Citations

Introduction: Understanding mid-term test-retest reliability and within-subject variability is important for interpreting changes observed in longitudinal and intervention studies. The reliability of resting-state functional magnetic resonance imaging (rs-fMRI) is known to vary across measures and brain regions. However, how reliability differs across functional networks and connectivity- and amplitude-based measures, and whether multi-echo acquisition and processing modify these patterns, remain incompletely characterized. Methods: Twenty-two healthy volunteers underwent two rs-fMRI sessions 15.7 ± 4.0 days apart on a Compact 3T scanner. Multi-echo, middle-echo, and independently acquired single-echo datasets were compared, with multi-echo independent component analysis additionally evaluated as a denoising approach. Functional connectivity (FC) and three amplitude-based measures were evaluated using the Schaefer 400 parcellation. Reliability was systematically assessed using intraclass correlation coefficient (ICC), within-subject standard deviation (wSD), and systematic bias at edge or regional, and network levels. Results: Acquisition-dependent differences in reliability were generally modest. Multi-echo acquisition and processing increased functional connectivity strength and the magnitude of amplitude-based measures and improved inferior cortical coverage, but these enhancements did not consistently translate into substantially higher ICC or lower wSD. In contrast, reliability showed clear network-dependent differences. FC reliability varied markedly across network pairs and was not explained by connectivity strength alone; pairs involving the default mode and control networks generally showed more favorable profiles than several somatomotor and visual network pairs. Fractional amplitude of low-frequency fluctuations (fALFF) also showed network-dependent reliability, with the most favorable regional reproducibility observed in the default mode and control networks and lower reproducibility in the somatomotor and visual networks. Conclusion: These findings provide practical mid-term reliability benchmarks for rs-fMRI on a Compact 3T scanner and show that measurement stability varies more clearly across measures and functional networks than across acquisition approaches.

Abstract White matter bundles play a crucial role in cognitive functions by rapidly transmitting information between brain regions. Inter-areal conduction guides the integration of information and conduction velocity is a fundamental parameter in theories and models of brain function. However, distributions of conduction velocity remain difficult to characterize in vivo in humans. In this work, we integrated diffusion magnetic resonance imaging (dMRI) tractography with intracranial electrical stimulation during clinical stereo-electroencephalography (sEEG) monitoring in 17 subjects to measure conduction velocity within four major white matter bundles. Our findings reveal that human brain conduction is characterized by high variability both within and between bundles, reflecting a predominance of slow connections alongside rare high-speed connections. Because conduction velocity in myelinated fibers follows an approximately linear relationship with axon diameter, we derive underlying axon diameter distributions and show that these estimates are comparable to previous post-mortem studies. These findings demonstrate a heavily skewed distribution of human neural conduction velocities and show that structural heterogeneity shapes the timing and integration of information in large-scale networks.

Abstract Hypoxia constrains cerebral oxygen availability and challenges brain function and stability. Although hypoxia-responsive functional connectivity (HR-FC) reorganizes rapidly with declining arterial oxygen partial pressure, its relationship to local neurovascular activity remains unclear. We examined time-resolved amplitude of low-frequency fluctuations (ALFF) in blood-oxygenation-level dependent (BOLD) fMRI during graded acute hypoxia in healthy adults, performing a continuous cognitive test (Go/No-go task) with concurrent physiological monitoring. Dynamic ALFF and functional connectivity were estimated using a sliding-window approach and analyzed across large-scale brain networks defined by Schaefer’s 17-network parcellation. Severe hypoxia elicited temporally dissociated responses across modalities. Functional connectivity increased monotonically, whereas ALFF exhibited pronounced nonlinear modulation, including phase-dependent divergence across networks. During hypoxic decompensation, the default mode network (DefaultA) showed marked ALFF suppression, whereas a ventral secondary somatosensory-dominant network (SomMotB) exhibited preferential preservation despite similar engagement in HR-FC. Together, these findings indicate that network-level ALFF captures a distinct yet complementary layer of functional dynamics, with a temporal profile distinct from functional connectivity. Spontaneous BOLD dynamics during acute hypoxia reflect structured network-level modulation rather than a uniform suppression attributable solely to reduced oxygen availability. These findings support a conceptual framework of cerebral oxygen budgeting , in which metabolic constraints reshape functional dynamics across brain networks.

Abstract Background Respiration has traditionally been considered a source of artifact in functional MRI (fMRI) due to chest motion. However, the respiratory cycle also induces changes in local oxygen concentration, resulting in fluctuations in the fMRI signal. These breathing‐triggered signals (BTS) may reflect underlying oxygen metabolism. This preliminary study developed a method to extract BTS from resting‐state BOLD fMRI and examined differences between healthy and mild cognitive impairment (MCI) groups. Method MRI scans were conducted under IRB approval on a compact 3T MRI system. Participants included two groups of 18 healthy volunteers (42.6±16.0 years) and 12 MCI patients (70.9±7.3 years). Each MRI scan included T 1 ‐weighted anatomy imaging and multi‐echo resting‐state fMRI acquisitions. The preprocessing pipeline was implemented by AFNI and FreeSurfer. Figure 1 illustrates the workflow for extracting and averaging fMRI data based on respiratory or cardiac cycle windows. As depicted in Figure 2(c,d), the mean fMRI signals corresponding to the breathing or cardiac cycles were modeled using a low‐order Fourier series to assess their amplitudes. A linear mixed‐effects model was employed to examine the effects of group and breathing cycle period, using MATLAB's ‘fitlme’ function with the formula: BTS ∼ Period + Group. Result As shown in Figure 2(e,f), breathing‐triggered BOLD signals were prominent, while cardiac‐driven BOLD signals were rarely observed. Figure 2(g) shows that global BTSs in the healthy group exhibited a linear relationship with the breathing cycle period, persisting even after artifact correction (RETROICOR for respiration and cardiac cycles and RVT). Figure 3 highlights significant regional differences between groups, particularly in the hippocampus and thalamus ( p < 0.05, uncorrected), where BTS amplitudes were greater in the MCI group. Potentially, the detected BTS could provide some insights into the coupling between respiration and cerebral oxygen metabolism and potentially serve as an imaging biomarker to assess brain health. However, due to the limited number of samples, these findings should be interpreted with caution, and further analysis is needed. Conclusion This preliminary study suggests that breathing‐triggered signals in resting‐state BOLD fMRI have the potential to serve as a noninvasive biomarker for early detection and monitoring of neurodegenerative conditions such as MCI.

Abstract Background Flow‐related ghost artifact from a 3D Magnetization Prepared Rapid Gradient Echo (MPRAGE) sequence results from unsaturated magnetization of incoming arterial flow. This is especially common on MR scanners equipped with smaller radiofrequency (RF) transmit coils. A high‐performance compact 3T (C3T) scanner features a smaller RF‐transmit coil (inner diameter 37 cm, length 40 cm), leading to a rapid fall‐off of the B1 field below the neck. This configuration results in more intense flow‐related ghost artifacts, especially in younger patients. Purpose The C3T scanner's smaller RF‐transmit coil provides RF field coverage over the brain region, causing bright in‐flow arterial signals and flow‐related artifacts in the conventional 3D‐MPRAGE scans. The purpose of this study is to suppress these artifacts by adding a RF saturation band (RFSB) pulses to the 3D‐MPRAGE sequence. Methods The RFSB was added to the 3D‐MPRAGE sequence as a preparation pulse option. To test the effectiveness, 37 subjects were scanned on the C3T under an IRB‐approved protocol using 3D‐MPRAGE with and without RFSB. Ten of those subjects underwent repeated scans with and without RFSB to evaluate test‐retest reliability. A consensus evaluation by two neuroradiologists was performed on all data to compare signal to noise ratio, image contrast, presence of artifacts, and diagnostic confidence. Quantitative analysis included calculating test‐retest differences by image subtraction and evaluating the variance in flow‐artifact‐induced image intensity between the scans with and without RFSB. Additionally, one subject was scanned on a whole‐body 3T scanner using a transmit/receive (T/R) head coil to demonstrate the method's applicability across different MRI platforms as a proof of concept. Results The Wilcoxon signed‐rank test of the neuroradiologist evaluations showed a significant reduction in artifacts and an improvement in diagnostic confidence in the posterior fossa region with and without RFSB ( p < 0.0001). Test–retest analysis showed that adding RFSB significantly reduced image intensity variability in the cerebellum, even among subjects without visible flow artifacts. The normalized difference decreased from 8.71% to 6.41% ( p = 0.0059), suggesting improved image reliability in regions prone to flow‐related artifacts. Additionally, similar findings were observed in scans on a whole‐body 3T with a T/R head coil, demonstrating the broader applicability of this method. Conclusion Incorporating RFSB into 3D‐MPRAGE scans effectively reduces flow‐related ghost artifact on the C3T scanner, improving image quality and diagnostic confidence. These findings suggest that the proposed method could be widely implemented across MRI systems utilizing a smaller RF‐transmit coil.

Women with type 2 diabetes (T2D) have a higher risk of being diagnosed with breast cancer and have worse survival than non-diabetic women if they do develop breast cancer. However, more research is needed to elucidate the biological underpinnings of these relationships. Here, we found that forkhead box A1 (FOXA1), a forkhead family transcription factor, and metformin (1,1-dimethylbiguanide hydrochloride), a medication used to treat T2D, may impact hormone-receptor-positive (HR+) breast cancer (BC) tumor cell growth and metastasis. Indeed, fourteen diabetes-associated genes are highly expressed in only three HR+ breast cancer cell lines but not the other subtypes utilizing a 53,805 gene database obtained from NCBI GEO. Among the diabetes-related genes, FOXA1, MTA3, PAK4, FGFR3, and KIF22 were highly expressed in HR+ breast cancer from 4032 breast cancer patient tissue samples using the Breast Cancer Gene Expression Omnibus. Notably, elevated FOXA1 expression correlated with poorer overall survival in patients with estrogen-receptor-positive/progesterone-receptor-positive (ER+/PR+) breast cancer. Furthermore, experiments demonstrated that loss of the FOXA1 gene inhibited tumor proliferation and invasion in vitro using MCF-7 and T47D HR+ breast cancer cell lines. Metformin, an anti-diabetic medication, significantly suppressed tumor cell growth in MCF-7 cells. Additionally, either metformin treatment or FOXA1 gene deletion enhanced tamoxifen-induced tumor growth inhibition in HR+ breast cancer cell lines within an ex vivo three-dimensional (3D) organoid model. Therefore, the diabetes-related medicine metformin and FOXA1 gene inhibition might be a new treatment for patients with HR+ breast cancer when combined with tamoxifen, an endocrine therapy.

AbstractBackgroundThe cardiac and respiratory cycles have been suggested as major drivers of cerebrospinal fluid(CSF) flow. The glymphatic system, one of the mechanisms for the clearance of amyloid‐beta and tau proteins, relies heavily on the movement(flow) of the CSF, and thus, investigating the forces that modulate the CSF flow is essential for understanding the glymphatic flux. Because breathing is trainable through exercise and self‐directed methods, various breathing methods may enhance the CSF flow.MethodReal‐time phase‐contrast MRI(pc‐MRI) was used to measure the CSF flow at the foramen magnum on a 3T. Fast resting‐state fMRI(rsfMRI;TR400ms) was conducted on a compact 3T. Under an IRB‐approved protocol, participants were instructed to breathe slowly and deeply, and subsequently switch to their spontaneous breathing. For rsfMRI data preprocessing, we performed motion correction, skull stripping, spatial smoothing(4mm), temporal filtering(0.01 to 0.1Hz), and linear and quadratic temporal trends removal. fMRI time courses were then normalized to Z‐score at each voxel before being averaged. On the pcMRI, the phase was summed in a CSF region‐of‐interest and plotted vs time. Additionally, we confirmed for possible confounding effects such as head motion or motion‐induced susceptibility changes.ResultrsfMRI findings showed that deep breathing promoted large oscillations in the CSF flow in the ventricles, while spontaneous breathing did not(Figure 1). Additionally, deep breathing resulted in large oscillations in lobar cortical regions. Similar results were observed in the pcMRI, with larger CSF velocity through the foramen magnum during the deep breathing compared to the spontaneous breathing(Figure 2A‐B). The cumulative summation result showed that the volume of CSF flow was increased during deep breathing(Figure 2C).ConclusionThis study provides new evidence that slow and deep breathing promotes CSF flow and global brain BOLD signal, which may be useful in promoting circulation in the brain. The study’s findings also open new avenues for research in the field of neurovascular coupling and mechanisms associated with glymphatic clearance. As hampered CSF flow and/or worsen glymphatic clearance have been shown to associate with pathological aging and dementia, including Alzheimer’s disease and Parkinson’s disease, future research is needed explore the potential of breathing training methods as a non‐pharmacological intervention to support brain health.

Abstract: Objectives: Locally low-rank (LLR) denoising of functional magnetic resonance imaging (fMRI) time series image data is extended to multi-echo (ME) data. The proposed method extends the capabilities of non-physiologic noise suppression beyond single-echo applications with a dedicated ME algorithm. Materials and Methods: Following an institutional review board (IRB) approved protocol, resting-state fMRI data were acquired in 7 healthy subjects. A compact 3T scanner enabled whole-brain acquisition of multiband ME fMRI data at high spatial resolution (1.4 × 1.4 × 2.8 mm3) with a 1810 ms repetition time (TR). Image data were denoised with ME-LLR preceding functional processing. The results of connectivity maps generated from denoised data were compared with maps generated with equivalent processing of non-denoised images. To assess ME-LLR as a method to reduce scan time, comparisons were made between maps computed from image data with full and retrospectively truncated durations. Assessments were completed with seed-based connectivity analyses using echo-combined image data. In a feasibility assessment, nondenoised and denoised full-duration echo-combined data were equivalently processed with independent component analysis (ICA) and compared. Results: ME-LLR denoising yielded strengthened resting-state network connectivity maps after nuisance regression and seed-based connectivity analysis. In assessing ME-LLR as a scan reduction mechanism, maps generated from denoised data at half scan time showed comparable quality with maps generated from full-duration, non-denoised data, at both single subject and group levels. ME-LLR substantially increased temporal signal-to-noise ratio (tSNR) for image data respective to each individual echo and for image data after nuisance regression. Among echo-specific image volumes, increases in tSNR yielded by ME-LLR were most pronounced for image data with the longest echo time and thereby lowest SNR. ICA showed resting-state networks consistently identified between non-denoised and denoised data, with clearer demarcation of networks for ME-LLR. Conclusions: ME-LLR is demonstrated to suppress non-physiologic noise, enhance functional connectivity map quality, and could potentially facilitate scan time reduction in ME-fMRI.

In blood-oxygen-level-dependent (BOLD)-based resting-state functional (RS-fMRI) studies, usage of multi-echo echo-planar-imaging (ME-EPI) is limited due to unacceptable late echo times when high spatial resolution is used. Equipped with high-performance gradients, the compact 3T MRI system (C3T) enables a three-echo whole-brain ME-EPI protocol with smaller than 2.5 mm isotropic voxel and shorter than 1 s repetition time, as required in landmark fMRI studies. The performance of the ME-EPI was comprehensively evaluated with signal variance reduction and region-of-interest-, seed- and independent-component-analysis-based functional connectivity analyses and compared with a counterpart of single-echo EPI with the shortest TR possible. Through the multi-echo combination, the thermal noise level is reduced. Functional connectivity, as well as signal intensity, are recovered in the medial orbital sulcus and anterior transverse collateral sulcus in ME-EPI. It is demonstrated that ME-EPI provides superior sensitivity and accuracy for detecting functional connectivity and/or brain networks in comparison with single-echo EPI. In conclusion, the high-performance gradient enabled high-spatial-temporal resolution ME-EPI would be the method of choice for RS-fMRI study on the C3T.

Abstract Objective . Interleaved reverse-gradient fMRI (RG-fMRI) with a point-spread-function (PSF) mapping-based distortion correction scheme has the potential to minimize signal loss in echo-planar-imaging (EPI). In this work, the RG-fMRI is further improved by imaging protocol optimization and application of reverse Fourier acquisition. Approach . Multi-band imaging was adapted for RG-fMRI to improve the temporal and spatial resolution. To better understand signal dropouts in forward and reverse EPIs, a simple theoretical relationship between echo shift and geometric distortion was derived and validated by the reliable measurements using PSF mapping method. After examining practical imaging protocols for RG-fMRI in three subjects on both a conventional whole-body and a high-performance compact 3 T, the results were compared and the feasibility to further improve the RG-fMRI scheme were explored. High-resolution breath-holding RG-fMRI was conducted with nine subjects on the compact 3 T and the fMRI reliability improvement in high susceptibility brain regions was demonstrated. Finally, reverse Fourier acquisition was applied to RG-fMRI, and its benefit was assessed by a simulation study based on the breath-holding RG-fMRI data. Main results . The temporal and spatial resolution of the multi-band RG-fMRI became feasible for whole-brain fMRI. Echo shift measurements from PSF mapping well estimated signal dropout effects in the EPI pair and were useful to further improve the RG-fMRI scheme. Breath-holding RG-fMRI demonstrated improved fMRI reliability in high susceptibility brain regions. Reverse partial Fourier acquisition omitting the late echoes could further improve the temporal or spatial resolution for RG-fMRI without noticeable signal degradation and spatial resolution loss. Significance . With the improved imaging scheme, RG-fMRI could reliably investigate the functional mechanisms of the human brain in the temporal and frontal areas suffering from susceptibility-induced functional sensitivity loss.