Pulsed field ablation (PFA) has proven to be a safe and effective non-thermal ablation modality for the treatment of atrial fibrillation (AF), but little outcome data beyond 1 year have been reported. Here we present results from the ADVENT-LTO study, which provides extended follow-up of the ADVENT trial, the first randomized trial comparing PFA with conventional thermal ablation. In ADVENT-LTO, 364 patients with paroxysmal AF (183 PFA, 181 thermal; 237 men, 127 women) participated and were followed for 1,332 ± 147 days. For the primary endpoint of 4-year treatment success, PFA demonstrated preserved effectiveness compared to thermal ablation (72.8% PFA, 64.3% thermal; P = 0.12). Moreover, there was a trend favoring PFA as compared to thermal ablation for the prespecified outcome of freedom from hospital-based arrhythmia intervention (85.6% PFA, 78.6% thermal; hazard ratio (HR) = 0.64, 95% confidence interval (CI): 0.38-1.05), including fewer repeat ablations (10.4% PFA, 17.7% thermal; P = 0.04) as well as a trend favoring PFA as compared to thermal ablation for the prespecified outcome of progression to persistent AF (2.6% PFA, 4.6% thermal; HR = 0.55, 95% CI: 0.16-1.88). Taken together, these data demonstrate that the favorable outcomes of PFA are maintained over the course of 4 years. Coupled with the safety advantages of PFA over thermal ablation, these long-term data support widespread adoption of PFA for the treatment of AF. ClinicalTrials.gov registration: NCT06526546 .

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder whose prevalence is rising with the aging of the global population. Among the proposed pathological hallmarks, the amyloidbeta (Aβ) peptide aggregates and soluble Aβ oligomers are established biomarkers and remain valuable diagnostic targets. While positron emission tomography (PET) imaging agents dominate AD diagnostic imaging, there are no FDA-approved MRI agents for AD. Herein, we report five bifunctional chelators built on the 2,11-diaza[3.3](2,6)pyridinophane framework, and which were evaluated as chelators for Mn2+-based MRI contrast agents. Based on in vitro studies, including thermodynamic stability and kinetic inertness measurements, T1 relaxivity and 17O transverse relaxivity measurements to extract hydration numbers and water-exchange parameters, we obtained a clear structure-activity correlation for the corresponding bifunctional chelators: anionic 2 picolinate and acetate arms increase thermodynamic stability and kinetic inertness, while the benzothiazolyl-phenol arm accelerates water exchange. Importantly, a high hydration number alone is insufficient, as a rapid water exchange is also needed for an appreciable contrast. Moreover, we show both the bifunctional chelators and and their Mn2+ complexes exhibit appreciable affinity for Aβ aggregates, both in vitro and in 5xFAD mouse brain sections. [Mn(TE-8)], the most kinetically inert complex with favorable relaxivity, log D, and Aβ affinity, was advanced to in vivo MRI studies. Unlike MnCl2, which accumulates non-specifically, [Mn(TE-8)] cleared through renal and hepatobiliary routes and produced measurable brain contrast enhancement. Together, these results establish the diazapyridinophane scaffold as a viable firstgeneration platform for blood-brain-barrier-permeable Mn2+ MRI contrast agents.

PURPOSE:Increase clinical acceptance of MRE and DTI by shortening the scan time by half and providing diffusive and mechanical property maps that are inherently co-registered. This proof-of-concept study evaluates the simultaneous DTI-MRE acquisition in the human brain and compares its results to conventional DTI and MRE measurements. METHODS:We optimized experimental parameters for in vivo human brain DTI-MRE acquisitions based on signal-to-noise ratio, encoding efficiency, and intravoxel phase dispersion mitigation. Five healthy subjects underwent scanning on a 3 T Siemens Prisma scanner, using two optimized parameter sets. Diffusive (mean diffusivity, fractional anisotropy) and mechanical (shear stiffness) property maps were computed and compared with conventional methods using Pearson's correlation analysis. RESULTS:DTI-MRE correlated with conventional DTI and MRE methods across all subjects. Mean diffusivity and fractional anisotropy maps showed excellent fidelity between methods (Pearson's coefficients of global mean values > 0.86, Pearson's coefficients of voxel-wise values > 0.7). Spatially averaged shear stiffness values were slightly lower in DTI-MRE. CONCLUSION:This proof-of-concept study confirms the feasibility of simultaneous DTI-MRE acquisition in the human brain, offering an efficient method for obtaining both diffusive and mechanical property maps. Further refinements in encoding strategies and inversion algorithms, such as the incorporation of a multi-frequency actuation approach in the DTI-MRE framework, could enhance accuracy, enabling broader clinical applications in neurology, neurosurgery, and brain injury assessment.

SimulScan is a new technique that enables the simultaneous collection of dynamic imaging of a mid-sagittal slice at the same time as functional MRI of the brain. This enables the monitoring of central control of speech and swallowing, important in the management of dysarthria and dysphagia. The dynamic imaging portion of the scan is drastically undersampled and a partial separability model is used to constrain the reconstruction to produce high-quality, high-speed imaging. The choice of temporal bases for this reconstruction is critically important for capturing the relevant oropharyngeal events. Current methods use a simple singular value decomposition (SVD) of the temporal navigator data. In this work, we explore the use of correlations with the brain functional data to drive the choice of temporal bases for the dynamic image reconstruction. We demonstrate that this can provide a dynamic image reconstruction that is more focused on the relevant task for the functional MRI experiment.

PURPOSE:Swallowing involves the precise coordination of muscles and brain areas and can be disrupted in a variety of neurological conditions. Current methods to visualize swallowing cannot examine both the biomechanics and brain activity associated with specific swallowing events. An updated version of a pulse sequence that simultaneously samples BOLD-based fMRI and dynamic imaging (called SimulScan) is introduced that provides higher quality and faster dynamic imaging, enabling data-driven analysis of swallowing function through a partial least squares (PLS) analysis. METHODS:Integrating updated dynamic imaging approaches, SimulScan achieved dynamic MRI at 23.75 frames per second with a 30 cm field of view with BOLD fMRI at a 1.6 s TR. Five subjects were scanned with SimulScan twice and with videofluoroscopy to compare the preliminary reliability of measuring swallowing biomechanics using computational analysis of swallowing mechanics (CASM) and the test-retest relationship in correlated functional and dynamic components of PLS. RESULTS:High reliability of biomechanical measures of swallowing was achieved across the two SimulScan runs with CASM (r = 0.891; p < 0.0001) and between SimulScan and videofluoroscopy (r = 0.686; p < 0.0001). Correlations between dynamic and functional imaging across runs also showed high reliability (mean correlation of first 3 latent variable timeseries was 0.49 (p < 0.001) within a run and 0.17 (p < 0.001) across runs), indicating that SimulScan with PLS can extract reliable maps of linked correlations between the brain and the oropharyngeal dynamics. CONCLUSION:The updated SimulScan with PLS analysis enables the study of central control of swallowing, providing simultaneous biomechanical visualization of the swallow along with brain functional signals.

PURPOSE:Aging impacts pulsatility of blood vessels in the brain, reflecting vascular health. Resolving characteristics of cardiac pulsatility requires faster acquisitions than traditional fMRI. An ultrafast fMRI method was developed and applied to sample several harmonics of cardiac pulsations at 7 T. METHODS:Leveraging partial separability, an ultrafast fMRI method (TR = 65 ms) was applied at 7 T with full brain coverage at 2 mm isotropic resolution and concurrent pulse plethysmographic (PPG) recordings in 28 healthy adults, 22 of whom had acceptable PPG and MRI data. The reliability of the pulsation was assessed for each voxel through even/odd splitting of heartbeats. The PPG was used to retrospectively temporally align signals across heartbeats, and analysis was performed on amplitudes of harmonic frequencies to explore age- and sex-related differences. Reliable measures of four harmonics of the heartbeat were characterized along with the ratios of the harmonics to the primary harmonic. RESULTS:High reliability of the pulsation was found near major arteries, tested by Spearman correlation between the first harmonic and a vessel atlas (p < 0.0001). Consistent with previous literature, older adults exhibited higher harmonic amplitudes with the strongest result in the second harmonic in gray matter with FDR-corrected q = 0.020. In addition, males had a higher third-to-first harmonic ratio. CONCLUSION:Ultrafast fMRI can reliably resolve several harmonics of cardiac pulsations in the brain in and around blood vessels. This may provide a way to characterize vascular health throughout the brain during aging.

Gadolinium-based contrast agents are commonly utilized in magnetic resonance imaging (MRI). However, manganese-based agents have attracted increasing interest due to their favorable relaxation properties and enhanced biocompatibility, particularly in light of concerns regarding nephrogenic systemic fibrosis associated with the administration of acyclic Gd3+ chelates. In this study, we developed a series of hexadentate and heptadentate chelators based on the 2,11-diaza[3.3](2,6)pyridinophane macrocycle to improve the relaxivity of the corresponding Mn(II) complexes. We evaluated how coordination number and pendant arm selection influence the efficiency of these Mn-based MRI contrast agents. Spectrophotometric titrations showed that 7-coordinate complexes are more thermodynamically stable than 6-coordinate complexes, as expected for Mn(II). However, the presence of additional chelating arms was shown to reduce the kinetic inertness of the Mn complexes by facilitating coordination with other metal ions such as Cu(II) and Zn(II), while amine methylation was found to enhance kinetic inertness and not affect relaxivity. Given its promising in vitro performance, one Mn complex was tested in mice using a 9.4 T MRI scanner, revealing that the compound was primarily cleared via the renal pathway, and low heart contrast enhancement indicated minimal albumin binding, consistent with the behavior of other promising MRI contrast agents.

IntroductionVirtual reality (VR) is seeing widespread use in medicine to assist with patient communication, medical education and training, and surgical planning. For the clinical team, VR has been shown to reduce the mental load associated with creating mental models of complicated surgical cases. Segmenting 3D medical images into digital twins, 3D models of patient specific anatomy, is a complicated, multi-step process requiring technical expertise.MethodsWe present a flexible pipeline and code that encompasses image processing, 3D segmentation, and mesh creation developed to convert clinical 3D medical images into VR-ready patient specific models. This pipeline is accompanied by example data and code.ResultsThe pipeline produces VR-compatible models of patient-specific anatomy from 3D medical images, and the accompanying code, example dataset, and guidelines allow the workflow to be reproduced and adapted.DiscussionBy lowering the barrier of entry to converting medical images into VR, this work enables non-technical researchers and clinical experts to leverage VR for visualization of patient-specific anatomy across clinical, educational, and research domains.

INTRODUCTION:Subjective cognitive concerns frequently diverge from objective cognitive performance in cognitively unimpaired (CU) older adults, yet the neurobiological basis of this mismatch remains unclear. METHODS:In 648 participants from the Investigating Gains in Neurocognition in an Intervention Trial of Exercise (IGNITE), we defined four profiles by integrating subjective and objective cognitive status. We examined associations with plasma neurofilament light chain (NfL), phosphorylated tau 217 (p-tau217), glial fibrillary acidic protein (GFAP), a magnetic resonance imaging-based volumetric Alzheimer's disease (AD) signature reflecting atrophy, and brain-predicted age difference (brain-PAD). RESULTS:Joint profiles were differentially associated with NfL (P = 0.0427) and brain-PAD (P = 0.0296). Follow-up contrasts further indicated higher NfL and lower volumetric AD signature in the concordant lower functioning profile, and higher brain-PAD in discordant profiles. p-tau217 and GFAP did not differ across profiles. DISCUSSION:Joint subjective-objective cognitive profiles may capture biologically meaningful heterogeneity relevant to neurodegeneration and brain aging in older adults. TRIAL REGISTRATION:ClinicalTrials.gov: NCT02875301.

Manganese-based magnetic resonance imaging (MRI) contrast agents were developed using chelators derived from the 2,11-diaza[3.3](2,6)pyridinophane macrocycle to enhance Mn2+ relaxivity. The synthesized chelators were assessed to determine how coordination number and pendant arm selection affect the efficiency of the resulting Mn-based MRI contrast agents. Two compounds demonstrated significant potential: [Mn(TE-1)] exhibited relaxivity comparable to clinical gadolinium-based agents (3.6 mM-1 s-1 at 1.4 T), while [Mn(TE-4)] displayed rapid renal clearance and strong contrast enhancement in the kidney and bladder. In vivo PET imaging with 52Mn confirmed that [Mn(TE-4)] undergoes renal excretion, supporting its further development as an MRI or PET imaging agent. The lipophilic [Mn(TE-1)] exhibited both biliary and renal excretion, indicating its suitability as a blood pool MRI agent and for potential immuno-PET applications.

We present an open, vendor-neutral BOLD SMS-EPI protocol tailored for multi-site fMRI studies, intended as a drop-in replacement for conventional vendor-specific acquisition and reconstruction pipelines. Built on Pulseq-an emerging standard for cross-platform MRI pulse sequence development-our protocol ensures identical SMS-EPI pulse sequences and image reconstruction across scanner vendors. This provides, for the first time, known and consistent experimental conditions across sites and scanner software versions. We begin by reviewing the current capabilities of the Pulseq framework, including vendor support and safety considerations. We then detail our SMS-EPI implementation and demonstrate its performance using resting-state fMRI pilot data from healthy volunteers, showing reduced site variance compared to corresponding vendor protocols on Siemens and GE scanners. To support adoption, we provide practical resources to help researchers integrate Pulseq fMRI into their studies, including example text for grant proposals and IRB submissions. These resources are freely available at https://github.com/HarmonizedMRI/Functional. Our vision is for Pulseq fMRI to become the standard for multi-site research, enabling more reproducible science and serving as a reference for the development of novel acquisition and reconstruction methods.

INTRODUCTION Poor sleep is associated with neurodegenerative disease, but mechanisms are unclear. Greater volume of the choroid plexus (ChP), a brain structure supporting neurotoxic waste clearance, is linked to neurodegeneration and cognitive decline. We tested whether poor sleep promotes neurodegeneration and cognitive deficits via ChP dysfunction.METHODS Baseline magnetic resonance imaging (MRI) -derived ChP, hippocampal, ventricular, and gray matter volumes from 635 cognitively unimpaired older adults were analyzed. Sleep was measured with the Pittsburgh Sleep Quality Index and accelerometry. Confirmatory factor analysis generated cognitive domain scores.RESULTS Poorer self-reported sleep quality was associated with greater ChP volume, while accelerometry measures were not. Greater ChP volume was associated with smaller hippocampi and gray matter, and larger ventricles. ChP mediated relationships between sleep quality and hippocampal and ventricular volumes. Gray matter mediated associations between ChP and cognitive domains.DISCUSSION Altered ChP morphology may link poor sleep to neurodegeneration and cognitive decline in older adults.

Value-based decision-making engages brain-wide motivational, cognitive, and motor processes. Yet, information integration and gating that culminate in immediate decisions upon salient events likely occur within small neural nuclei and cortical layers at the mesoscale not resolved with conventional human neuroimaging. Using submillimeter-resolution 7 T functional MRI with acquisition-matched anatomical references and a lottery choice task incorporating salient superhigh stakes, we dissociated mesoscale operations spanning a brainstem-prefrontal-striatal pathway during choice and outcome processing. The locus coeruleus, caudate, and prefrontal cortex showed enhanced activity during superhigh-stake choices, while the substantia nigra/ventral tegmental area and nucleus accumbens additionally distinguished gains from losses. In contrast, gray-matter bridges between caudate and putamen were associated with faster responses. Laminar analyses revealed deeper prefrontal layers predominating during choice selection and superficial layers during outcome evaluation. Here, we show a mesoscale framework integrating brainstem modulation, striatal gating, and laminar cortical computation in human decision-making upon salient events.

The hippocampus, a key neural structure supporting episodic memory, comprises distinct subfields including the dentate gyrus (DG), Cornu Ammonis (CA1-3), and subiculum. Hippocampal subfields typically show age-related volumetric decline across adulthood, but the regional aging may be differentially vulnerable to cardiovascular risk factors. Here, we examined the association between hippocampal subfield volumes and cardiovascular risk indices-hypertension, blood pressure variation (BPV), body mass index (BMI), and waist-to-hip ratio-in groups of younger (n = 37, ages 18-29 years) and older adults (n = 22, ages 60-79 years). The findings revealed a specific link between cardiovascular health and hippocampal subfield volumes, with the subiculum showing greater sensitivity. Among younger adults, hypertension predicted smaller subiculum, while higher BMI correlated with larger CA1-2 volumes. For older adults, higher BPV predicted smaller subiculum volume, independent of hypertension that correlated with larger regional volume. Age moderated the relation between all indices and subiculum volume except waist-to-hip ratio. These findings highlight age-dependent, subfield-specific risk factors for hippocampal aging and underscore the potential for identifying sensitive periods for both risk and protection against late-life cognitive decline.