Anisotropic longitudinal water proton relaxation in white matter investigated ex vivo in porcine spinal cord with sample rotation.

A variation of the longitudinal relaxation time T 1 in brain regions that differ in their main fiber direction has been occasionally reported, however, with inconsistent results. Goal of the present study was to clarify such inconsistencies, and the origin of potential T 1 orientation dependence, by applying direct sample rotation and comparing the results from different approaches to measure T 1 . A section of fixed porcine spinal cord white matter was investigated at 3 T with variation of the fiber-to-field angle θ FB . The experiments included one-dimensional inversion-recovery, MP2RAGE, and variable flip-angle T 1 measurements at 22 °C and 36 °C as well as magnetization-transfer (MT) and diffusion-weighted acquisitions. Depending on the technique, different degrees of T 1 anisotropy (between 2 and 10%) were observed as well as different dependencies on θ FB (monotonic variation or T 1 maximum at 30-40°). More pronounced anisotropy was obtained with techniques that are more sensitive to MT effects. Furthermore, strong correlations of θ FB -dependent MT saturation and T 1 were found. A comprehensive analysis based on the binary spin-bath model for MT revealed an interplay of several orientation-dependent parameters, including the transverse relaxation times of the macromolecular and the water pool as well as the longitudinal relaxation time of the macromolecular pool.

Chaos and COSMOS-Considerations on QSM methods with multiple and single orientations and effects from local anisotropy.

PURPOSE: Field-to-susceptibility inversion in quantitative susceptibility mapping (QSM) is ill-posed and needs numerical stabilization through either regularization or oversampling by acquiring data at three or more object orientations. Calculation Of Susceptibility through Multiple Orientations Sampling (COSMOS) is an established oversampling approach and regarded as QSM gold standard. It achieves a well-conditioned inverse problem, requiring rotations by 0°, 60° and 120° in the yz-plane. However, this is impractical in vivo, where head rotations are typically restricted to a range of ±25°. Non-ideal sampling degrades the conditioning with residual streaking artifacts whose mitigation needs further regularization. Moreover, susceptibility anisotropy in white matter is not considered in the COSMOS model, which may introduce additional bias. The current work presents a thorough investigation of these effects in primate brain. METHODS: Gradient-recalled echo (GRE) data of an entire fixed chimpanzee brain were acquired at 7 T (350 µm resolution, 10 orientations) including ideal COSMOS sampling and realistic rotations in vivo. Comparisons of the results included ideal COSMOS, in-vivo feasible acquisitions with 3-8 orientations and single-orientation iLSQR QSM. RESULTS: In-vivo feasible and optimal COSMOS yielded high-quality susceptibility maps with increased SNR resulting from averaging multiple acquisitions. COSMOS reconstructions from non-ideal rotations about a single axis required additional L2-regularization to mitigate residual streaking artifacts. CONCLUSION: In view of unconsidered anisotropy effects, added complexity of the reconstruction, and the general challenge of multi-orientation acquisitions, advantages of sub-optimal COSMOS schemes over regularized single-orientation QSM appear limited in in-vivo settings.

Radiation damping at clinical field strength: Characterization and compensation in quantitative measurements.

PURPOSE: In any MR experiment, the bulk magnetization acts on itself, caused by the induced current in the RF receiver circuit that generates an oscillating damping field. This effect, known as "radiation damping" (RD), is usually weak and, therefore, unconsidered in MRI, but can affect quantitative studies performed with dedicated coils that provide a high SNR. The current work examined RD in a setup for investigations of small tissue specimens including a quantitative characterization of the spin-coil system. THEORY AND METHODS: A custom-made Helmholtz coil (radius and spacing 16 mm) was interfaced to a transmit-receive (Tx/Rx) switch with integrated passive feedback for modulation or suppression of RD similar to preamplifier decoupling. Pulse sequences included pulse-width arrays to demonstrate the absence/ presence of RD and difference techniques employing gradient pulses or composite RF pulses to quantify RD effects during free precession and transmission, respectively. Experiments were performed at 3T in small samples of MnCl2 solution. RESULTS: Significant RD effects may impact RF pulse application and evolution periods. Effective damping time constants were comparable to typical T2 * times or echo spacings in multi-echo sequences. Measurements of the phase relation showed that deviations from the commonly assumed 90° angle between the damping field and the transverse magnetization may occur. CONCLUSION: Radiation damping may affect the accuracy of quantitative MR measurements performed with dedicated RF coils. Efficient mitigation can be achieved hardware-based or by appropriate consideration in the pulse sequence.

Diffusion-weighted MR spectroscopy: Consensus, recommendations, and resources from acquisition to modeling.

Brain cell structure and function reflect neurodevelopment, plasticity, and aging; and changes can help flag pathological processes such as neurodegeneration and neuroinflammation. Accurate and quantitative methods to noninvasively disentangle cellular structural features are needed and are a substantial focus of brain research. Diffusion-weighted MRS (dMRS) gives access to diffusion properties of endogenous intracellular brain metabolites that are preferentially located inside specific brain cell populations. Despite its great potential, dMRS remains a challenging technique on all levels: from the data acquisition to the analysis, quantification, modeling, and interpretation of results. These challenges were the motivation behind the organization of the Lorentz Center workshop on "Best Practices & Tools for Diffusion MR Spectroscopy" held in Leiden, the Netherlands, in September 2021. During the workshop, the dMRS community established a set of recommendations to execute robust dMRS studies. This paper provides a description of the steps needed for acquiring, processing, fitting, and modeling dMRS data, and provides links to useful resources.

Convergent imaging-transcriptomic evidence for disturbed iron homeostasis in Gilles de la Tourette syndrome.

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric movement disorder with reported abnormalities in various neurotransmitter systems. Considering the integral role of iron in neurotransmitter synthesis and transport, it is hypothesized that iron exhibits a role in GTS pathophysiology. As a surrogate measure of brain iron, quantitative susceptibility mapping (QSM) was performed in 28 patients with GTS and 26 matched controls. Significant susceptibility reductions in the patients, consistent with reduced local iron content, were obtained in subcortical regions known to be implicated in GTS. Regression analysis revealed a significant negative association of tic scores and striatal susceptibility. To interrogate genetic mechanisms that may drive these reductions, spatially specific relationships between susceptibility and gene-expression patterns from the Allen Human Brain Atlas were assessed. Correlations in the striatum were enriched for excitatory, inhibitory, and modulatory neurochemical signaling mechanisms in the motor regions, mitochondrial processes driving ATP production and iron­sulfur cluster biogenesis in the executive subdivision, and phosphorylation-related mechanisms affecting receptor expression and long-term potentiation in the limbic subdivision. This link between susceptibility reductions and normative transcriptional profiles suggests that disruptions in iron regulatory mechanisms are involved in GTS pathophysiology and may lead to pervasive abnormalities in mechanisms regulated by iron-containing enzymes.

Convergent imaging-transcriptomic evidence for disturbed iron homeostasis in Gilles de la Tourette syndrome.

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric movement disorder with reported abnormalities in various neurotransmitter systems. Considering the integral role of iron in neurotransmitter synthesis and transport, it is hypothesized that iron exhibits a role in GTS pathophysiology. As a surrogate measure of brain iron, quantitative susceptibility mapping (QSM) was performed in 28 patients with GTS and 26 matched controls. Significant susceptibility reductions in the patient cohort, consistent with reduced local iron content, were obtained in subcortical regions known to be implicated in GTS. Regression analysis revealed a significant negative association of tic scores and striatal susceptibility. To interrogate genetic mechanisms that may drive these reductions, spatially specific relationships between susceptibility and gene-expression patterns extracted from the Allen Human Brain Atlas were assessed. Correlations in the striatum were enriched for excitatory, inhibitory, and modulatory neurochemical signaling mechanisms in the motor regions, mitochondrial processes driving ATP production and iron-sulfur cluster biogenesis in the executive subdivision, and phosphorylation-related mechanisms that affect receptor expression and long-term potentiation. This link between susceptibility reductions and normative transcriptional profiles suggests that disruptions in iron regulatory mechanisms are involved in GTS pathophysiology and may lead to pervasive abnormalities in mechanisms regulated by iron-containing enzymes.

High angular resolution susceptibility imaging and estimation of fiber orientation distribution functions in primate brain.

Uncovering brain-tissue microstructure including axonal characteristics is a major neuroimaging research focus. Within this scope, anisotropic properties of magnetic susceptibility in white matter have been successfully employed to estimate primary axonal trajectories using mono-tensorial models. However, anisotropic susceptibility has not yet been considered for modeling more complex fiber structures within a voxel, such as intersecting bundles, or an estimation of orientation distribution functions (ODFs). This information is routinely obtained by high angular resolution diffusion imaging (HARDI) techniques. In applications to fixed tissue, however, diffusion-weighted imaging suffers from an inherently low signal-to-noise ratio and limited spatial resolution, leading to high demands on the performance of the gradient system in order to mitigate these limitations. In the current work, high angular resolution susceptibility imaging (HARSI) is proposed as a novel, phase-based methodology to estimate ODFs. A multiple gradient-echo dataset was acquired in an entire fixed chimpanzee brain at 61 orientations by reorienting the specimen in the magnetic field. The constant solid angle method was adapted for estimating phase-based ODFs. HARDI data were also acquired for comparison. HARSI yielded information on whole-brain fiber architecture, including identification of peaks of multiple bundles that resembled features of the HARDI results. Distinct differences between both methods suggest that susceptibility properties may offer complementary microstructural information. These proof-of-concept results indicate a potential to study the axonal organization in post-mortem primate and human brain at high resolution.

Brain dysconnectivity with heart failure.

Structural brain damage associated with heart failure is well described; however, little is known about associated changes in various specific brain functions that bear immediate clinical relevance. A satisfactory pathophysiological link between heart failure and decline in cognitive function is still missing. In the present study, we aim to detect functional correlates of heart failure in terms of alterations in functional brain connectivity (quantified by functional magnetic resonance imaging) related to cognitive performance assessed by neuropsychological testing. Eighty patients were post hoc grouped into subjects with and without coronary artery disease. The coronary artery disease patients were further grouped as presenting with or without heart failure according to the guidelines of the European Society of Cardiology. On the basis of resting-state functional magnetic resonance imaging, brain connectivity was investigated using network centrality as well as seed-based correlation. Statistical analysis aimed at specifying centrality group differences and potential correlations between centrality and heart failure-related measures including left ventricular ejection fraction and serum concentrations of N-terminal fragment of the pro-hormone brain-type natriuretic peptide. The resulting correlation maps were then analysed using a flexible factorial model with the factors 'heart failure' and 'cognitive performance'. Our core findings are: (i) A statistically significant network centrality decrease was found to be associated with heart failure primarily in the precuneus, i.e. we show a positive correlation between centrality and left ventricular ejection fraction as well as a negative correlation between centrality and N-terminal fragment of the pro-hormone brain-type natriuretic peptide. (ii) Seed-based correlation analysis showed a significant interaction between heart failure and cognitive performance related to a significant decrease of precuneus connectivity to other brain regions. We obtained these results by different analysis approaches indicating the robustness of the findings we report here. Our results suggest that the precuneus is a brain region involved in connectivity decline in patients with heart failure, possibly primarily or already at an early stage. Current models of Alzheimer's disease-having pathophysiological risk factors in common with cerebrovascular disorders-also consider reduced precuneus connectivity as a marker of brain degeneration. Consequently, we propose that heart failure and Alzheimer's disease exhibit partly overlapping pathophysiological paths or have common endpoints associated with a more or less severe decrease in brain connectivity. This is further supported by specific functional connectivity alterations between the precuneus and widely distributed cortical regions, particularly in patients showing reduced cognitive performance.

Improving fMRI in Parkinson's disease by accounting for brain region-specific activity patterns.

In functional magnetic imaging (fMRI) in Parkinson's disease (PD), a paradigm consisting of blocks of finger tapping and rest along with a corresponding general linear model (GLM) is often used to assess motor activity. However, this method has three limitations: (i) Due to the strong magnetic field and the confined environment of the cylindrical bore, it is troublesome to accurately monitor motor output and, therefore, variability in the performed movement is typically ignored. (ii) Given the loss of dopaminergic neurons and ongoing compensatory brain mechanisms, motor control is abnormal in PD. Therefore, modeling of patients' tapping with a constant amplitude (using a boxcar function) and the expected Parkinsonian motor output are prone to mismatch. (iii) The motor loop involves structures with distinct hemodynamic responses, for which only one type of modeling (e.g., modeling the whole block of finger tapping) may not suffice to capture these structure's temporal activation. The first two limitations call for considering results from online recordings of the real motor output that may lead to significant sensitivity improvements. This was shown in previous work using a non-magnetic glove to capture details of the patients' finger movements in a so-called kinematic approach. For the third limitation, modeling motion initiation instead of the whole tapping block has been suggested to account for different temporal activation signatures of the motor loop's structures. In the present study we propose improvements to the GLM as a tool to study motor disorders. For this, we test the robustness of the kinematic approach in an expanded cohort (n = 31), apply more conservative statistics than in previous work, and evaluate the benefits of an event-related model function. Our findings suggest that the integration of the kinematic approach offers a general improvement in detecting activations in subcortical structures, such as the basal ganglia. Additionally, modeling motion initiation using an event-related design yielded superior performance in capturing medication-related effects in the putamen. Our results may guide adaptations in analysis strategies for functional motor studies related to PD and also in more general applications.

Germany's journey toward 14 Tesla human magnetic resonance.

Multiple sites within Germany operate human MRI systems with magnetic fields either at 7 Tesla or 9.4 Tesla. In 2013, these sites formed a network to facilitate and harmonize the research being conducted at the different sites and make this technology available to a larger community of researchers and clinicians not only within Germany, but also worldwide. The German Ultrahigh Field Imaging (GUFI) network has defined a strategic goal to establish a 14 Tesla whole-body human MRI system as a national research resource in Germany as the next progression in magnetic field strength. This paper summarizes the history of this initiative, the current status, the motivation for pursuing MR imaging and spectroscopy at such a high magnetic field strength, and the technical and funding challenges involved. It focuses on the scientific and science policy process from the perspective in Germany, and is not intended to be a comprehensive systematic review of the benefits and technical challenges of higher field strengths.

High-resolution magnetization-transfer imaging of post-mortem marmoset brain: Comparisons with relaxometry and histology.

Cell membranes and macromolecules or paramagnetic compounds interact with water proton spins, which modulates magnetic resonance imaging (MRI) contrast providing information on tissue composition. For a further investigation, quantitative magnetization transfer (qMT) parameters (at 3T), including the ratio of the macromolecular and water proton pools, F, and the exchange-rate constant as well as the (observed) longitudinal and the effective transverse relaxation rates (at 3T and 7T), R1obs and R2*, respectively, were measured at high spatial resolution (200 µm) in a slice of fixed marmoset brain and compared to histology results obtained with Gallyas' myelin stain and Perls' iron stain. R1obs and R2* were linearly correlated with the iron content for the entire slice, whereas distinct differences were obtained between gray and white matter for correlations of relaxometry and qMT parameters with myelin content. The combined results suggest that the macromolecular pool interacting with water consists of myelin and (less efficient) non-myelin contributions. Despite strong correlation of F and R1obs, none of these parameters was uniquely specific to myelination. Due to additional sensitivity to iron stores, R1obs and R2* were more sensitive for depicting microstructural differences between cortical layers than F.

Considerations on gradual glutamate accumulation related to cognitive task performance.

Long-lasting activities with high demand in cognitive control are known to result in cognitive fatigue. However, the reason for control cost inflation remains elusive. A neurometabolic account was proposed in a recent study combining magnetic resonance spectroscopy (MRS) with daylong execution of behavioral tasks. It suggests that control cost during high-demand work is related to the necessity of recycling potentially toxic substances, specifically glutamate, which may accumulate extracellularly. As MRS provides estimates of metabolite concentrations, further evaluations are possible how well this hypothesis fits with fundamental consequences from the dynamic equilibrium of intercompartmental glutamate distributions.

Rapid volumetric brain changes after acute psychosocial stress.

Stress is an important trigger for brain plasticity: Acute stress can rapidly affect brain activity and functional connectivity, and chronic or pathological stress has been associated with structural brain changes. Measures of structural magnetic resonance imaging (MRI) can be modified by short-term motor learning or visual stimulation, suggesting that they also capture rapid brain changes. Here, we investigated volumetric brain changes (together with changes in T1 relaxation rate and cerebral blood flow) after acute stress in humans as well as their relation to psychophysiological stress measures. Sixty-seven healthy men (25.8±2.7 years) completed a standardized psychosocial laboratory stressor (Trier Social Stress Test) or a control version while blood, saliva, heart rate, and psychometrics were sampled. Structural MRI (T1 mapping / MP2RAGE sequence) at 3T was acquired 45 min before and 90 min after intervention onset. Grey matter volume (GMV) changes were analysed using voxel-based morphometry. Associations with endocrine, autonomic, and subjective stress measures were tested with linear models. We found significant group-by-time interactions in several brain clusters including anterior/mid-cingulate cortices and bilateral insula: GMV was increased in the stress group relative to the control group, in which several clusters showed a GMV decrease. We found a significant group-by-time interaction for cerebral blood flow, and a main effect of time for T1 values (longitudinal relaxation time). In addition, GMV changes were significantly associated with state anxiety and heart rate variability changes. Such rapid GMV changes assessed with VBM may be induced by local tissue adaptations to changes in energy demand following neural activity. Our findings suggest that endogenous brain changes are counteracted by acute psychosocial stress, which emphasizes the importance of considering homeodynamic processes and generally highlights the influence of stress on the brain.

Multi-echo investigations of positive and negative CBF and concomitant BOLD changes.

Unlike the positive blood oxygenation level-dependent (BOLD) response (PBR), commonly taken as an indication of an 'activated' brain region, the physiological origin of negative BOLD signal changes (i.e. a negative BOLD response, NBR), also referred to as 'deactivation' is still being debated. In this work, an attempt was made to gain a better understanding of the underlying mechanism by obtaining a comprehensive measure of the contributing cerebral blood flow (CBF) and its relationship to the NBR in the human visual cortex, in comparison to a simultaneously induced PBR in surrounding visual regions. To overcome the low signal-to-noise ratio (SNR) of CBF measurements, a newly developed multi-echo version of a center-out echo planar-imaging (EPI) readout was employed with pseudo-continuous arterial spin labeling (pCASL). It achieved very short echo and inter-echo times and facilitated a simultaneous detection of functional CBF and BOLD changes at 3 T with improved sensitivity. Evaluations of the absolute and relative changes of CBF and the effective transverse relaxation rate, R2*, the coupling ratios, and their dependence on CBF at rest, CBFrest, indicated differences between activated and deactivated regions. Analysis of the shape of the respective functional responses also revealed faster negative responses with more pronounced post-stimulus transients. Resulting differences in the flow-metabolism coupling ratios were further examined for potential distinctions in the underlying neuronal contributions.

Enhancing neuroimaging genetics through meta-analysis for Tourette syndrome (ENIGMA-TS): A worldwide platform for collaboration.

Tourette syndrome (TS) is characterized by multiple motor and vocal tics, and high-comorbidity rates with other neuropsychiatric disorders. Obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), major depressive disorder (MDD), and anxiety disorders (AXDs) are among the most prevalent TS comorbidities. To date, studies on TS brain structure and function have been limited in size with efforts mostly fragmented. This leads to low-statistical power, discordant results due to differences in approaches, and hinders the ability to stratify patients according to clinical parameters and investigate comorbidity patterns. Here, we present the scientific premise, perspectives, and key goals that have motivated the establishment of the Enhancing Neuroimaging Genetics through Meta-Analysis for TS (ENIGMA-TS) working group. The ENIGMA-TS working group is an international collaborative effort bringing together a large network of investigators who aim to understand brain structure and function in TS and dissect the underlying neurobiology that leads to observed comorbidity patterns and clinical heterogeneity. Previously collected TS neuroimaging data will be analyzed jointly and integrated with TS genomic data, as well as equivalently large and already existing studies of highly comorbid OCD, ADHD, ASD, MDD, and AXD. Our work highlights the power of collaborative efforts and transdiagnostic approaches, and points to the existence of different TS subtypes. ENIGMA-TS will offer large-scale, high-powered studies that will lead to important insights toward understanding brain structure and function and genetic effects in TS and related disorders, and the identification of biomarkers that could help inform improved clinical practice.

Macromolecular background signal and non-Gaussian metabolite diffusion determined in human brain using ultra-high diffusion weighting.

PURPOSE: Definition of a macromolecular MR spectrum based on diffusion properties rather than relaxation time differences and characterization of non-Gaussian diffusion of brain metabolites with strongly diffusion-weighted MR spectroscopy. METHODS: Short echo time MRS with strong diffusion-weighting with b-values up to 25 ms/µm2 at two diffusion times was implemented on a Connectom system and applied in combination with simultaneous spectral and diffusion decay modeling. Motion-compensation was performed with a combined method based on the simultaneously acquired water and a macromolecular signal. RESULTS: The motion compensation scheme prevented spurious signal decay reflected in very small apparent diffusion constants for macromolecular signal. Macromolecular background signal patterns were determined using multiple fit strategies. Signal decay corresponding to non-Gaussian metabolite diffusion was represented by biexponential fit models yielding parameter estimates for human gray matter that are in line with published rodent data. The optimal fit strategies used constraints for the signal decay of metabolites with limited signal contributions to the overall spectrum. CONCLUSION: The determined macromolecular spectrum based on diffusion properties deviates from the conventional one derived from longitudinal relaxation time differences calling for further investigation before use as experimental basis spectrum when fitting clinical MR spectra. The biexponential characterization of metabolite signal decay is the basis for investigations into pathologic alterations of microstructure.

A unified 3D map of microscopic architecture and MRI of the human brain.

We present the first three-dimensional (3D) concordance maps of cyto- and fiber architecture of the human brain, combining histology, immunohistochemistry, and 7-T quantitative magnetic resonance imaging (MRI), in two individual specimens. These 3D maps each integrate data from approximately 800 microscopy sections per brain, showing neuronal and glial cell bodies, nerve fibers, and interneuronal populations, as well as ultrahigh-field quantitative MRI, all coaligned at the 200-µm scale to the stacked blockface images obtained during sectioning. These unprecedented 3D multimodal datasets are shared without any restrictions and provide a unique resource for the joint study of cell and fiber architecture of the brain, detailed anatomical atlasing, or modeling of the microscopic underpinnings of MRI contrasts.

Decreased thalamo-cortico connectivity during an implicit sequence motor learning task and 7 days escitalopram intake.

Evidence suggests that selective serotonin reuptake inhibitors (SSRIs) reorganize neural networks via a transient window of neuroplasticity. While previous findings support an effect of SSRIs on intrinsic functional connectivity, little is known regarding the influence of SSRI-administration on connectivity during sequence motor learning. To investigate this, we administered 20 mg escitalopram or placebo for 1-week to 60 healthy female participants undergoing concurrent functional magnetic resonance imaging and sequence motor training in a double-blind randomized controlled design. We assessed task-modulated functional connectivity with a psycho-physiological interaction (PPI) analysis in the thalamus, putamen, cerebellum, dorsal premotor, primary motor, supplementary motor, and dorsolateral prefrontal cortices. Comparing an implicit sequence learning condition to a control learning condition, we observed decreased connectivity between the thalamus and bilateral motor regions after 7 days of escitalopram intake. Additionally, we observed a negative correlation between plasma escitalopram levels and PPI connectivity changes, with higher escitalopram levels being associated with greater thalamo-cortico decreases. Our results suggest that escitalopram enhances network-level processing efficiency during sequence motor learning, despite no changes in behaviour. Future studies in more diverse samples, however, with quantitative imaging of neurochemical markers of excitation and inhibition, are necessary to further assess neural responses to escitalopram.