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.

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.

A high-resolution multi-shell 3T diffusion magnetic resonance imaging dataset as part of the Amsterdam Ultra-high field adult lifespan database (AHEAD).

In order to further our understanding of brain function and the underlying networks, more advanced diffusion weighted magnetic resonance imaging (DWI MRI) data are essential. Here we present freely available high-resolution multi-shell multi-directional 3 Tesla (T) DWI MRI data as part of the 'Amsterdam Ultra-high field adult lifespan database' (AHEAD). The 3T DWI AHEAD dataset include 1.28mm isotropic whole brain DWI data of 49 healthy adult participants between 18 and 90 years old. The acquired data include DWIs at three non-zero b-values (48 directions, b-value 700 s/mm2; 56 directions, b-value 1000 s/mm2; 64 directions, b-value 1600 s/mm2) including a total of twelve volumes with a b-value of 0 s/mm2 (b0 volumes). In addition, eight b0 volumes with a reversed phase encoding direction were acquired to correct for distortions. To facilitate future use, the DWI data have been denoised, corrected for eddy currents, susceptibility-induced off-resonance field distortions, bias fields, and are skull stripped.

Hypermetabolism in mice caused by the central action of an unliganded thyroid hormone receptor alpha1.

Thyroid hormone, via its nuclear receptors TRalpha and TRbeta, controls metabolism by acting locally in peripheral tissues and centrally by regulating sympathetic signaling. We have defined aporeceptor regulation of metabolism by using mice heterozygous for a mutant TRalpha1 with low affinity to T3. The animals were hypermetabolic, showing strongly reduced fat depots, hyperphagia and resistance to diet-induced obesity accompanied by induction of genes involved in glucose handling and fatty acid metabolism in liver and adipose tissues. Increased lipid mobilization and beta-oxidation occurred in adipose tissues, whereas blockade of sympathetic signaling to brown adipose tissue normalized the metabolic phenotype despite a continued perturbed hormone signaling in this cell type. The results define a novel and important role for the TRalpha1 aporeceptor in governing metabolic homeostasis. Furthermore, the data demonstrate that a nuclear hormone receptor affecting sympathetic signaling can override its autonomous effects in peripheral tissues.

Compression of the optic chiasm is associated with permanent shorter sleep duration in patients with pituitary insufficiency.

OBJECTIVE: Patients with pituitary insufficiency often experience some degree of impaired sleep. Sleep-wake rhythm is regulated to a large extent by the suprachiasmatic nucleus (SCN). Because the SCN is located just superior to the optic chiasm, we hypothesized that a history of compression of the optic chiasm (CC) due to a tumour with suprasellar extension is associated with altered sleep patterns in patients with pituitary insufficiency. DESIGN: Case-control study. PATIENTS: We studied 38 patients (mean age 55·7 ± 13·1 years; 71·1% men) with CC and 18 patients (mean age 53·3 ± 16·6 years, 38·9% men) without CC. MEASUREMENTS: Objective measures of sleep patterns were assessed by wrist actigraphy. Validated sleep questionnaires were used to evaluate subjective sleep parameters. RESULTS: Objective total sleep duration was 36 min shorter in patients with CC than in patients without CC [454 (295-553) vs 490 (432-740) min, P = 0·034]. Moreover, patients with CC had a later habitual bedtime [23:15 (22:30-03:00) vs 22:55 (20:00-02:00) h, P = 0·044] and a later actigraphic sleep onset [23:57 (22:31-01:33) vs 23·16 (19:47-03:04) h, P = 0·020]. Linear regression analysis confirmed the difference in total sleep duration after adjustment for age, sex, body mass index, cranial radiotherapy and pituitary/hypothalamic surgery. Subjective sleep parameters were similar in both groups. CONCLUSIONS: Compression of the optic chiasm due to a tumour with suprasellar extension is associated with permanent changes in total sleep duration in patients with pituitary insufficiency.

Imaging of the human subthalamic nucleus.

The human subthalamic nucleus (STN) is a small lens shaped iron rich nucleus, which has gained substantial interest as a target for deep brain stimulation surgery for a variety of movement disorders. The internal anatomy of the human STN has not been fully elucidated, and an intensive debate, discussing the level of overlap between putative limbic, associative, and motor zones within the STN is still ongoing. In this chapter, we have summarized anatomical information obtained using different neuroimaging modalities focusing on the anatomy of the STN. Additionally, we have highlighted a number of major challenges faced when using magnetic resonance imaging (MRI) approaches for the visualization of small iron rich deep brain structures such as the STN. In vivo MRI and postmortem microscopy efforts provide valuable complementary information on the internal structure of the STN, although the results are not always fully aligned. Finally, we provide an outlook on future efforts that could contribute to the development of an integrative research approach that will help with the reconciliation of seemingly divergent results across research approaches.

Structure-function similarities in deep brain stimulation targets cross-species.

Deep Brain Stimulation (DBS) is an effective neurosurgical treatment to alleviate motor symptoms of advanced Parkinson's disease. Due to its potential, DBS usage is rapidly expanding to target a large number of brain regions to treat a wide range of diseases and neuropsychiatric disorders. The identification and validation of new target regions heavily rely on the insights gained from rodent and primate models. Here we present a large-scale automatic meta-analysis in which the structure-function associations within and between species are compared for 21 DBS targets in humans. The results indicate that the structure-function association for the majority of the 21 included subcortical areas were conserved cross-species. A subset of structures showed overlapping functional association. This can potentially be attributed to shared brain networks and might explain why multiple brain areas are targeted for the same disease or neuropsychiatric disorder.

Quantity and quality: Normative open-access neuroimaging databases.

The focus of this article is to compare twenty normative and open-access neuroimaging databases based on quantitative measures of image quality, namely, signal-to-noise (SNR) and contrast-to-noise ratios (CNR). We further the analysis through discussing to what extent these databases can be used for the visualization of deeper regions of the brain, such as the subcortex, as well as provide an overview of the types of inferences that can be drawn. A quantitative comparison of contrasts including T1-weighted (T1w) and T2-weighted (T2w) images are summarized, providing evidence for the benefit of ultra-high field MRI. Our analysis suggests a decline in SNR in the caudate nuclei with increasing age, in T1w, T2w, qT1 and qT2* contrasts, potentially indicative of complex structural age-dependent changes. A similar decline was found in the corpus callosum of the T1w, qT1 and qT2* contrasts, though this relationship is not as extensive as within the caudate nuclei. These declines were accompanied by a declining CNR over age in all image contrasts. A positive correlation was found between scan time and the estimated SNR as well as a negative correlation between scan time and spatial resolution. Image quality as well as the number and types of contrasts acquired by these databases are important factors to take into account when selecting structural data for reuse. This article highlights the opportunities and pitfalls associated with sampling existing databases, and provides a quantitative backing for their usage.

Functional segregation and integration within the human subthalamic nucleus from a micro- and meso-level perspective.

The subthalamic nucleus (STN) is a core basal ganglia structure involved in the control of motor, cognitive, motivational and affective functions. The (challenged) tripartite subdivision hypothesis places these functions into distinct sensorimotor, cognitive/associative, and limbic subregions based on the topography of cortical projections. To a large extent, this hypothesis is used to motivate the choice of target coordinates for implantation of deep brain stimulation electrodes for treatment of neurological and psychiatric disorders. Yet, the parallel organization of basal ganglia circuits has been known to allow considerable cross-talk, which might contribute to the occurrence of neuropsychiatric side effects when stimulating the dorsolateral, putative sensorimotor, part of the STN for treatment of Parkinson's disease. Any functional segregation within the STN is expected to be reflected both at micro-level microscopy and meso-level neural population activity. As such, we review the current empirical evidence from anterograde tracing and immunocytochemistry studies and from local field potential recordings for delineating the STN into distinct subregions. The spatial distribution of immunoreactivity presents as a combination of gradients, and although neural activity in distinct frequency bands appears spatially clustered, there is substantial overlap in peak locations. We argue that regional specialization without sharply defined borders is likely most representative of the STN's functional organization.

Multi-contrast anatomical subcortical structures parcellation.

The human subcortex is comprised of more than 450 individual nuclei which lie deep in the brain. Due to their small size and close proximity, up until now only 7% have been depicted in standard MRI atlases. Thus, the human subcortex can largely be considered as terra incognita. Here, we present a new open-source parcellation algorithm to automatically map the subcortex. The new algorithm has been tested on 17 prominent subcortical structures based on a large quantitative MRI dataset at 7 Tesla. It has been carefully validated against expert human raters and previous methods, and can easily be extended to other subcortical structures and applied to any quantitative MRI dataset. In sum, we hope this novel parcellation algorithm will facilitate functional and structural neuroimaging research into small subcortical nuclei and help to chart terra incognita.

Methodological Considerations for Neuroimaging in Deep Brain Stimulation of the Subthalamic Nucleus in Parkinson's Disease Patients.

Deep brain stimulation (DBS) of the subthalamic nucleus is a neurosurgical intervention for Parkinson's disease patients who no longer appropriately respond to drug treatments. A small fraction of patients will fail to respond to DBS, develop psychiatric and cognitive side-effects, or incur surgery-related complications such as infections and hemorrhagic events. In these cases, DBS may require recalibration, reimplantation, or removal. These negative responses to treatment can partly be attributed to suboptimal pre-operative planning procedures via direct targeting through low-field and low-resolution magnetic resonance imaging (MRI). One solution for increasing the success and efficacy of DBS is to optimize preoperative planning procedures via sophisticated neuroimaging techniques such as high-resolution MRI and higher field strengths to improve visualization of DBS targets and vasculature. We discuss targeting approaches, MRI acquisition, parameters, and post-acquisition analyses. Additionally, we highlight a number of approaches including the use of ultra-high field (UHF) MRI to overcome limitations of standard settings. There is a trade-off between spatial resolution, motion artifacts, and acquisition time, which could potentially be dissolved through the use of UHF-MRI. Image registration, correction, and post-processing techniques may require combined expertise of traditional radiologists, clinicians, and fundamental researchers. The optimization of pre-operative planning with MRI can therefore be best achieved through direct collaboration between researchers and clinicians.