Edited by: Gilbert Jean Kirouac, University of Manitoba, Canada
Reviewed by: Junqian Xu, Baylor College of Medicine, United States; Miguel Ángel Sánchez-González, Autonomous University of Madrid, Spain
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The paraventricular thalamic nucleus (PVT) is a small but highly connected nucleus of the dorsal midline thalamus. The PVT has garnered recent attention as a context-sensitive node within the thalamocortical arousal system that modulates state-dependent motivated behaviors. Once considered related to generalized arousal responses with non-specific impacts on behavior, accumulating evidence bolsters the contemporary view that discrete midline thalamic subnuclei belong to specialized corticolimbic and corticostriatal circuits related to attention, emotions, and cognition. However, the functional connectivity patterns of the human PVT have yet to be mapped. Here, we combined high-quality, high-resolution 7T and 3T resting state MRI data from 121 young adult participants from the Human Connectome Project (HCP) and thalamic subnuclei atlas masks to investigate resting state functional connectivity of the human PVT. The 7T results demonstrated extensive positive functional connectivity with the brainstem, midbrain, ventral and dorsal medial prefrontal cortex (mPFC), anterior and posterior cingulate, ventral striatum, hippocampus, and amygdala. These connections persist upon controlling for functional connectivity of the rest of the thalamus. Whole-brain contrasts provided further evidence that, compared to three nearby midline thalamic subnuclei, functional connectivity of the PVT is strong with the hippocampus, amygdala, ventral and dorsal mPFC, and middle temporal gyrus. These findings suggest that, even during rest, the human PVT is functionally coupled with many regions known to be structurally connected to rodent and non-human primate PVT. Further, cosine similarity analysis results suggested the PVT is integrated into the default mode network (DMN), an intrinsic connectivity network associated with episodic memory and self-referential thought. The current work provides a much-needed foundation for ongoing and future work examining the functional roles of the PVT in humans.
The thalamus (Greek for “inner chamber”) is well known for its role as a sensory and motor signal relay region. However, accumulating evidence of discrete thalamo-limbic, thalamo-striatal, and thalamo-cortical projections, circuits, and functional connectivity suggests the thalamus acts more as an integrator of specific behaviors than as a passive relay station (Groenewegen and Berendse,
The PVT was first described in rats by Gurdjian (
Post-mortem anatomical studies in humans have described the PVT as an unmyelinated, ovoid-shaped structure located along the most medial-dorsal portion of the thalamus (Uroz et al.,
Recent work in humans demonstrated discrete thalamo-cortical connectivity related to episode memory—showing medial thalamic engagement was selective to the retrieval phase of episodic memory (Pergola et al.,
The PVT has been implicated in depressive-, anxiety-, and fear-like behaviors (Li et al.,
All of these diverse and important functions of the PVT, position this region as a key brain node. Thus, understanding the functional connectivity of the PVT in the resting state is a prerequisite for future research to test cognitive and emotional functions of the PVT in both healthy individuals and in psychopathology.
To our knowledge, there is no prior work specifically examining resting state functional connectivity of the PVT using high-resolution 7T resting state functional magnetic resonance imaging (rsfMRI). The present study mapped the resting state functional connectivity of the PVT in a large sample of healthy young adults (
We analyzed 7T and 3T rsfMRI data from the publicly available HCP (Smith et al.,
The study was approved by Washington University in the St. Louis’ Human Research Protection Office (IRB #201204036). Written informed consent was obtained from all study participants. No study activities or procedures with human subjects took place at the authors’ institution. The current secondary analysis of the HCP data was deemed exempt from review by the Institutional Review Board of University of California, Irvine. All data were de-identified by HCP before public release and all HCP participants provided written informed consent to study procedures and data sharing outlined by HCP.
The 3T structural scan (T1 3D MPRAGE, TR = 2,400 ms, TE = 2.14 ms, flip angle = 8 degrees, FOV = 224 mm × 224 mm, 0.7 mm isotropic voxels). See
The HCP 7T rsfMRI data consisted of two, 16-minute functional scans [900 frames per run, 1.6 mm isotropic voxels, TR = 1000 ms, TE = 22.2 ms, flip angle = 45 degrees, FOV = 208 × 208 mm, 85 slices, multi-band factor = 5, image acceleration factor (iPAT) = 2; Smith et al.,
The HCP 3T rsfMRI consists of two, 15-min resting state scans (1,200 frames per run, 2.0 mm isotropic voxels, TR = 720 ms, TE = 33.1 ms, flip angle = 52 degrees, FOV = 208 × 180 mm, 72 slices, multi-band factor = 8; Smith et al.,
We utilized the “minimally preprocessed” datasets provided by the HCP 1200 Release (HCP filename: rfMRI*hp2000_clean.nii.gz), which includes gradient-nonlinearity-induced distortion correction, rigid body head motion correction, EPI image distortion correction, co-registration between the fMRI and structural data, normalization to MNI space, high-pass filtering (1/2,000 Hz), and brain masking (Glasser et al.,
We entered the minimally preprocessed structural images (HCP filenames: T1w_restore.1.60.nii.gz for 7T and T1w_restore_brain.nii.gz for 3T) and ICA-FIX functionals (rfMRI*hp2000_clean.nii.gz files) into separate projects for the 7T and 3T data using the CONN Toolbox Version 19c (Whitfield-Gabrieli and Nieto-Castanon,
The smoothing kernel sizes were chosen based on prior recommendations to select a kernel FWHM that is 2–3 times the functional voxel size (Mikl et al.,
Artifact identification was performed using Artifact Detection Tools (ART) implemented in CONN. We enforced conservative motion censoring thresholds, scrubbing frames exceeding > 0.5 mm frame-wise motion or Global Signal
The functional data were further denoised using the CONN Toolbox’s
We utilized 3D digital seed masks from the “Thalamus Atlas” of the Swiss Federal Institute of Technology (ETH) in Zurich and University of Zurich, Switzerland (Krauth et al.,
Thalamus seed regions entered into functional connectivity analyses.
To avoid the loss of small ROI information in the 1.6 mm and 2 mm functional spaces, the CONN Toolbox whole-brain seed-to-voxel analysis extracts and averages the BOLD timeseries from the closest corresponding voxels (e.g., 14 total voxels for the PVT) in the functional maps to correlate with the non-PVT voxels in the smoothed maps. This approach, as opposed to first resampling the small ROI subnuclei, guarantees an appropriate partial-volume weighting of the functional data and no loss of smaller ROIs like the PVT or the subnuclei.
The digitized subnuclei regions (e.g., PVT, CeM, CL, Pf) were received in standard MNI space. SPM12’s
The goal of the current study was to identify resting state functional connectivity of the PVT, with a focus on connectivity patterns that withstand controlling for signals from the rest of the thalamus or other nearby midline subnuclei. First, whole-brain standard bivariate correlations of the PVT alone were assessed separately in a seed-based functional connectivity (SBC) analysis. Next, multivariate seed-based connectivity (mSBC) was calculated as the semipartial correlation coefficients between the BOLD timeseries of the PVT and all other individual voxel timeseries in the brain after controlling for the BOLD timeseries of the other seeds (e.g., the rest of the thalamus in a first analysis and specific midline thalamic subnuclei in a separate second analysis; Whitfield-Gabrieli and Nieto-Castanon,
Group functional connectivity statistics were calculated as voxel-level cluster-inferences using TFCE (Smith and Nichols,
To quantify similarity of PVT functional connectivity with known large-scale cortical resting-state networks (Thomas Yeo et al.,
7T PVT functional connectivity. Positive (red) and negative (blue) functional connectivity of the PVT controlling for average signal from the rest of the thalamus. Results thresholded at
Circular graph summarizing positive functional connectivity of the PVT, controlling for the rest of the thalamus. Lines are color-coded by Fisher
Methods and results for identifying PVT functional connectivity macro-structures.
Controlling for the average signal from the remainder of the thalamus (i.e., thalamus without the PVT mask) using semi-partial correlations demarcated unique functional connectivity while controlling for average thalamic signal. However, to reveal functional connectivity that was stronger for the PVT compared to other midline areas we conducted further analyses comparing semi-partial PVT correlations individually to other nearby medial subnuclei (CeM, CL, and Pf, see
The TFCE maps used to identify significant voxels were binarized and then applied to the SBC unthresholded
The first analysis examined PVT functional connectivity that survived partial correlation with functional connectivity from the rest of the thalamus (i.e., the conjunction of the bivariate and semi-partial maps of PVT connectivity). The results of the 7T group analysis are shown in
Summary table of brain regions that show significant positive FC with the PVT, controlling for the rest of the thalamus (corresponds to positive FC results shown in
Lobe | Gyrus | Modified cyto-architectonic |
---|---|---|
Frontal | Middle frontal gyrus (MFG) | Area 46, dorsal area 9/46, lateral area 10, ventrolateral area 8. |
Orbital gyrus (OrG) | Area 13, orbital and lateral area 12/47 and medial 14, medial and lateral area 11 (including vmPFC). | |
Superior frontal gyrus (SFG) | Dorsolateral area 8, medial area 10, medial and lateral area 9 (including dmPFC). | |
Insular (INS) | Ventral agranular and granular insula. | |
Limbic | Cingulate gyrus (CG) | Subgenual area 32, pregenual area 32, caudal and dorsal area 23, rostroventral area 24, ventral area 23. |
Occipital | Cuneus (Cun) | Rostral cuneus gyrus, ventromedial parietooccipital sulcus. |
Parietal | Inferior parietal lobule (IPL), Angular gyrus | Caudal area 39, rostrodorsal area 39, rostroventral area 39. |
Precuneus (Pcun) | Area 31, dorsomedial parietooccipital sulcus, medial area 7. | |
Subcortical | Amygdala (Amyg) | Medial and lateral amygdala. |
Hippocampus (Hipp) | Caudal and rostral hippocampus. | |
Striatum (Str) | Dorsal and ventral caudate, nucleus accumbens, ventromedial putamen. | |
Temporal | Fusiform gyrus (FuG) | Rostroventral area 20, lateroventral area 37. |
Inferior temporal gyrus (ITG) | Intermediate lateral area 20, rostral area 20. | |
Middle temporal gyrus (MTG) | Anterior superior temporal sulcus, caudal area 21, rostral area 21. | |
Parahippocampal gyrus (PhG) | Area 28/34 (EC, entorhinal cortex), area TI (temporal agranular insular cortex), area TL (lateral PPHC, posterior parahippocampal gyrus), area TH (medial PPHC), caudal area 35/36. | |
Superior temporal gyrus (STG) | Medial and lateral areas 22 and 38 (temporal pole). | |
Other | Brainstem and midbrain | Bed nucleus of the stria terminalis (BNST), hypothalamus, periaqueductal gray (PAG), ventral tegmental area (VTA). |
TFCE analysis of only the SBC bivariate map of the PVT identified three large clusters with significant positive functional connectivity and two clusters with significant negative functional connectivity (see
As expected, positive functional connectivity was observed with portions of the brainstem, hypothalamus, and basal forebrain (see
In the striatum, unique positive functional connectivity of the PVT was observed in the NAc (see
Cortically, positive functional connectivity was observed in large swaths of the medial PFC, precuneus, and cingulate as well as the angular gyrus, middle and superior temporal gyrus, and the temporal pole. The coverage in the cingulate included the sub-genual cingulate area.
Negative functional connectivity was observed with portions of visual processing cortex (including the cuneus, lingual gyrus, superior and middle occipital gyri, lateral occipital cortex, fusiform gyrus, inferior temporal gyrus), superior parietal lobule, inferior parietal lobule (including the supramarginal and angular gyri), somato-motor areas (including the pre- and post-central gyrus), and ventro-lateral PFC/inferior frontal gyrus. Negative fluctuations were also observed with the insula, mostly in the dorsal dysgranular area. See activity displayed in blue in
We used cosine similarity analysis to determine which known intrinsic functional connectivity network (Thomas Yeo et al.,
Cosine similarity between binary vectors representing a 7-Network Parcellation of large-scale functional networks (Thomas Yeo et al.,
Thus far, the results report on significant PVT functional connectivity that survives controlling for functional connectivity of the control regions and represents unique functional connectivity. We next tested where PVT functional connectivity exceeded that of the control regions. Whole-brain comparisons of the semi-partial correlations for the PVT compared to the CeM, CL, and Pf, separately, showed greater positive PVT functional connectivity with the amygdala, hippocampus, ventromedial PFC/orbital frontal gyrus (Brodmann area 11) and dorsomedial PFC (Brodmann area 9 and 10), left lateral orbital frontal gyrus (Brodmann area 47), and middle temporal gyrus/temporal pole [see overlap of the three maps shown in white (left) and corresponding raincloud plots (right) in
A similar pattern was observed for the whole-brain comparison of PVT > Rest of the Thalamus (
Recognizing that the 3T FC maps are likely noisier than the 7T maps, we nonetheless sought to test the PVT functional connectivity in the 3T data of the same participants. Indeed, the positive FC 3T maps (shown in green in
3T PVT positive functional connectivity (green) showed with the 7T results (shown in red). Regions shown in yellow demarcate regions that showed positive FC in both the 7T and 3T datasets. Each maps controls for the average signal from the rest of the thalamus. All results thresholded at
All thresholded and unthresholded 3T and 7T maps can be viewed in
The present study utilized high-quality, long-duration, high-resolution 7T rsfMRI data from The Human Connectome Project in conjunction with thalamic subnuclei masks derived from multiple-histological data to demarcate resting state functional connectivity patterns of the human PVT. We observed pronounced PVT functional connectivity with the brainstem, midbrain, ventral striatum, MTL (including the hippocampus and amygdala), cingulate, mPFC, and lateral temporal cortex. The principal findings of the current study are that resting human PVT functional connectivity shows: (1) substantial overlap with the known anatomical and functional connectivity shown in animal PVT, (2) distinctive connectivity patterns with subcortical and cortical structures compared to the average thalamus signal and other nearby midline-thalamic regions, and (3) appears to be linked at rest with the DMN. These findings are largely consistent with the known structural and functional connectivity of the PVT in experimental animals, highlights important cortical nodes in humans, and additionally situates the PVT within the resting DMN. Here we discuss the results of PVT functional connectivity with specific brain regions and networks as well as potential relevance to psychopathology.
The PVT showed positive resting functional connectivity with the hypothalamus at coordinates corresponding to the lateral and medial hypothalamus (Baroncini et al.,
As expected, the PVT was functionally connected with the NAc. PVT-NAc connections are thought to be associated with reward and motivation (Barson et al.,
The functional connectivity of the PVT with the hippocampus and amygdala was consistently implicated in all analyses, including the whole-brain comparisons of FC strength compared to that of the nearby subnuclei control regions. These findings are aligned with prior work showing dense connectivity between the PVT and the hippocampus and amygdala and contribute to accumulating evidence that the PVT is functionally well-positioned to subserve emotional memory functions (Su and Bentivoglio,
The amygdala, particularly the central amygdala, is a major PVT target (Li and Kirouac,
The positive functional connectivity maps also covered large swaths of medial PFC, including vmPFC/medial orbital cortex, dmPFC, subgenual area 25 and dorsal areas of the anterior cingulate, In rodents and non-human primates, the PVT has strong reciprocal connections with the IL and PL (medial PFC; Chiba et al.,
Consistent with prior work, we observed PVT functional connectivity with the anterior agranular insula (Berendse and Groenewegen,
In addition to positive functional coupling with discrete brain regions, we investigated the possibility that the PVT is functionally linked with distinct, intrinsic macrostructures, such as the DMN, a network strongly associated with self-referential thought/affective decisions as well as episodic memory retrieval, and the subjective experience of memory (Andrews-Hanna et al.,
Here, we used the cortical network parcellations by Thomas Yeo and colleagues (Thomas Yeo et al.,
Notably, the PVT showed greater functional connectivity in DMN+ regions compared to the CeM and Pf (see activity in cool colors in
Several recent frameworks have placed the PVT within the DMN. Given anterior thalamic lesion evidence of memory deficits, the anterior thalamic nuclei have been previously situated with the DMN in a network called the Posterior Medial System (Ranganath and Ritchey,
The PVT has been implicated in depressive-, anxiety-, and fear-like behaviors (Li et al.,
There are several limitations to our study and caveats to bear in mind when interpreting the present results. First, due to the atlas-construction process implemented by Krauth et al. (
The current work used a large sample of high-quality, long-duration fMRI data from The Human Connectome Project to map the resting FC of the PVT at the highest available 7T resolution with the aim of bridging the work for investigators using 3T MRI scanners. For future 3T fMRI work using the PVT seed from Krauth et al. (
Future work will capitalize on this study to determine PVT functional connectivity separately in men and women. The developmental profile of PVT connectivity, as well as changes with aging, requires examination. Importantly, establishment of global or specific alterations of the PVT connectivity map in the context of affective and cognitive disorders should be a major focus of future work, and will strongly benefit from the normative data provided here.
The thalamus is classically known for its role in relaying sensory information, but accumulating evidence in animals and humans converge on discrete roles of the subnuclei of the midline thalamus (Van der Werf et al.,
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: The 3D results Nifti file masks generated for this study can be found in the Open Science Framework (OSF) at:
The study was approved by Washington University in the St. Louis’ Human Research Protection Office (IRB #201204036). Written informed consent was obtained from all study participants. No study activities or procedures with human subjects took place at the authors’ institution. The current secondary analysis of the HCP data was deemed exempt from review by the Institutional Review Board of University of California, Irvine. All data were de-identified by HCP before public release and all HCP participants provided written informed consent to study procedures and data sharing outlined by HCP.
SMK, TZB, and MAY conceived the design of the study. SMK processed and analyzed the data. SMK and MAY interpreted the results. SMK wrote the article with input from TZB, MTB, and MAY who provided critical revision and feedback. All authors contributed to the article and approved the submitted version.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Data were provided (in part) by the Human Connectome Project, WU-Minn Consortium (Principal Investigators: David Van Essen and Kamil Ugurbil; 1U54MH091657) funded by the 16 NIH Institutes and Centers that support the NIH Blueprint for Neuroscience Research; and by the McDonnell Center for Systems Neuroscience at Washington University. We are grateful to the UCI Translational Neuroscience Laboratory and UC Irvine, particularly John Janecek for his assistance with data processing and management and Dr. Luis Colon-Perez for his thoughtful discussions and suggestions.
The Supplementary Material for this article can be found online at:
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