The structural connectivity mapping of the intralaminar thalamic nuclei.

The intralaminar nuclei of the thalamus play a pivotal role in awareness, conscious experience, arousal, sleep, vigilance, as well as in cognitive, sensory, and sexual processing. Nonetheless, in humans, little is known about the direct involvement of these nuclei in such multifaceted functions and their structural connections in the brain. Thus, examining the versatility of structural connectivity of the intralaminar nuclei with the rest of the brain seems reasonable. Herein, we attempt to show the direct structural connectivity of the intralaminar nuclei to diencephalic, mesencephalic, and cortical areas using probabilistic tracking of the diffusion data from the human connectome project. The intralaminar nuclei fiber distributions span a wide range of subcortical and cortical areas. Moreover, the central medial and parafascicular nucleus reveal similar connectivity to the temporal, visual, and frontal cortices with only slight variability. The central lateral nucleus displays a refined projection to the superior colliculus and fornix. The centromedian nucleus seems to be an essential component of the subcortical somatosensory system, as it mainly displays connectivity via the medial and superior cerebellar peduncle to the brainstem and the cerebellar lobules. The subparafascicular nucleus projects to the somatosensory processing areas. It is interesting to note that all intralaminar nuclei have connections to the brainstem. In brief, the structural connectivity of the intralaminar nuclei aligns with the structural core of various functional demands for arousal, emotion, cognition, sensory, vision, and motor processing. This study sheds light on our understanding of the structural connectivity of the intralaminar nuclei with cortical and subcortical structures, which is of great interest to a broader audience in clinical and neuroscience research.

Functional mapping of sensorimotor activation in the human thalamus at 9.4 Tesla.

Although the thalamus is perceived as a passive relay station for almost all sensory signals, the function of individual thalamic nuclei remains unresolved. In the present study, we aimed to identify the sensorimotor nuclei of the thalamus in humans using task-based fMRI at a field strength of 9.4T by assessing the individual subject-specific sensorimotor BOLD response during a combined active motor (finger-tapping) and passive sensory (tactile-finger) stimulation. We demonstrate that both tasks increase BOLD signal response in the lateral nuclei group (VPL, VA, VLa, and VLp), and in the pulvinar nuclei group (PuA, PuM, and PuL). Finger-tapping stimuli evokes a stronger BOLD response compared to the tactile stimuli, and additionally engages the intralaminar nuclei group (CM and Pf). In addition, our results demonstrate reproducible thalamic nuclei activation during motor and tactile stimuli. This work provides important insight into understanding the function of individual thalamic nuclei in processing various input signals and corroborates the benefits of using ultra-high-field MR scanners for functional imaging of fine-scale deeply located brain structures.

Relay and higher-order thalamic nuclei show an intertwined functional association with cortical-networks.

Almost all functional processing in the cortex strongly depends on thalamic interactions. However, in terms of functional interactions with the cerebral cortex, the human thalamus nuclei still partly constitute a terra incognita. Hence, for a deeper understanding of thalamic-cortical cooperation, it is essential to know how the different thalamic nuclei are associated with cortical networks. The present work examines network-specific connectivity and task-related topical mapping of cortical areas with the thalamus. The study finds that the relay and higher-order thalamic nuclei show an intertwined functional association with different cortical networks. In addition, the study indicates that relay-specific thalamic nuclei are not only involved with relay-specific behavior but also in higher-order functions. The study enriches our understanding of interactions between large-scale cortical networks and the thalamus, which may interest a broader audience in neuroscience and clinical research.

Quantitative Susceptibility Mapping of the Basal Ganglia and Thalamus at 9.4 Tesla.

The thalamus (Th) and basal ganglia (BG) are central subcortical connectivity hubs of the human brain, whose functional anatomy is still under intense investigation. Nevertheless, both substructures contain a robust and reproducible functional anatomy. The quantitative susceptibility mapping (QSM) at ultra-high field may facilitate an improved characterization of the underlying functional anatomy in vivo. We acquired high-resolution QSM data at 9.4 Tesla in 21 subjects, and analyzed the thalamic and BG by using a prior defined functional parcellation. We found a more substantial contribution of paramagnetic susceptibility sources such as iron in the pallidum in contrast to the caudate, putamen, and Th in descending order. The diamagnetic susceptibility sources such as myelin and calcium revealed significant contributions in the Th parcels compared with the BG. This study presents a detailed nuclei-specific delineation of QSM-provided diamagnetic and paramagnetic susceptibility sources pronounced in the BG and the Th. We also found a reasonable interindividual variability as well as slight hemispheric differences. The results presented here contribute to the microstructural knowledge of the Th and the BG. In specific, the study illustrates QSM values (myelin, calcium, and iron) in functionally similar subregions of the Th and the BG.

The anterior and medial thalamic nuclei and the human limbic system: tracing the structural connectivity using diffusion-weighted imaging.

The limbic system is a phylogenetically old, behaviorally defined system that serves as a center for emotions. It controls the expression of anger, fear, and joy and also influences sexual behavior, vegetative functions, and memory. The system comprises a collection of tel-, di-, and mesencephalic structures whose components have evolved and increased over time. Previous animal research indicates that the anterior nuclear group of the thalamus (ANT), as well as the habenula (Hb) and the adjacent mediodorsal nucleus (MD) each play a vital role in the limbic circuitry. Accordingly, diffusion imaging data of 730 subjects obtained from the Human Connectome Project and the masks of six nuclei (anterodorsal, anteromedial, anteroventral, lateral dorsal, Hb, and MD) served as seed regions for a direct probabilistic tracking to the rest of the brain using diffusion-weighted imaging. The results revealed that the ANT nuclei are part of the limbic and the memory system as they mainly connect via the mammillary tract, mammillary body, anterior commissure, fornix, and retrosplenial cortices to the hippocampus, amygdala, medio-temporal, orbito-frontal and occipital cortices. Furthermore, the ANT nuclei showed connections to the mesencephalon and brainstem to varying extents, a pattern rarely described in experimental findings. The habenula-usually defined as part of the epithalamus-was closely connected to the tectum opticum and seems to serve as a neuroanatomical hub between the visual and the limbic system, brainstem, and cerebellum. Finally, in contrast to experimental findings with tracer studies, directly determined connections of MD were mainly confined to the brainstem, while indirect MD fibers form a broad pathway connecting the hippocampus and medio-temporal areas with the mediofrontal cortex.

Dynamic B0 shimming of the motor cortex and cerebellum with a multicoil shim setup for BOLD fMRI at 9.4T.

PURPOSE: We assessed how improved static magnetic field (B0 ) homogeneity with a dynamic multicoil shimming can influence the blood oxygen level dependent (BOLD) contrast to noise when echo planar imaging (EPI) sequence is used for a motor task functional MRI study. We showed that a multicoil shim setup can be a proper choice for dynamic shimming of 2 spatially distant areas with different inhomogeneity distributions. METHODS: A 16-channel multicoil shim setup is used to provide improved B0 homogeneity by dynamic slice-wise shimming. The performance of dynamic B0 shimming was investigated in 2 distinct brain regions, the motor cortex and the cerebellum, in the same experiment during a finger-tapping task. Temporal SNR (tSNR), geometric distortion of the EPIs, and results of an analysis with a general linear model before and after shimming with the multicoil were compared. RESULTS: Reduced B0 deviation by 30% and 52% in the cerebellum and motor cortex, respectively, resulted in higher tSNR and a reduction of distortions in the EPI. Statistical analysis applied to the EPIs showed higher t values and increased number of voxels above significance threshold when shimming with the multicoil setup. CONCLUSIONS: Improved B0 homogeneity leads to higher tSNR and enhances the detection of BOLD signal.

Nerve Growth Factor Serum Levels Are Associated With Regional Gray Matter Volume Differences in Schizophrenia Patients.

Numerous neuroimaging studies have revealed structural brain abnormalities in schizophrenia patients. There is emerging evidence that dysfunctional nerve growth factor (NGF) signaling may contribute to structural brain alterations found in these patients. In this pilot study, we investigated whether there was a correlation between NGF serum levels and gray matter volume (GMV) in schizophrenia patients. Further, we investigated whether there was an overlap between the correlative findings and cross-sectional GMV differences between schizophrenia patients (n = 18) and healthy controls (n = 19). Serum NGF was significantly correlated to GMV in the left prefrontal lobe, the left midcingulate cortex, and the brainstem in schizophrenia patients. However, we did not find any correlations of NGF serum levels with GMV in healthy controls. Schizophrenia patients showed smaller GMV than healthy controls in brain regions located in the bilateral limbic system, bilateral parietal lobe, bilateral insula, bilateral primary auditory cortex, left frontal lobe, and bilateral occipital regions. In a conjunction analysis, GMV in the left midcingulate cortex (MCC) appears negatively correlated to NGF serum levels in the group of schizophrenia patients and also to be reduced compared to healthy controls. These results suggest an increased vulnerability of schizophrenia patients to changes in NGF levels compared to healthy controls and support a role for NGF signaling in the pathophysiology of schizophrenia. As our pilot study is exploratory in nature, further studies enrolling larger sample sizes will be needed to further corroborate our findings and to investigate the influence of additional covariates.

Pattern of Cerebellar Atrophy in Friedreich's Ataxia-Using the SUIT Template.

Whole-brain voxel-based morphometry (VBM) studies revealed patterns of patchy atrophy within the cerebellum of Friedreich's ataxia patients, missing clear clinico-anatomic correlations. Studies so far are lacking an appropriate registration to the infratentorial space. To circumvent these limitations, we applied a high-resolution atlas template of the human cerebellum and brainstem (SUIT template) to characterize regional cerebellar atrophy in Friedreich's ataxia (FRDA) on 3-T MRI data. We used a spatially unbiased voxel-based morphometry approach together with T2-based manual segmentation, T2 histogram analysis, and atlas generation of the dentate nuclei in a representative cohort of 18 FRDA patients and matched healthy controls. We demonstrate that the cerebellar volume in FRDA is generally not significantly different from healthy controls but mild lobular atrophy develops beyond normal aging. The medial parts of lobule VI, housing the somatotopic representation of tongue and lips, are the major site of this lobular atrophy, which possibly reflects speech impairment. Extended white matter affection correlates with disease severity across and beyond the cerebellar inflow and outflow tracts. The dentate nucleus, as a major site of cerebellar degeneration, shows a mean volume loss of about 30%. Remarkably, not the atrophy but the T2 signal decrease of the dentate nuclei highly correlates with disease duration and severity.

Corrigendum: Nerve Growth Factor Serum Levels Are Associated With Regional Gray Matter Volume Differences in Schizophrenia Patients.

[This corrects the article DOI: 10.3389/fpsyt.2019.00275.].

LISA improves statistical analysis for fMRI.

One of the principal goals in functional magnetic resonance imaging (fMRI) is the detection of local activation in the human brain. However, lack of statistical power and inflated false positive rates have recently been identified as major problems in this regard. Here, we propose a non-parametric and threshold-free framework called LISA to address this demand. It uses a non-linear filter for incorporating spatial context without sacrificing spatial precision. Multiple comparison correction is achieved by controlling the false discovery rate in the filtered maps. Compared to widely used other methods, it shows a boost in statistical power and allows to find small activation areas that have previously evaded detection. The spatial sensitivity of LISA makes it especially suitable for the analysis of high-resolution fMRI data acquired at ultrahigh field (≥7 Tesla).

In-vivo quantitative structural imaging of the human midbrain and the superior colliculus at 9.4T.

We explored anatomical details of the superior colliculus (SC) by in vivo magnetic resonance imaging (MRI) at 9.4T. The high signal-to-noise ratio allowed the acquisition of high resolution, multi-modal images with voxel sizes ranging between 176 × 132 × 600 µm and (800)3µm. Quantitative mapping of the longitudinal relaxation rate R1, the effective transverse relaxation rate R2*, and the magnetic susceptibility QSM was performed in 14 healthy volunteers. The images were analyzed in native space as well as after normalization to a common brain space (MNI). The coefficient-of-variation (CoV) across subjects was evaluated in prominent regions of the midbrain, reaching the best reproducibility (CoV of 5%) in the R2* maps of the SC in MNI space, while the CoV in the QSM maps remained high regardless of brain-space. To investigate whether more complex neurobiological architectural features could be detected, depth profiles through the SC layers towards the red nucleus (RN) were evaluated at different levels of the SC along the rostro-caudal axis. This analysis revealed alterations of the quantitative MRI parameters concordant with previous post mortem histology studies of the cyto- and myeloarchitecture of the SC. In general, the R1 maps were hyperintense in areas characterized by the presence of abundant myelinated fibers, and likely enabled detection of the deep white layer VII of the SC adjacent to the periaqueductal gray. While R1 maps failed to reveal finer details, possibly due to the relatively coarse spatial sampling used for this modality, these could be recovered in R2* maps and in QSM. In the central part of the SC along its rostro-caudal axis, increased R2* values and decreased susceptibility values were observed 2 mm below the SC surface, likely reflecting the myelinated fibers in the superficial optic layer (layer III). Towards the deeper layers, a second increase in R2* was paralleled by a paramagnetic shift in QSM suggesting the presence of an iron-rich layer about 3 mm below the surface of the SC, attributed to the intermediate gray layer (IV) composed of multipolar neurons. These results dovetail observations in histological specimens and animal studies and demonstrate that high-resolution multi-modal MRI at 9.4T can reveal several microstructural features of the SC in vivo.

Functional parcellation using time courses of instantaneous connectivity.

Functional neuroimaging studies have led to understanding the brain as a collection of spatially segregated functional networks. It is thought that each of these networks is in turn composed of a set of distinct sub-regions that together support each network's function. Considering the sub-regions to be an essential part of the brain's functional architecture, several strategies have been put forward that aim at identifying the functional sub-units of the brain by means of functional parcellations. Current parcellation strategies typically employ a bottom-up strategy, creating a parcellation by clustering smaller units. We propose a novel top-down parcellation strategy, using time courses of instantaneous connectivity to subdivide an initial region of interest into sub-regions. We use split-half reproducibility to choose the optimal number of sub-regions. We apply our Instantaneous Connectivity Parcellation (ICP) strategy on high-quality resting-state FMRI data, and demonstrate the ability to generate parcellations for thalamus, entorhinal cortex, motor cortex, and subcortex including brainstem and striatum. We evaluate the subdivisions against available cytoarchitecture maps to show that our parcellation strategy recovers biologically valid subdivisions that adhere to known cytoarchitectural features.

Functional anatomy of the human thalamus at rest.

In the present work, we used resting state-fMRI to investigate the functional anatomy of the thalamus at rest by applying an Independent Component Analysis to delineate thalamic substructures into stable and reproducible parcels for the left and right thalamus. We determined 15 functionally distinct thalamic parcels, which differed in laterality and size but exhibited a correspondence with 18 cytoarchitectonally defined nuclei. We characterized their structural connectivity in determining DWI based cortical fiber pathways and found selected projections to different cortical areas. In contrast, the functional connections of these parcels were not confined to certain cortical areas or lobes. We, finally evaluated cortical projections and found particular subcortical and cortical pattern for each parcel, which partly exhibited a correspondence with the thalamo-cortical connectivity maps of the mouse.

Direct diffusion-based parcellation of the human thalamus.

To assess stable anatomical features of the human thalamus, an unbiased diffusion tensor parcellation approach was used to segment thalamic substructures with similar spatial orientation. We determined localization, size and individual variations of 21 thalamic clusters in a group of 63 healthy human subjects (32 males/31 females). The laterality differences accounted for ± 6% and gender differences for ± 4% of the thalamic volume. Consecutively, five stable clusters in the anterior, medial, lateral and posterior thalamus were selected, which were common to 90% of all subjects and contained at least 10 voxels. These clusters could be assigned to the anteroventral nucleus (AN) group, the mediodorsal (MD) nucleus, the medial pulvinar (PuM), and the lateral nuclei group. The subcortical and cortical connectivity of these clusters revealed that: (1) the oblique cranio-caudal-oriented fibers of the AN cluster mainly connect to limbic structures, (2) the numerous dorso-frontal-oriented fibers of MD mainly project to the prefrontal cortex and the medial temporal lobe, (3) the fibers of the PuM running in parallel with the x-axis project to medio-occipital and medio-temporal areas and connect visual areas with the hippocampus and amygdala and via intrathalamic pathways with medio-frontal areas, and (4) the oblique caudo-cranial fibers of the two lateral clusters located anteriorly in the motor and posteriorly in the sensory thalamus are routing sensory-motor information from the brain stem via the internal capsule to pre- and peri-central regions of the cortex.

Recovery of biological motion perception and network plasticity after cerebellar tumor removal.

Visual perception of body motion is vital for everyday activities such as social interaction, motor learning or car driving. Tumors to the left lateral cerebellum impair visual perception of body motion. However, compensatory potential after cerebellar damage and underlying neural mechanisms remain unknown. In the present study, visual sensitivity to point-light body motion was psychophysically assessed in patient SL with dysplastic gangliocytoma (Lhermitte-Duclos disease) to the left cerebellum before and after neurosurgery, and in a group of healthy matched controls. Brain activity during processing of body motion was assessed by functional magnetic resonance imaging (MRI). Alterations in underlying cerebro-cerebellar circuitry were studied by psychophysiological interaction (PPI) analysis. Visual sensitivity to body motion in patient SL before neurosurgery was substantially lower than in controls, with significant improvement after neurosurgery. Functional MRI in patient SL revealed a similar pattern of cerebellar activation during biological motion processing as in healthy participants, but located more medially, in the left cerebellar lobules III and IX. As in normalcy, PPI analysis showed cerebellar communication with a region in the superior temporal sulcus, but located more anteriorly. The findings demonstrate a potential for recovery of visual body motion processing after cerebellar damage, likely mediated by topographic shifts within the corresponding cerebro-cerebellar circuitry induced by cerebellar reorganization. The outcome is of importance for further understanding of cerebellar plasticity and neural circuits underpinning visual social cognition.

Structural loop between the cerebellum and the superior temporal sulcus: evidence from diffusion tensor imaging.

The cerebellum is believed to play an essential role in a variety of motor and cognitive functions through reciprocal interaction with the cerebral cortex. Recent findings suggest that cerebellar involvement in the network specialized for visual body motion processing may be mediated through interaction with the right superior temporal sulcus (STS). Yet, the underlying pattern of structural connectivity between the STS and the cerebellum remains unidentified. In the present work, diffusion tensor imaging analysis on seeds derived from functional magnetic resonance imaging during a task on point-light biological motion perception uncovers a structural pathway between the right posterior STS and the left cerebellar lobule Crus I. The findings suggest existence of a structural loop underpinning bidirectional communication between the STS and cerebellum. This connection might also be of potential value for other visual social abilities.

Overlapping and parallel cerebello-cerebral networks contributing to sensorimotor control: an intrinsic functional connectivity study.

In concert with sensorimotor control areas of the cerebrum, the cerebellum shows differential activation patterns during a variety of sensorimotor-related tasks. However, the spatial details and extent of the complex and heterogeneous cerebello-cerebral systems involved in action control remain uncertain. In this study, we use intrinsic functional connectivity (iFC) to examine cerebello-cerebral networks of five cerebellar lobules (I-IV, V, VI, and VIIIa/b) that have been empirically identified to form the functional basis of sensorimotor processes. A refined cerebellar seed-region selection allowed us to identify a network of primary sensorimotor and supplementary motor areas (I-V), a network of prefrontal, premotor, occipito-temporal and inferior-parietal regions (VI), and two largely overlapping networks involving premotor and superior parietal regions, the temporo-parietal junction as well as occipito-temporal regions (VIIIa/b). All networks involved the medial prefrontal/cingulate cortex. These cerebral clusters were used in a partial correlation analysis to systematically map cerebral connectivity throughout the entire cerebellum. We discuss these findings in the framework of affective and cognitive control, sensorimotor, multisensory systems, and executive/language systems. Within the cerebellum we found that cerebro-cerebellar systems seem to run in parallel, as indicated by distinct sublobular functional topography of prefrontal, parietal, sensorimotor, cingulate, and occipito-temporal regions. However, all areas showed overlapping connectivity to various degrees in both hemispheres. The results of both analyses demonstrate that different sublobular parts of the cerebellar lobules may dominate in different aspects of primary or higher-order sensorimotor processing. This systems-level cerebellar organization provides a more detailed structure for cerebello-cerebral interaction which contributes to our understanding of complex motor behavior.

Different types of laughter modulate connectivity within distinct parts of the laughter perception network.

Laughter is an ancient signal of social communication among humans and non-human primates. Laughter types with complex social functions (e.g., taunt and joy) presumably evolved from the unequivocal and reflex-like social bonding signal of tickling laughter already present in non-human primates. Here, we investigated the modulations of cerebral connectivity associated with different laughter types as well as the effects of attention shifts between implicit and explicit processing of social information conveyed by laughter using functional magnetic resonance imaging (fMRI). Complex social laughter types and tickling laughter were found to modulate connectivity in two distinguishable but partially overlapping parts of the laughter perception network irrespective of task instructions. Connectivity changes, presumably related to the higher acoustic complexity of tickling laughter, occurred between areas in the prefrontal cortex and the auditory association cortex, potentially reflecting higher demands on acoustic analysis associated with increased information load on auditory attention, working memory, evaluation and response selection processes. In contrast, the higher degree of socio-relational information in complex social laughter types was linked to increases of connectivity between auditory association cortices, the right dorsolateral prefrontal cortex and brain areas associated with mentalizing as well as areas in the visual associative cortex. These modulations might reflect automatic analysis of acoustic features, attention direction to informative aspects of the laughter signal and the retention of those in working memory during evaluation processes. These processes may be associated with visual imagery supporting the formation of inferences on the intentions of our social counterparts. Here, the right dorsolateral precentral cortex appears as a network node potentially linking the functions of auditory and visual associative sensory cortices with those of the mentalizing-associated anterior mediofrontal cortex during the decoding of social information in laughter.