (FUS-Flex) to improve the signal-to-noise ratio (SNR) and thus the quality of MR images during MRgFUS procedures. Acoustic simulations/experiments exhibit transparency of the FUS-Flex coil as high as 97% at 650 kHz. Electromagnetic simulations show a SNR increase of 13× over the body coil. In vivo results show an increase of the SNR over the body coil by a factor of 7.3 with 2× acceleration (equivalent to 11× without acceleration) in the brain of a healthy volunteer, which agrees well with simulation. These preliminary results show that the use of a FUS-Flex coil in MRgFUS surgery can increase MR image quality, which could yield improved focal precision, real-time intraprocedural anatomical imaging, and real-time 3D thermometry mapping.

Ethmoidal meningoencephalocele in a C57BL/6J mouse.

An otherwise healthy two-month-old female C57BL/6J mouse presented with a left-sided head tilt. Differential diagnoses included idiopathic necrotizing arteritis, bacterial otitis media/interna (Pasteurella pneumotropica, Pseudomonas aeruginosa, Streptococcus sp., Mycoplasma pulmonis and Burkholderia gladioli), encephalitis, an abscess, neoplasia, a congenital malformation and an accidental or iatrogenic head trauma. Magnetic resonance imaging (MRI) revealed a large space-occupying right olfactory lobe intra-axial lesion with severe secondary left-sided subfalcine herniation. Following imaging, the animal was euthanized due to poor prognosis. Histopathologic examination revealed a unilateral, full-thickness bone defect at the base of the cribriform plate and nasal conchae dysplasia, resulting in the herniation of the olfactory bulb into the nasal cavity. There was also a left midline-shift of the frontal cortex and moderate catarrhal sinusitis in the left mandibular sinus. The MRI and histopathologic changes are consistent with a congenital malformation of the nasal cavity and frontal aspect of the skull known as an ethmoidal meningoencephalocele. Encephaloceles are rare abnormalities caused by herniation of contents of the brain through a defect in the skull which occur due to disruption of the neural tube closure at the level anterior neuropore or secondary to trauma, surgical complications, cleft palate or increased intracranial pressure. The etiology is incompletely understood but hypotheses include genetics, vitamin deficiency, teratogens, infectious agents and environmental factors. Ethmoidal encephaloceles have been reported in multiple species including humans but have not been reported previously in mice. There are multiple models for spontaneous and induced craniofacial malformation in mice, but none described for ethmoidal encephaloceles.

Prevalent and sex-biased breathing patterns modify functional connectivity MRI in young adults.

Resting state functional connectivity magnetic resonance imaging (fMRI) is a tool for investigating human brain organization. Here we identify, visually and algorithmically, two prevalent influences on fMRI signals during 440 h of resting state scans in 440 healthy young adults, both caused by deviations from normal breathing which we term deep breaths and bursts. The two respiratory patterns have distinct influences on fMRI signals and signal covariance, distinct timescales, distinct cardiovascular correlates, and distinct tendencies to manifest by sex. Deep breaths are not sex-biased. Bursts, which are serial taperings of respiratory depth typically spanning minutes at a time, are more common in males. Bursts share features of chemoreflex-driven clinical breathing patterns that also occur primarily in males, with notable neurological, psychiatric, medical, and lifespan associations. These results identify common breathing patterns in healthy young adults with distinct influences on functional connectivity and an ability to differentially influence resting state fMRI studies.

MRI characterization of early CNS transport kinetics post intrathecal gadolinium injection: Trends of subarachnoid and parenchymal distribution in healthy volunteers.

PURPOSE: To quantify CSF transport kinetics and brain glymphatic distribution using MRI following intrathecal injection of gadolinium contrast in healthy adults. SUBJECTS AND METHODS: Eight completely healthy volunteer subjects underwent intrathecal injection of gadolinium via image guided lumbar puncture and serial MRI's at six subsequent time points up to 11 h post-injection. Rate of enhancement and deposition were calculated for various regions and lobes of the brain. RESULTS: Normalized cranial data revealed that gadolinium in the intracranial CSF spaces peaked within 1-3 h and started to decrease at 7 h. In some regions of the brain parenchyma, such as the cerebral cortex and white matter, enhancement was increasing after 11 h. Differential rates of uptake between the parietal and frontal (p = 0.0003), cingulate (p = 0.002) and temporal (p = 0.018) lobes were shown as well as a several fold change between various cortical regions. Lastly, a linear regression comparing laterality between 35 cortical regions yielded (R2 = 0.90, p < 0.001) with a slope of 1.01 showing symmetry in uptake. CONCLUSIONS: Gadolinium enhancement after lumbar intrathecal injection demonstrated differential CSF flow and brain parenchymal penetration, which illustrated the distributory function of the glymphatic system.

Sparse learning of partial differential equations with structured dictionary matrix.

This paper presents a "structured" learning approach for the identification of continuous partial differential equation (PDE) models with both constant and spatial-varying coefficients. The identification problem of parametric PDEs can be formulated as an ℓ1/ℓ2-mixed optimization problem by explicitly using block structures. Block-sparsity is used to ensure parsimonious representations of parametric spatiotemporal dynamics. An iterative reweighted ℓ1/ℓ2 algorithm is proposed to solve the ℓ1/ℓ2-mixed optimization problem. In particular, the estimated values of varying coefficients are further used as data to identify functional forms of the coefficients. In addition, a new type of structured random dictionary matrix is constructed for the identification of constant-coefficient PDEs by introducing randomness into a bounded system of Legendre orthogonal polynomials. By exploring the restricted isometry properties of the structured random dictionary matrices, we derive a recovery condition that relates the number of samples to the sparsity and the probability of failure in the Lasso scheme. Numerical examples, such as the Schrödinger equation, the Fisher-Kolmogorov-Petrovsky-Piskunov equation, the Burger equation, and the Fisher equation, suggest that the proposed algorithm is fairly effective, especially when using a limited amount of measurements.

A vascular-task response dependency and its application in functional imaging of brain tumors.

PURPOSE: Preoperative functional MRI (fMRI) is limited by a muted BOLD response caused by abnormal vasoreactivity and resultant neurovascular uncoupling adjacent to malignant brain tumors. We propose to overcome this limitation and more accurately identify eloquent areas adjacent to brain tumors by independently assessing vasoreactivity using breath-holding and incorporating these data into the fMRI analysis. METHODS: Local vasoreactivity using a breath-holding paradigm with the same timing as the functional motor and language tasks was determined in 16 patients (9 glioblastomas, 1 anaplastic astrocytoma, 5 low grade astrocytomas, and 1 metastasis) and 6 healthy control subjects. We derived an fMRI model based on an observed vaso-task response dependency that takes into account the altered hemodynamics adjacent to brain tumors. RESULTS: In both healthy controls and brain tumor subjects, we found a statistical dependency between breath-hold and task BOLD response. In tumor subjects, activation maps that take into account this vaso-task dependency demonstrated clinically meaningful areas of activation that were not seen using the task-only analysis in about half of the cases studied. This included localization of language areas adjacent to brain tumors. CONCLUSIONS: The present preliminary results demonstrate that neurovascular uncoupling known to affect the accuracy of BOLD fMRI adjacent to brain tumors may be, at least partially, overcome by incorporating an observed vaso-task dependency in the BOLD signal analysis.

A delayed-feedback filter with negative group delay.

A filter with delay-induced negative group delay is presented. The filter consists of multiple time-delayed feedback terms, which lead to a negative group delay for frequencies in the baseband. It can be used for the real-time prediction of band-limited signals. The filter is universal as it does not rely on a specific model of the signal. Specifically, as long as the signal to be predicted is band-limited with a known cutoff frequency, the filter predicts the signal in real time up to a prediction horizon that depends on the cutoff frequency. How signal prediction arises from the negative group delay of the filter is worked out in detail. Its properties, including stability, are derived analytically and demonstrated by numerical simulations. For chaotic systems, the filter is predictive during phases of high predictability.

Cortical Response to the Natural Speech Envelope Correlates with Neuroimaging Evidence of Cognition in Severe Brain Injury.

Recent studies identify severely brain-injured patients with limited or no behavioral responses who successfully perform functional magnetic resonance imaging (fMRI) or electroencephalogram (EEG) mental imagery tasks [1-5]. Such tasks are cognitively demanding [1]; accordingly, recent studies support that fMRI command following in brain-injured patients associates with preserved cerebral metabolism and preserved sleep-wake EEG [5, 6]. We investigated the use of an EEG response that tracks the natural speech envelope (NSE) of spoken language [7-22] in healthy controls and brain-injured patients (vegetative state to emergence from minimally conscious state). As audition is typically preserved after brain injury, auditory paradigms may be preferred in searching for covert cognitive function [23-25]. NSE measures are obtained by cross-correlating EEG with the NSE. We compared NSE latencies and amplitudes with and without consideration of fMRI assessments. NSE latencies showed significant and progressive delay across diagnostic categories. Patients who could carry out fMRI-based mental imagery tasks showed no statistically significant difference in NSE latencies relative to healthy controls; this subgroup included patients without behavioral command following. The NSE may stratify patients with severe brain injuries and identify those patients demonstrating "cognitive motor dissociation" (CMD) [26] who show only covert evidence of command following utilizing neuroimaging or electrophysiological methods that demand high levels of cognitive function. Thus, the NSE is a passive measure that may provide a useful screening tool to improve detection of covert cognition with fMRI or other methods and improve stratification of patients with disorders of consciousness in research studies.

Apoε4 disrupts neurovascular regulation and undermines white matter integrity and cognitive function.

The ApoE4 allele is associated with increased risk of small vessel disease, which is a cause of vascular cognitive impairment. Here, we report that mice with targeted replacement (TR) of the ApoE gene with human ApoE4 have reduced neocortical cerebral blood flow compared to ApoE3-TR mice, an effect due to reduced vascular density rather than slowing of microvascular red blood cell flow. Furthermore, homeostatic mechanisms matching local delivery of blood flow to brain activity are impaired in ApoE4-TR mice. In a model of cerebral hypoperfusion, these cerebrovascular alterations exacerbate damage to the white matter of the corpus callosum and worsen cognitive dysfunction. Using 3-photon microscopy we found that the increased white matter damage is linked to an enhanced reduction of microvascular flow resulting in local hypoxia. Such alterations may be responsible for the increased susceptibility to hypoxic-ischemic lesions in the subcortical white matter of individuals carrying the ApoE4 allele.