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.

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.

Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases.

Pathological alterations to the locus coeruleus, the major source of noradrenaline in the brain, are histologically evident in early stages of neurodegenerative diseases. Novel MRI approaches now provide an opportunity to quantify structural features of the locus coeruleus in vivo during disease progression. In combination with neuropathological biomarkers, in vivo locus coeruleus imaging could help to understand the contribution of locus coeruleus neurodegeneration to clinical and pathological manifestations in Alzheimer's disease, atypical neurodegenerative dementias and Parkinson's disease. Moreover, as the functional sensitivity of the noradrenergic system is likely to change with disease progression, in vivo measures of locus coeruleus integrity could provide new pathophysiological insights into cognitive and behavioural symptoms. Locus coeruleus imaging also holds the promise to stratify patients into clinical trials according to noradrenergic dysfunction. In this article, we present a consensus on how non-invasive in vivo assessment of locus coeruleus integrity can be used for clinical research in neurodegenerative diseases. We outline the next steps for in vivo, post-mortem and clinical studies that can lay the groundwork to evaluate the potential of locus coeruleus imaging as a biomarker for neurodegenerative diseases.

Comparing functional MRI protocols for small, iron-rich basal ganglia nuclei such as the subthalamic nucleus at 7 T and 3 T.

The basal ganglia (BG) form a network of subcortical nuclei. Functional magnetic resonance imaging (fMRI) in the BG could provide insight in its functioning and the underlying mechanisms of Deep Brain Stimulation (DBS). However, fMRI of the BG with high specificity is challenging, because the nuclei are small and variable in their anatomical location. High resolution fMRI at field strengths of 7 Tesla (T) could help resolve these challenges to some extent. A set of MR protocols was developed for functional imaging of the BG nuclei at 3 T and 7 T. The protocols were validated using a stop-signal reaction task (Logan et al. []: J Exp Psychol: Human Percept Perform 10:276-291). Compared with sub-millimeter 7 T fMRI protocols aimed at cortex, a reduction of echo time and spatial resolution was strictly necessary to obtain robust Blood Oxygen Level Dependent (BOLD) sensitivity in the BG. An fMRI protocol at 3 T with identical resolution to the 7 T showed no robust BOLD sensitivity in any of the BG nuclei. The results suggest that the subthalamic nucleus, as well as the substantia nigra, red nucleus, and the internal and external parts of the globus pallidus show increased activation in failed stop trials compared with successful stop and go trials. Hum Brain Mapp 38:3226-3248, 2017. © 2017 Wiley Periodicals, Inc.

Automated segmentation of the substantia nigra, subthalamic nucleus and red nucleus in 7T data at young and old age.

With recent developments in MR acquisition at 7T, smaller brainstem structures such as the red nuclei, substantia nigra and subthalamic nuclei can be imaged with good contrast and resolution. These structures have important roles both in the study of the healthy brain and in diseases such as Parkinson's disease, but few methods have been described to automatically segment them. In this paper, we extend a method that we have previously proposed for segmentation of the striatum and globus pallidus to segment these deeper and smaller structures. We modify the method to allow more direct control over segmentation smoothness by using a Markov random field prior. We investigate segmentation performance in three age groups and show that the method produces consistent results that correspond well with manual segmentations. We perform a vertex-based analysis to identify changes with age in the shape of the structures and present results suggesting that the method may be at least as effective as manual delineation in capturing differences between subjects.

Automatic segmentation of the striatum and globus pallidus using MIST: Multimodal Image Segmentation Tool.

Accurate segmentation of the subcortical structures is frequently required in neuroimaging studies. Most existing methods use only a T1-weighted MRI volume to segment all supported structures and usually rely on a database of training data. We propose a new method that can use multiple image modalities simultaneously and a single reference segmentation for initialisation, without the need for a manually labelled training set. The method models intensity profiles in multiple images around the boundaries of the structure after nonlinear registration. It is trained using a set of unlabelled training data, which may be the same images that are to be segmented, and it can automatically infer the location of the physical boundary using user-specified priors. We show that the method produces high-quality segmentations of the striatum, which is clearly visible on T1-weighted scans, and the globus pallidus, which has poor contrast on such scans. The method compares favourably to existing methods, showing greater overlap with manual segmentations and better consistency.

The Age-ility Project (Phase 1): Structural and functional imaging and electrophysiological data repository.

Our understanding of the complex interplay between structural and functional organisation of brain networks is being advanced by the development of novel multi-modal analyses approaches. The Age-ility Project (Phase 1) data repository offers open access to structural MRI, diffusion MRI, and resting-state fMRI scans, as well as resting-state EEG recorded from the same community participants (n=131, 15-35 y, 66 male). Raw imaging and electrophysiological data as well as essential demographics are made available via the NITRC website. All data have been reviewed for artifacts using a rigorous quality control protocol and detailed case notes are provided.

The impact of MRI scanner environment on perceptual decision-making.

Despite the widespread use of functional magnetic resonance imaging (fMRI), few studies have addressed scanner effects on performance. The studies that have examined this question show a wide variety of results. In this article we report analyses of three experiments in which participants performed a perceptual decision-making task both in a traditional setting as well as inside an MRI scanner. The results consistently show that response times increase inside the scanner. Error rates also increase, but to a lesser extent. To reveal the underlying mechanisms that drive the behavioral changes when performing a task inside the MRI scanner, the data were analyzed using the linear ballistic accumulator model of decision-making. These analyses show that, in the scanner, participants exhibit a slow down of the motor component of the response and have less attentional focus on the task. However, the balance between focus and motor slowing depends on the specific task requirements.

The subthalamic nucleus during decision-making with multiple alternatives.

Several prominent neurocomputational models predict that an increase of choice alternatives is modulated by increased activity in the subthalamic nucleus (STN). In turn, increased STN activity allows prolonged accumulation of information. At the same time, areas in the medial frontal cortex such as the anterior cingulate cortex (ACC) and the pre-SMA are hypothesized to influence the information processing in the STN. This study set out to test concrete predictions of STN activity in multiple-alternative decision-making using a multimodal combination of 7 Tesla structural and functional Magnetic Resonance Imaging, and ancestral graph (AG) modeling. The results are in line with the predictions in that increased STN activity was found with an increasing amount of choice alternatives. In addition, our study shows that activity in the ACC is correlated with activity in the STN without directly modulating it. This result sheds new light on the information processing streams between medial frontal cortex and the basal ganglia.

Ultra-high 7T MRI of structural age-related changes of the subthalamic nucleus.

The subthalamic nucleus (STh) is a small subcortical structure which is involved in regulating motor as well as cognitive functions. Due to its small size and close proximity to other small subcortical structures, it has been a challenge to localize and visualize it using magnetic resonance imaging (MRI). Currently there are several standard atlases available that are used to localize the STh in functional MRI studies and clinical procedures such as deep brain stimulation (DBS). DBS is an increasingly common neurosurgical procedure that has been successfully used to alleviate motor symptoms present in Parkinson's disease. However, current atlases are based on low sample sizes and restricted age ranges (Schaltenbrand and Wahren, 1977), and hence the use of these atlases effectively ignores the substantial structural brain changes that are associated with aging. In the present study, ultra-high field 7 tesla (T) magnetic resonance imaging (MRI) in humans was used to visualize and segment the STh in young, middle-aged, and elderly participants. The resulting probabilistic atlas maps for all age groups show that the STh shifts in the lateral direction with increasing age. In sum, the results of the present study suggest that age has to be taken into account in atlases for the optimal localization of the STh in healthy and diseased brains.

TMS over M1 reveals expression and selective suppression of conflicting action impulses.

Goal-directed action control comes into play when selecting between competing action alternatives. Response capture reflects the susceptibility of the motor system to incitement by task-irrelevant action impulses; the subsequent selective suppression of incorrect action impulses aims to counteract response capture and facilitate the desired response. The goal of this experiment was to clarify physiological mechanisms of response capture and suppression of action impulses during conflict at the level of the motor system. We administered single-pulse TMS at various intervals preceding speeded choice responses. The correct response side was designated by stimulus color, whereas stimulus location (which could match or conflict with response side) was to be ignored. TMS pulses triggered motor evoked potential and silent period, providing sensitive indices of cortico-spinal excitation and inhibition. Motor evoked potential data showed the typical progressive increase in cortico-spinal motor excitability leading up to the imminent (correct) response, which started earlier on nonconflict than on conflict trials. On conflict trials, the irrelevant stimulus location captured the incorrect response, as expressed by an early and transient rise in excitability. Silent period data showed that, already early during the response process, inhibition of the incorrect response was stronger for conflict than for nonconflict trials. Furthermore, inhibition decreased over time for nonconflict trials facilitating the imminent correct response while maintaining higher levels of inhibition on conflict trials. In conclusion, dynamic patterns of cortico-spinal excitability provide unique physiological evidence for the expression and selective suppression of action impulses captured by competing action alternatives.

A gradual increase of iron toward the medial-inferior tip of the subthalamic nucleus.

The subthalamic nucleus (STN) is an important node of the cortico-basal ganglia network and the main target of deep brain stimulation (DBS) in Parkinson's disease. Histological studies have revealed an inhomogeneous iron distribution within the STN, which has been related to putative subdivisions within this nucleus. Here, we investigate the iron distribution in more detail using quantitative susceptibility mapping (QSM), a novel magnetic resonance imaging (MRI) contrast mechanism. QSM allows for detailed assessment of iron content in both in vivo and postmortem tissue. Twelve human participants and 7 postmortem brain samples containing the STN were scanned using ultra-high field 7 Tesla (T) MRI. Iron concentrations were found to be higher in the medial-inferior tip of the STN. Using quantitative methods we show that the increase of iron concentration towards the medial-inferior tip is of a gradual rather than a discrete nature.

Cortico-subthalamic white matter tract strength predicts interindividual efficacy in stopping a motor response.

The subthalamic nucleus (STN) is a small but vitally important structure in the basal ganglia. Because of its small volume, and its localization in the basal ganglia, the STN can best be visualized using ultra-high resolution 7 Tesla (T) magnetic resonance imaging (MRI). In the present study, first we individually segmented 7 T MRI STN masks to generate atlas probability maps. Secondly, the individually segmented STN masks and the probability maps were used to derive cortico-subthalamic white matter tract strength. Tract strength measures were then taken to test two functional STN hypotheses which account for the efficiency in stopping a motor response: the right inferior fronto-subthalamic (rIFC-STN) hypothesis and the posterior medial frontal cortex-subthalamic (pMFC-STN) hypothesis. Results of two independent experiments show that increased white matter tract strength between the pMFC and STN results in better stopping behaviour.

7T functional MRI finds no evidence for distinct functional subregions in the subthalamic nucleus during a speeded decision-making task.

The subthalamic nucleus (STN) is a small, subcortical brain structure. It is a target for deep brain stimulation, an invasive treatment that reduces motor symptoms of Parkinson's disease. Side effects of DBS are commonly explained using the tripartite model of STN organization, which proposes three functionally distinct subregions in the STN specialized in cognitive, limbic, and motor processing. However, evidence for the tripartite model exclusively comes from anatomical studies and functional studies using clinical patients. Here, we provide the first experimental tests of the tripartite model in healthy volunteers using ultra-high field 7 Tesla (T) functional magnetic resonance imaging (fMRI). Thirty-four participants performed a random-dot motion decision-making task with a difficulty manipulation and a choice payoff manipulation aimed to differentially affect cognitive and limbic networks. Moreover, participants responded with their left and right index finger, differentially affecting motor networks. We analysed BOLD signal in three subregions of the STN along the dorsolateral-ventromedial axis, identified using manually delineated high resolution anatomical images and based on a previously published atlas. Using these paradigms, all segments responded equally to the experimental manipulations, and the tasks did not provide evidence for the tripartite model.

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.

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.

Variability in subthalamic nucleus targeting for deep brain stimulation with 3 and 7 Tesla magnetic resonance imaging.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective surgical treatment for Parkinson's disease (PD). Side-effects may, however, be induced when the DBS lead is placed suboptimally. Currently, lower field magnetic resonance imaging (MRI) at 1.5 or 3 Tesla (T) is used for targeting. Ultra-high-field MRI (7 T and above) can obtain superior anatomical information and might therefore be better suited for targeting. This study aims to test whether optimized 7 T imaging protocols result in less variable targeting of the STN for DBS compared to clinically utilized 3 T images. Three DBS-experienced neurosurgeons determined the optimal STN DBS target site on three repetitions of 3 T-T2, 7 T-T2*, 7 T-R2* and 7 T-QSM images for five PD patients. The distance in millimetres between the three repetitive coordinates was used as an index of targeting variability and was compared between field strength, MRI contrast and repetition with a Bayesian ANOVA. Further, the target coordinates were registered to MNI space, and anatomical coordinates were compared between field strength, MRI contrast and repetition using a Bayesian ANOVA. The results indicate that the neurosurgeons are stable in selecting the DBS target site across MRI field strength, MRI contrast and repetitions. The analysis of the coordinates in MNI space however revealed that the actual selected location of the electrode is seemingly more ventral when using the 3 T scan compared to the 7 T scans.

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.