The effect of ketamine on affective modulation of the startle reflex and its resting-state brain correlates.

Ketamine is a rapid-acting antidepressant that also influences neural reactivity to affective stimuli. However, the effect of ketamine on behavioral affective reactivity is yet to be elucidated. The affect-modulated startle reflex paradigm (AMSR) allows examining the valence-specific aspects of behavioral affective reactivity. We hypothesized that ketamine alters the modulation of the startle reflex during processing of unpleasant and pleasant stimuli and weakens the resting-state functional connectivity (rsFC) within the modulatory pathway, namely between the centromedial nucleus of the amygdala and nucleus reticularis pontis caudalis. In a randomized, double-blind, placebo-controlled, cross-over study, thirty-two healthy male participants underwent ultra-high field resting-state functional magnetic resonance imaging at 7 T before and 24 h after placebo and S-ketamine infusions. Participants completed the AMSR task at baseline and one day after each infusion. In contrast to our hypothesis, ketamine infusion did not impact startle potentiation during processing of unpleasant stimuli but resulted in diminished startle attenuation during processing of pleasant stimuli. This diminishment significantly correlated with end-of-infusion plasma levels of ketamine and norketamine. Furthermore, ketamine induced a decrease in rsFC within the modulatory startle reflex pathway. The results of this first study on the effect of ketamine on the AMSR suggest that ketamine might attenuate the motivational significance of pleasant stimuli in healthy participants one day after infusion.

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 genetic architecture of the human thalamus and its overlap with ten common brain disorders.

The thalamus is a vital communication hub in the center of the brain and consists of distinct nuclei critical for consciousness and higher-order cortical functions. Structural and functional thalamic alterations are involved in the pathogenesis of common brain disorders, yet the genetic architecture of the thalamus remains largely unknown. Here, using brain scans and genotype data from 30,114 individuals, we identify 55 lead single nucleotide polymorphisms (SNPs) within 42 genetic loci and 391 genes associated with volumes of the thalamus and its nuclei. In an independent validation sample (n = 5173) 53 out of the 55 lead SNPs of the discovery sample show the same effect direction (sign test, P = 8.6e-14). We map the genetic relationship between thalamic nuclei and 180 cerebral cortical areas and find overlapping genetic architectures consistent with thalamocortical connectivity. Pleiotropy analyses between thalamic volumes and ten psychiatric and neurological disorders reveal shared variants for all disorders. Together, these analyses identify genetic loci linked to thalamic nuclei and substantiate the emerging view of the thalamus having central roles in cortical functioning and common brain disorders.

The missing role of gray matter in studying brain controllability.

Brain controllability properties are normally derived from the white matter fiber tracts in which the neural substrate of the actual energy consumption, namely the gray matter, has been widely ignored. Here, we study the relationship between gray matter volume of regions across the whole cortex and their respective control properties derived from the structural architecture of the white matter fiber tracts. The data suggests that the ability of white fiber tracts to exhibit control at specific nodes not only depends on the connection strength of the structural connectome but additionally depends on gray matter volume at the host nodes. Our data indicate that connectivity strength and gray matter volume interact with respect to the brain's control properties. Disentangling effects of the regional gray matter volume and connectivity strength, we found that frontal and sensory areas play crucial roles in controllability. Together these results suggest that structural and regional properties of the white matter and gray matter provide complementary information in studying the control properties of the intrinsic structural and functional architecture of the brain.

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.

Linking spatial gene expression patterns to sex-specific brain structural changes on a mouse model of 16p11.2 hemideletion.

Neurodevelopmental disorders, such as ASD and ADHD, affect males about three to four times more often than females. 16p11.2 hemideletion is a copy number variation that is highly associated with neurodevelopmental disorders. Previous work from our lab has shown that a mouse model of 16p11.2 hemideletion (del/+) exhibits male-specific behavioral phenotypes. We, therefore, aimed to investigate with magnetic resonance imaging (MRI), whether del/+ animals also exhibited a sex-specific neuroanatomical endophenotype. Using the Allen Mouse Brain Atlas, we analyzed the expression patterns of the 27 genes within the 16p11.2 region to identify which gene expression patterns spatially overlapped with brain structural changes. MRI was performed ex vivo and the resulting images were analyzed using Voxel-based morphometry for T1-weighted sequences and tract-based spatial statistics for diffusion-weighted images. In a subsequent step, all available in situ hybridization (ISH) maps of the genes involved in the 16p11.2 hemideletion were aligned to Waxholm space and clusters obtained by sex-specific group comparisons were analyzed to determine which gene(s) showed the highest expression in these regions. We found pronounced sex-specific changes in male animals with increased fractional anisotropy in medial fiber tracts, especially in those proximate to the striatum. Moreover, we were able to identify gene expression patterns spatially overlapping with male-specific structural changes that were associated with neurite outgrowth and the MAPK pathway. Of note, previous molecular studies have found convergent changes that point to a sex-specific dysregulation of MAPK signaling. This convergent evidence supports the idea that ISH maps can be used to meaningfully analyze imaging data sets.

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.