Charting human subcortical maturation across the adult lifespan with in vivo 7 T MRI.

The human subcortex comprises hundreds of unique structures. Subcortical functioning is crucial for behavior, and disrupted function is observed in common neurodegenerative diseases. Despite their importance, human subcortical structures continue to be difficult to study in vivo. Here we provide a detailed account of 17 prominent subcortical structures and ventricles, describing their approximate iron and myelin contents, morphometry, and their age-related changes across the normal adult lifespan. The results provide compelling insights into the heterogeneity and intricate age-related alterations of these structures. They also show that the locations of many structures shift across the lifespan, which is of direct relevance for the use of standard magnetic resonance imaging atlases. The results further our understanding of subcortical morphometry and neuroimaging properties, and of normal aging processes which ultimately can improve our understanding of neurodegeneration.

Measuring the iron content of dopaminergic neurons in substantia nigra with MRI relaxometry.

In Parkinson's disease, the depletion of iron-rich dopaminergic neurons in nigrosome 1 of the substantia nigra precedes motor symptoms by two decades. Methods capable of monitoring this neuronal depletion, at an early disease stage, are needed for early diagnosis and treatment monitoring. Magnetic resonance imaging (MRI) is particularly suitable for this task due to its sensitivity to tissue microstructure and in particular, to iron. However, the exact mechanisms of MRI contrast in the substantia nigra are not well understood, hindering the development of powerful biomarkers. In the present report, we illuminate the contrast mechanisms in gradient and spin echo MR images in human nigrosome 1 by combining quantitative 3D iron histology and biophysical modeling with quantitative MRI on post mortem human brain tissue. We show that the dominant contribution to the effective transverse relaxation rate (R2*) in nigrosome 1 originates from iron accumulated in the neuromelanin of dopaminergic neurons. This contribution is appropriately described by a static dephasing approximation of the MRI signal. We demonstrate that the R2* contribution from dopaminergic neurons reflects the product of cell density and cellular iron concentration. These results demonstrate that the in vivo monitoring of neuronal density and iron in nigrosome 1 may be feasible with MRI and provide directions for the development of biomarkers for an early detection of dopaminergic neuron depletion in Parkinson's disease.

Towards a mechanistic understanding of the human subcortex.

The human subcortex is a densely populated part of the brain, of which only 7% of the individual structures are depicted in standard MRI atlases. In vivo MRI of the subcortex is challenging owing to its anatomical complexity and its deep location in the brain. The technical advances that are needed to reliably uncover this 'terra incognita' call for an interdisciplinary human neuroanatomical approach. We discuss the emerging methods that could be used in such an approach and the incorporation of the data that are generated from these methods into model-based cognitive neuroscience frameworks.

The Amsterdam Ultra-high field adult lifespan database (AHEAD): A freely available multimodal 7 Tesla submillimeter magnetic resonance imaging database.

Normative databases allow testing of novel hypotheses without the costly collection of magnetic resonance imaging (MRI) data. Here we present the Amsterdam Ultra-high field adult lifespan database (AHEAD). The AHEAD consists of 105 7 Tesla (T) whole-brain structural MRI scans tailored specifically to imaging of the human subcortex, including both male and female participants and covering the entire adult life span (18-80 yrs). We used these data to create probability maps for the subthalamic nucleus, substantia nigra, internal and external segment of the globus pallidus, and the red nucleus. Data was acquired at a submillimeter resolution using a multi-echo (ME) extension of the second gradient-echo image of the MP2RAGE sequence (MP2RAGEME) sequence, resulting in complete anatomical alignment of quantitative, R1-maps, R2*-maps, T1-maps, T1-weighted images, T2*-maps, and quantitative susceptibility mapping (QSM). Quantitative MRI maps, and derived probability maps of basal ganglia structures are freely available for further analyses.

Sharpness in motion corrected quantitative imaging at 7T.

Sub-millimeter imaging at 7T has opened new possibilities for qualitatively and quantitatively studying brain structure as it evolves throughout the life span. However, subject motion introduces image blurring on the order of magnitude of the spatial resolution and is thus detrimental to image quality. Such motion can be corrected for, but widespread application has not yet been achieved and quantitative evaluation is lacking. This raises a need to quantitatively measure image sharpness throughout the brain. We propose a method to quantify sharpness of brain structures at sub-voxel resolution, and use it to assess to what extent limited motion is related to image sharpness. The method was evaluated in a cohort of 24 healthy volunteers with a wide and uniform age range, aiming to arrive at results that largely generalize to larger populations. Using 3D fat-excited motion navigators, quantitative R1, R2* and Quantitative Susceptibility Maps and T1-weighted images were retrospectively corrected for motion. Sharpness was quantified in all modalities for selected regions of interest (ROI) by fitting the sigmoidally shaped error function to data within locally homogeneous clusters. A strong, almost linear correlation between motion and sharpness improvement was observed, and motion correction significantly improved sharpness. Overall, the Full Width at Half Maximum reduced from 0.88 mm to 0.70 mm after motion correction, equivalent to a 2.0 times smaller voxel volume. Motion and sharpness were not found to correlate with the age of study participants. We conclude that in our data, motion correction using fat navigators is overall able to restore the measured sharpness to the imaging resolution, irrespective of the amount of motion observed during scanning.

Do we need to revise the tripartite subdivision hypothesis of the human subthalamic nucleus (STN)?

The exciting development of ultra-high resolution 7Tesla (T) magnetic resonance imaging (MRI) has made it possible to clearly visualize and delineate the subthalamic nucleus (STN). Ultra-high resolution MRI provides a first step in the ongoing improvement of imaging techniques rendering it likely that in the near future specific subareas of small brain nuclei such as the STN can be visualized. These developments can contribute to improve clinical imaging, allowing even more accurate targeting of the STN. This is interesting in view of putative limbic, associative, and sensomotoric subdivisions within the STN. The concept of anatomically distinct subdivisions is attractive, both from an anatomical as well as a clinical perspective. However, we argue that the current leading hypothesis of three STN subdivisions is based on low numbers of clinical observations and primate tracing studies. 7T imaging provides us with markers that could potentially help us to distinguish subdivisions, but our preliminary findings do not indicate the existence of subdivisions. In our opinion additional research is needed. As a consequence the tripartite hypothesis should therefore still be a topic of debate. In view of the possible clinical implications, we would like to raise the question whether anatomical evidence on the topological organization within the STN points towards delineated subdivisions, or an organization without strict anatomical boundaries or septa. The latter would require a revision of the current tripartite hypothesis of the human STN.

Mixed methodology in human brain research: integrating MRI and histology.

Postmortem magnetic resonance imaging (MRI) can provide a bridge between histological observations and the in vivo anatomy of the human brain. Approaches aimed at the co-registration of data derived from the two techniques are gaining interest. Optimal integration of the two research fields requires detailed knowledge of the tissue property requirements for individual research techniques, as well as a detailed understanding of the consequences of tissue fixation steps on the imaging quality outcomes for both MRI and histology. Here, we provide an overview of existing studies that bridge between state-of-the-art imaging modalities, and discuss the background knowledge incorporated into the design, execution and interpretation of postmortem studies. A subset of the discussed challenges transfer to animal studies as well. This insight can contribute to furthering our understanding of the normal and diseased human brain, and to facilitate discussions between researchers from the individual disciplines.

Manual delineation approaches for direct imaging of the subcortex.

The growing interest in the human subcortex is accompanied by an increasing number of parcellation procedures to identify deep brain structures in magnetic resonance imaging (MRI) contrasts. Manual procedures continue to form the gold standard for parcellating brain structures and is used for the validation of automated approaches. Performing manual parcellations is a tedious process which requires a systematic and reproducible approach. For this purpose, we created a series of protocols for the anatomical delineation of 21 individual subcortical structures. The intelligibility of the protocols was assessed by calculating Dice similarity coefficients for ten healthy volunteers. In addition, dilated Dice coefficients showed that manual parcellations created using these protocols can provide high-quality training data for automated algorithms. Here, we share the protocols, together with three example MRI datasets and the created manual delineations. The protocols can be applied to create high-quality training data for automated parcellation procedures, as well as for further validation of existing procedures and are shared without restrictions with the research community.