Neuropsychological evidence of multi-domain network hubs in the human thalamus
Abstract
Hubs in the human brain support behaviors that arise from brain network interactions. Previous studies have identified hub regions in the human thalamus that are connected with multiple functional networks. However, the behavioral significance of thalamic hubs has yet to be established. Our framework predicts that thalamic subregions with strong hub properties are broadly involved in functions across multiple cognitive domains. To test this prediction, we studied human patients with focal thalamic lesions in conjunction with network analyses of the human thalamocortical functional connectome. In support of our prediction, lesions to thalamic subregions with stronger hub properties were associated with widespread deficits in executive, language, and memory functions, whereas lesions to thalamic subregions with weaker hub properties were associated with more limited deficits. These results highlight how a large-scale network model can broaden our understanding of thalamic function for human cognition.
Data availability
We have made all code and lesion-derived measures used in the manuscript freely available on github (https://github.com/kaihwang/LTH), including neuropsych assessment outcome, derivatives from lesion analyses, data used for functional connectivity analyses, and mRNA expression analyses. Functional connectivity analyses utilized publicly available datasets (Holmes et al., 2015; Nooner et al., 2012). The only data that we cannot post without restrictions are each patient's clinical MRI data and lesion data. Patients were enrolled into the Iowa Lesion Patient Registry the past few decades, and most did not consent to post their clinical MRI data publicly. To gain access to those data, the interested party will have to contact the PI of the lesion registry, Dr. Dan Tranel, and the corresponding author of this project, Dr. Kai Hwang. The user will require to sign a data use agreement. This institutional policy was designed to ensure the appropriate use of the data for academic and not commercial purposes. A study plan of the proposed research will have to be submitted, and we will work with the interested party to obtain the necessary IRB approval from both institutions.
-
Brain Genomics Superstruct ProjectBrain Genomics Superstruct Project initial data release with structural, functional, and behavioral measures.
-
NKI-Rockland sampleThe enhanced Nathan Kline Institute-Rockland Sample (NKI-RS).
Article and author information
Author details
Funding
National Institutes of Health (R01MH122613)
- Kai Hwang
- Daniel Tranel
- Aaron Boes
National Institutes of Health (RO1MH117772)
- James M Shine
National Institutes of Health (P50MH094258)
- Daniel Tranel
Kiwanis Neuroscience Research Foundation
- Daniel Tranel
National Institutes of Health (R01NS114405)
- Aaron Boes
National Institutes of Health (R21MH120441)
- Aaron Boes
National Health and Medical Research Council (GNT1156536)
- James M Shine
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: All participants gave written informed consent, and the study was approved by the University of Iowa Institutional Review Board (protocol #200105018).
Copyright
© 2021, Hwang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,605
- views
-
- 272
- downloads
-
- 34
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Neuroscience
The concept that dimeric protein complexes in synapses can sequentially replace their subunits has been a cornerstone of Francis Crick’s 1984 hypothesis, explaining how long-term memories could be maintained in the face of short protein lifetimes. However, it is unknown whether the subunits of protein complexes that mediate memory are sequentially replaced in the brain and if this process is linked to protein lifetime. We address these issues by focusing on supercomplexes assembled by the abundant postsynaptic scaffolding protein PSD95, which plays a crucial role in memory. We used single-molecule detection, super-resolution microscopy and MINFLUX to probe the molecular composition of PSD95 supercomplexes in mice carrying genetically encoded HaloTags, eGFP, and mEoS2. We found a population of PSD95-containing supercomplexes comprised of two copies of PSD95, with a dominant 12.7 nm separation. Time-stamping of PSD95 subunits in vivo revealed that each PSD95 subunit was sequentially replaced over days and weeks. Comparison of brain regions showed subunit replacement was slowest in the cortex, where PSD95 protein lifetime is longest. Our findings reveal that protein supercomplexes within the postsynaptic density can be maintained by gradual replacement of individual subunits providing a mechanism for stable maintenance of their organization. Moreover, we extend Crick’s model by suggesting that synapses with slow subunit replacement of protein supercomplexes and long-protein lifetimes are specialized for long-term memory storage and that these synapses are highly enriched in superficial layers of the cortex where long-term memories are stored.
-
- Medicine
- Neuroscience
The advent of midazolam holds profound implications for modern clinical practice. The hypnotic and sedative effects of midazolam afford it broad clinical applicability. However, the specific mechanisms underlying the modulation of altered consciousness by midazolam remain elusive. Herein, using pharmacology, optogenetics, chemogenetics, fiber photometry, and gene knockdown, this in vivo research revealed the role of locus coeruleus (LC)-ventrolateral preoptic nucleus noradrenergic neural circuit in regulating midazolam-induced altered consciousness. This effect was mediated by α1 adrenergic receptors. Moreover, gamma-aminobutyric acid receptor type A (GABAA-R) represents a mechanistically crucial binding site in the LC for midazolam. These findings will provide novel insights into the neural circuit mechanisms underlying the recovery of consciousness after midazolam administration and will help guide the timing of clinical dosing and propose effective intervention targets for timely recovery from midazolam-induced loss of consciousness.