Characterization of pulsations in the brain and cerebrospinal fluid using ultra-high field magnetic resonance imaging.

The development of innovative non-invasive neuroimaging methods and biomarkers is critical for studying brain disease. Imaging of cerebrospinal fluid (CSF) pulsatility may inform the brain fluid dynamics involved in clearance of cerebral metabolic waste. In this work, we developed a methodology to characterize the frequency and spatial localization of whole brain CSF pulsations in humans. Using 7 Tesla (T) human magnetic resonance imaging (MRI) and ultrafast echo-planar imaging (EPI), in-vivo images were obtained to capture pulsations of the CSF signal. Physiological data were simultaneously collected and compared with the 7 T MR data. The primary components of signal pulsations were identified using spectral analysis, with the most evident frequency bands identified around 0.3, 1.2, and 2.4 Hz. These pulsations were mapped spatially and temporally onto the MR image domain and temporally onto the physiological measures of electrocardiogram and respiration. We identified peaks in CSF pulsations that were distinct from peaks in grey matter and white matter regions. This methodology may provide novel in vivo biomarkers of disrupted brain fluid dynamics.

An open-source MRI compatible frame for multimodal presurgical mapping in macaque and capuchin monkeys.

BACKGROUND: High-precision neurosurgical targeting in nonhuman primates (NHPs) often requires presurgical anatomical mapping with noninvasive neuroimaging techniques (MRI, CT, PET), allowing for translation of individual anatomical coordinates to surgical stereotaxic apparatus. Given the varied tissue contrasts that these imaging techniques produce, precise alignment of imaging-based coordinates to surgical apparatus can be cumbersome. MRI-compatible stereotaxis with radiopaque fiducial markers offer a straight-forward and reliable solution, but existing commercial options do not fit in conformal head coils that maximize imaging quality. NEW METHOD: We developed a compact MRI-compatible stereotaxis suitable for a variety of NHP species (Macaca mulatta, Macaca fascicularis, and Cebus apella) that allows multimodal alignment through technique-specific fiducial markers. COMPARISON WITH EXISTING METHODS: With the express purpose of compatibility with clinically available MRI, CT, and PET systems, the frame is no larger than a human head, while allowing for imaging NHPs in the supinated position. This design requires no marker implantation, special software, or additional knowledge other than the operation of a common large animal stereotaxis. RESULTS: We demonstrated the applicability of this 3D-printable apparatus across a diverse set of experiments requiring presurgical planning: 1) We demonstrate the accuracy of the fiducial system through a within-MRI cannula insertion and subcortical injection of a viral vector. 2) We also demonstrated accuracy of multimodal (MRI and CT) alignment and coordinate transfer to guide a surgical robot electrode implantation for deep-brain electrophysiology. CONCLUSIONS: The computer-aided design files and engineering drawings are publicly available, with the modular design allowing for low cost and manageable manufacturing.

Hippocampal subfields and thalamic nuclei associations with clinical outcomes in multiple sclerosis: An ultrahigh field MRI study.

BACKGROUND: Previous studies have shown that thalamic and hippocampal neurodegeneration is associated with clinical decline in Multiple Sclerosis (MS). However, contributions of the specific thalamic nuclei and hippocampal subfields require further examination. OBJECTIVE: Using 7 Tesla (7T) magnetic resonance imaging (MRI), we investigated the cross-sectional associations between functionally grouped thalamic nuclei and hippocampal subfields volumes and T1 relaxation times (T1-RT) and subsequent clinical outcomes in MS. METHODS: High-resolution T1-weighted and T2-weighted images were acquired at 7T (n=31), preprocessed, and segmented using the Thalamus Optimized Multi Atlas Segmentation (THOMAS, for thalamic nuclei) and the Automatic Segmentation of Hippocampal Subfields (ASHS, for hippocampal subfields) packages. We calculated Pearson correlations between hippocampal subfields and thalamic nuclei volumes and T1-RT and subsequent multi-modal rater-determined and patient-reported clinical outcomes (∼2.5 years after imaging acquisition), correcting for confounders and multiple tests. RESULTS: Smaller volume bilaterally in the anterior thalamus region correlated with worse performance in gait function, as measured by the Patient Determined Disease Steps (PDDS). Additionally, larger volume in most functional groups of thalamic nuclei correlated with better visual information processing and cognitive function, as measured by the Symbol Digit Modalities Test (SDMT). In bilateral medial and left posterior thalamic regions, there was an inverse association between volumes and T1-RT, potentially indicating higher tissue degeneration in these regions. We also observed marginal associations between the right hippocampal subfields (both volumes and T1-RT) and subsequent clinical outcomes, though they did not survive correction for multiple testing. CONCLUSION: Ultrahigh field MRI identified markers of structural damage in the thalamic nuclei associated with subsequently worse clinical outcomes in individuals with MS. Longitudinal studies will enable better understanding of the role of microstructural integrity in these brain regions in influencing MS outcomes.

Manual segmentation of the paraventricular nucleus of the hypothalamus and the dorsal and ventral bed nucleus of stria terminalis using multimodal 7 Tesla structural MRI: probabilistic atlases for a stress-control triad.

The paraventricular nucleus of the hypothalamus (PVN) is uniquely capable of proximal control over autonomic and neuroendocrine stress responses, and the bed nucleus of the stria terminalis (BNST) directly modulates PVN function, as well as playing an important role in stress control itself. The dorsal BNST (dBNST) is predominantly preautonomic, while the ventral BNST (vBNST) is predominantly viscerosensory, receiving dense noradrenergic signaling. Distinguishing the dBNST and vBNST, along with the PVN, may facilitate our understanding of dynamic interactions among these regions. T1-weighted MPRAGE and high resolution gradient echo (GRE) modalities were acquired at 7T. GRE was coregistered to MPRAGE and segmentations were performed in MRIcroGL based on their Atlas of the Human Brain depictions. The dBNST, vBNST and PVN were manually segmented in 25 participants; 10 images were rated by 2 raters. These segmentations were normalized and probabilistic atlases for each region were generated in MNI space, now available as resources for future research. We found moderate-high inter-rater reliability [n = 10; Mean Dice (SD); PVN = 0.69 (0.04); dBNST = 0.77 (0.04); vBNST = 0.62 (0.04)]. Probabilistic atlases were reverse normalized into native space for six additional participants that were segmented but not included in the original 25. We also found moderate to moderate-high reliability between the probabilistic atlases and manual segmentations [n = 6; Mean Dice (SD); PVN = 0.55 (0.12); dBNST = 0.60 (0.10); vBNST = 0.47 (0.12 SD)]. By isolating these hypothalamic and BNST subregions using ultra-high field MRI modalities, more specific delineations of these regions can facilitate greater understanding of mechanisms underlying stress-related function and psychopathology.

Characterization of oscillations in the brain and cerebrospinal fluid using ultra-high field magnetic resonance imaging.

Development of innovative non-invasive neuroimaging methods and biomarkers are critical for studying brain disease. In this work, we have developed a methodology to characterize the frequency responses and spatial localization of oscillations and movements of cerebrospinal fluid (CSF) flow in the human brain. Using 7 Tesla human MRI and ultrafast echo-planar imaging (EPI), in-vivo images were obtained to capture CSF oscillations and movements. Physiological data was simultaneously collected and correlated with the 7T MR data. The primary components of CSF oscillations were identified using spectral analysis (with frequency bands identified around 0.3Hz, 1.2Hz and 2.4Hz) and were mapped spatially and temporally onto the MR image domain and temporally onto the physiological domain. The developed methodology shows a good consistency and repeatability (standard deviation of 0.052 and 0.078 for 0.3Hz and 1.2Hz bands respectively) in-vivo for potential brain dynamics and CSF flow and clearance studies.

Inducing Vascular Grammars for Anomaly Classification in Brain Angiograms.

As machine learning is used to make strides in medical diagnostics, few methods provide heuristics from which human doctors can learn directly. This work introduces a method for leveraging human observable structures, such as macroscale vascular formations, for producing assessments of medical conditions with relatively few training cases, and uncovering patterns that are potential diagnostic aids. The approach draws on shape grammars, a rule-based technique, pioneered in design and architecture, and accelerated through a recursive subgraph mining algorithm. The distribution of rule instances in the data from which they are induced is then used as an intermediary representation enabling common classification and anomaly detection approaches to identify indicative rules with relatively small data sets. The method is applied to seven-tesla time-of-flight angiography MRI (n = 54) of human brain vasculature. The data were segmented and induced to generate representative grammar rules. Ensembles of rules were isolated to implicate vascular conditions reliably. This application demonstrates the power of automated structured intermediary representations for assessing nuanced biological form relationships, and the strength of shape grammars, in particular for identifying indicative patterns in complex vascular networks.

Applying Deep Learning to Accelerated Clinical Brain Magnetic Resonance Imaging for Multiple Sclerosis.

Background: Magnetic resonance (MR) scans are routine clinical procedures for monitoring people with multiple sclerosis (PwMS). Patient discomfort, timely scheduling, and financial burden motivate the need to accelerate MR scan time. We examined the clinical application of a deep learning (DL) model in restoring the image quality of accelerated routine clinical brain MR scans for PwMS. Methods: We acquired fast 3D T1w BRAVO and fast 3D T2w FLAIR MRI sequences (half the phase encodes and half the number of slices) in parallel to conventional parameters. Using a subset of the scans, we trained a DL model to generate images from fast scans with quality similar to the conventional scans and then applied the model to the remaining scans. We calculated clinically relevant T1w volumetrics (normalized whole brain, thalamic, gray matter, and white matter volume) for all scans and T2 lesion volume in a sub-analysis. We performed paired t-tests comparing conventional, fast, and fast with DL for these volumetrics, and fit repeated measures mixed-effects models to test for differences in correlations between volumetrics and clinically relevant patient-reported outcomes (PRO). Results: We found statistically significant but small differences between conventional and fast scans with DL for all T1w volumetrics. There was no difference in the extent to which the key T1w volumetrics correlated with clinically relevant PROs of MS symptom burden and neurological disability. Conclusion: A deep learning model that improves the image quality of the accelerated routine clinical brain MR scans has the potential to inform clinically relevant outcomes in MS.

Analysis of hippocampal subfields in sickle cell disease using ultrahigh field MRI.

Sickle cell disease (SCD) is an inherited hemoglobinopathy that causes organ dysfunction, including cerebral vasculopathy and neurological complications. Hippocampal segmentation with newer and advanced 7 Tesla (7T) MRI protocols has revealed atrophy in specific subregions in other neurodegenerative and neuroinflammatory diseases, however, there is limited evidence of hippocampal involvement in SCD. Thus, we explored whether SCD may be also associated with abnormalities in hippocampal subregions. We conducted 7T MRI imaging in individuals with SCD, including the HbSS, HbSC and HbS/beta thalassemia genotypes (n = 53), and healthy race and age-matched controls (n = 47), using a customized head coil. Both T1- and T2-weighted images were used for automatic segmentation of the hippocampal subfields. Individuals with SCD had, on average, significantly smaller volume of the region including the Dentate Gyrus and Cornu Ammonis (CA) 2 and 3 as compared to the control group. Other hippocampal subregions also showed a trend towards smaller volumes in the SCD group. These findings support and extend previous reports of reduced volume in the temporal lobe in SCD patients. Further studies are necessary to investigate the mechanisms that lead to structural changes in the hippocampus subfields and their relationship with cognitive performance in SCD patients.

Improved 7 Tesla transmit field homogeneity with reduced electromagnetic power deposition using coupled Tic Tac Toe antennas.

Recently cleared by the FDA, 7 Tesla (7 T) MRI is a rapidly growing technology that can provide higher resolution and enhanced contrast in human MRI images. However, the increased operational frequency (~ 297 MHz) hinders its full potential since it causes inhomogeneities in the images and increases the power deposition in the tissues. This work describes the optimization of an innovative radiofrequency (RF) head coil coupled design, named Tic Tac Toe, currently used in large scale human MRI scanning at 7 T; to date, this device was used in more than 1,300 neuro 7 T MRI scans. Electromagnetic simulations of the coil were performed using the finite-difference time-domain method. Numerical optimizations were used to combine the calculated electromagnetic fields produced by these antennas, based on the superposition principle, resulting in homogeneous magnetic field distributions at low levels of power deposition in the tissues. The simulations were validated in-vivo using the Tic Tac Toe RF head coil system on a 7 T MRI scanner.

A comprehensive electromagnetic evaluation of an MRI anthropomorphic head phantom.

Electromagnetic simulations are an important tool for the safety assessment of RF coils. They are a useful resource for MRI RF coil designers, especially when complemented with experimental measurements and testing using physical phantoms. Regular-shaped (spherical/cylindrical) homogeneous phantoms are the MRI standard for RF testing but are somewhat inaccurate when compared with anthropomorphic anatomies, especially at high frequencies. In this work, using a recently developed anthropomorphic heterogeneous human head phantom, studies were performed to analyze the scattering parameters (S-parameters) and the electric and magnetic field distributions using (1) the B1+ field mapping method on a 7 T human MRI scanner and (2) numerical full-wave electromagnetic simulations. All studies used the following: a recently developed six-compartment refillable 3D-printed anthropomorphic head phantom (developed from MRI scans obtained in vivo), where the phantom itself is filled in its entirety with either heterogeneous loading, or homogeneous brain or water loading, in vivo imaging, and a commercial homogeneous spherical water phantom. Our results determined that the calculated S-parameters for all the anthropomorphic head phantom models were comparable to the model that is based on the volunteer (within 17% difference of the reflection coefficient value) but differed for the commercial homogeneous spherical water phantom (within 45% difference). The experimentally measured B1+ field maps of the anthropomorphic heterogeneous and homogeneous brain head phantoms were most comparable to the in vivo measured values. The numerical simulations also show that both the anthropomorphic homogeneous water and brain phantom models were less accurate in terms of electric field intensities/distributions when compared with the segmented in-vivo-based head model and the anthropomorphic heterogeneous head phantom model. The presented data highlights the differences between the physical phantoms/phantom models, and the in vivo measurements/segmented in-vivo-based head model. The results demonstrate the usefulness of 3D-printed anthropomorphic phantoms for RF coil evaluation and testing.

Resting-State Function Connectivity Associated With Being a "Morning-Type" Dementia Caregiver and Having Lower Depression Symptom Severity.

OBJECTIVES: A lack of "morningness" predicts greater depression symptom severity over time, including in a vulnerable group of older adults: family dementia caregivers (dCGs). Evidence regarding the neurobiological basis of these correlations is needed to guide future research towards biomarker-informed detection and prevention approaches. We therefore primarily aimed to identify simple resting-state biomarkers that correlated with a lack of "morningness" in dCGs. METHOD: We examined 54 dCGs (mean age = 70, range: 61-84; 70% female) of whom 40% were definite "morning types" according to Composite Scale of Morningness (CSM). Using a 7 Tesla resting-state sequence, we compared the functional connectivity of nodes in networks previously implicated in depression (fronto-parietal, default mode, limbic, and salience) between caregivers who were and were not "morning types." RESULTS: Correcting for voxel-wise comparisons, "morning-type" dCGs had less amygdala-posterior cingulate connectivity (Cohen's d = -1.3), which statistically mediated ~32% of the association between the degree of "morningness" and lower depression severity. Post hoc analyses of CSM items found significant correlations, with both amygdala-posterior cingulate FC and depression severity, for 4/6 items pertaining to difficulty, 2/5 items pertaining to preference, and 0/2 items pertaining to typical patterns. DISCUSSION: Prior research shows that amygdala-posterior cingulate connectivity increases when allocating attention to peripheral aspects of negative emotional stimuli. As such, difficulty with morning activation may relate to the ongoing direction of focus around distressing content; in contrast, morning activity participation may serve to limit focus on distress. Replication and experimental studies are required to confirm these associations and their modifiability.

White Matter Integrity Underlying Depressive Symptoms in Dementia Caregivers.

OBJECTIVE: We sought to determine whether the aspects of white matter connectivity implicated in major depression also relate to mild depressive symptoms in family dementia caregivers (dCGs). METHODS: Forty-one dCGs (average age=69 years, standard deviation=6.4) underwent a 7 Tesla 64-direction (12-minute) diffusion-weighted imaging sequence. We compared the fractional anisotropy (FA) of 11 white matter features between dCGs with (n=20) and without (n=21) depressive symptoms (Patient Health Questionnaire-9 scores ≥5). RESULTS: Caregivers reporting depression symptoms had lower FA in tracts connecting to the posterior cingulate cortex (Cohen's d = -0.9) and connecting dorsolateral prefrontal with rostral cingulate regions (Cohen's d = -1.2). CONCLUSIONS: Posterior cingulate and dorsolateral prefrontal-to-rostral cingulate white matter, implicated in prior studies of major depression, appear relevant to mild depression in dCGs.

Neuroimaging of Small Vessel Disease in Late-Life Depression.

Cerebral small vessel disease is associated with late-life depression, cognitive impairment, executive dysfunction, distress, and loss of life for older adults. Late-life depression is becoming a substantial public health burden, and a considerable number of older adults presenting to primary care have significant clinical depression. Even though white matter hyperintensities are linked with small vessel disease, white matter hyperintensities are nonspecific to small vessel disease and can co-occur with other brain diseases. Advanced neuroimaging techniques at the ultrahigh field magnetic resonance imaging are enabling improved characterization, identification of cerebral small vessel disease and are elucidating some of the mechanisms that associate small vessel disease with late-life depression.

Physical Activity and Cerebral Small Vein Integrity in Older Adults.

Identifying promoters of cerebral small vein integrity is important to counter vascular contributions to cognitive impairment and dementia. PURPOSE: In this preliminary investigation, the effects of a randomized 24-month physical activity (PA) intervention on changes in cerebral small vein integrity were compared to those of a health education (HE) control. METHODS: Cerebral small vein integrity was measured in 24 older adults (n = 8, PA; n = 16, HE) using ultra-high field MRI before and at the end of the 24-month intervention. Deep medullary veins were defined as straight or tortuous; percent change in straight length, tortuous length, and tortuosity ratio were computed. Microbleed count and white matter hyperintensities were also rated. RESULTS: Accelerometry-based values of PA increased by 17.2% in the PA group but declined by 28.0% in the HE group. The PA group, but not the HE group, had a significant increase in straight vein length from baseline to 24-month follow-up (P = 0.02 and P = 0.21, respectively); the between-group difference in percent change in straight length was significant (increase: median, 93.6%; interquartile range, 112.9 for PA; median, 28.4%; interquartile range, 90.6 for HE; P = 0.07). Between group differences in other markers were nonsignificant. CONCLUSIONS: Increasing PA in late-life may promote cerebral small vein integrity. This should be confirmed in larger studies.

Computational and experimental evaluation of the Tic-Tac-Toe RF coil for 7 Tesla MRI.

A variety of 7 Tesla RF coil systems have been proposed to produce spin excitation (B1+ field) and MR image acquisition. Different groups have attempted to mitigate the challenges at high and ultra-high field MRI by proposing novel hardware and software solutions to obtain uniformly high spin excitation at acceptable RF absorption levels. In this study, we extensively compare the designs of two distributed-circuit based RF coils: the Tic-Tac-Toe (TTT) head coil and TEM head coil on multiple anatomically detailed head models and in-vivo. Bench measurements of s-parameters and experimental B1+ field distribution were obtained in volunteers and compared with numerical simulations. RF absorption, quantified by both average and peak SAR, and B1+ field intensity and homogeneity, calculated/measured in terms of maximum over minimum and coefficient of variation (CV) in the region of interest (ROI), are presented for both coils. A study of the RF consistency of both coils across multiple head models for different RF excitation strategies is also presented.

How to design and construct a 3D-printed human head phantom.

In this paper, we will provide a methodology for head phantom development based on in vivo imaging data attained utilizing MRI. The anthropomorphic phantom can be designed to mimic human anatomy.

In-vivo and numerical analysis of the eigenmodes produced by a multi-level Tic-Tac-Toe head transmit array for 7 Tesla MRI.

Radio-frequency (RF) field inhomogeneities and higher levels of specific absorption rate (SAR) still present great challenges in ultrahigh-field (UHF) MRI. In this study, an in-depth analysis of the eigenmodes of a 20-channel transmit Tic-Tac-Toe (TTT) RF array for 7T neuro MRI is presented. The eigenmodes were calculated for five different Z levels (along the static magnetic field direction) of the coil. Four eigenmodes were obtained for each Z level (composed of 4 excitation ports), and they were named based on the characteristics of their field distributions: quadrature, opposite-phase, anti-quadrature, and zero-phase. Corresponding finite-difference time-domain (FDTD) simulations were performed and experimental B1+ field maps were acquired using a homogeneous spherical phantom and human head (in-vivo). The quadrature mode is the most efficient and it excites the central brain regions; the opposite-phase mode excites the brain peripheral regions; anti-quadrature mode excites the head periphery; and the zero-phase mode excites cerebellum and temporal lobes. Using this RF array, up to five eigenmodes (from five different Z levels) can be simultaneously excited. The superposition of these modes has the potential to produce homogeneous excitation with full brain coverage and low levels of SAR at 7T MRI.

Association of Hippocampal Substructure Resting-State Functional Connectivity with Memory Performance in Older Adults.

OBJECTIVES: Hippocampal hyperactivation marks preclinical dementia pathophysiology, potentially due to differences in the connectivity of specific medial temporal lobe structures. Our aims were to characterize the resting-state functional connectivity of medial temporal lobe sub-structures in older adults, and evaluate whether specific substructural (rather than global) functional connectivity relates to memory function. METHODS: In 15 adults (mean age: 69 years), we evaluated the resting state functional connectivity of medial temporal lobe substructures: dentate/Cornu Ammonis (CA) 4, CA1, CA2/3, subiculum, the molecular layer, entorhinal cortex, and parahippocampus. We used 7-Tesla susceptibility weighted imaging and magnetization-prepared rapid gradient echo sequences to segment substructures of the hippocampus, which were used as structural seeds for examining functional connectivity in a resting BOLD sequence. We then assessed correlations between functional connectivity with memory performance (short and long delay free recall on the California Verbal Learning Test [CVLT]). RESULTS: All the seed regions had significant connectivity within the temporal lobe (including the fusiform, temporal, and lingual gyri). The left CA1 was the only seed with significant functional connectivity to the amygdala. The left entorhinal cortex was the only seed to have significant functional connectivity with frontal cortex (anterior cingulate and superior frontal gyrus). Only higher left dentate-left lingual connectivity was associated with poorer CVLT performance (Spearman r = -0.81, p = 0.0003, Benjamini-Hochberg false discovery rate: 0.01) after multiple comparison correction. CONCLUSIONS: Rather than global hyper-connectivity of the medial temporal lobe, left dentate-lingual connectivity may provide a specific assay of medial temporal lobe hyper-connectivity relevant to memory in aging.

Correction: Design and fabrication of a realistic anthropomorphic heterogeneous head phantom for MR purposes.

[This corrects the article DOI: 10.1371/journal.pone.0183168.].

A new RF transmit coil for foot and ankle imaging at 7T MRI.

A four-channel Tic-Tac-Toe (TTT) transmit RF coil was designed and constructed for foot and ankle imaging at 7T MRI. Numerical simulations using an in-house developed FDTD package and experimental analyses using a homogenous phantom show an excellent agreement in terms of B1+ field distribution and s-parameters. Simulations performed on an anatomically detailed human lower leg model demonstrated an B1+ field distribution with a coefficient of variation (CV) of 23.9%/15.6%/28.8% and average B1+ of 0.33µT/0.56µT/0.43µT for 1W input power (i.e., 0.25W per channel) in the ankle/calcaneus/mid foot respectively. In-vivo B1+ mapping shows an average B1+ of 0.29µT over the entire foot/ankle. This newly developed RF coil also presents acceptable levels of average SAR (0.07W/kg for 10g per 1W of input power) and peak SAR (0.34W/kg for 10g per 1W of input power) over the whole lower leg. Preliminary in-vivo images in the foot/ankle were acquired using the T2-DESS MRI sequence without the use of a dedicated receive-only array.