Computational modeling of threat learning reveals links with anxiety and neuroanatomy in humans
Abstract
Influential theories implicate variations in the mechanisms supporting threat learning in the severity of anxiety symptoms. We use computational models of associative learning in conjunction with structural imaging to explicate links among the mechanisms underlying threat learning, their neuroanatomical substrates, and anxiety severity in humans. We recorded skin-conductance data during a threat-learning task from individuals with and without anxiety disorders (N=251; 8-50 years; 116 females). Reinforcement-learning model variants quantified processes hypothesized to relate to anxiety: threat conditioning, threat generalization, safety learning, and threat extinction. We identified the best-fitting models for these processes and tested associations among latent learning parameters, whole-brain anatomy, and anxiety severity. Results indicate that greater anxiety severity related specifically to slower safety learning and slower extinction of response to safe stimuli. Nucleus accumbens gray-matter volume moderated learning-anxiety associations. Using a modeling approach, we identify computational mechanisms linking threat learning and anxiety severity and their neuroanatomical substrates.
Data availability
We cannot share the full dataset due to the NIH IRB requirements, which require participants to explicitly consent to their data being shared publicly. An important element in that is to protect patients who agree to participate in studies that relate to their psychopathology. Such consent was not acquired from most participants; as such, we cannot upload our complete dataset in its raw or deidentified form, or derivatives of the data, since we will be violating IRB protocols. Still, a subset of participants did consent to data sharing and we have uploaded their data as noted in the revised manuscript (https://github.com/rany-abend/threat_learning_eLife). Researchers interested in potentially acquiring access to the data could contact Dr. Daniel Pine (pined@mail.nih.gov), Chief of the Emotion and Development Branch at NIH, with a research proposal; as per IRB rules, the IRB may approve adding such researchers as Associate Investigators if a formal collaboration is initiated. No commercial use of the data is a lowed. The modeling and imaging analyses have now been uploaded in full as source code files.
Article and author information
Author details
Funding
National Institutes of Health (ZIAMH002781-15)
- Daniel S Pine
National Institutes of Health (R00MH091183)
- Jennifer C Britton
Brain and Behavior Research Foundation (28239)
- Rany Abend
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Human Subjects: Yes Ethics Statement: Written informed consent was obtained from adult (greater than or equal to 18 years) participants as we l as parents, and written assent was obtained from youth. Procedures were approved by the NIMH Institutional Review Board (protocol 01-M-0192).
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Metrics
-
- 2,346
- views
-
- 402
- downloads
-
- 8
- 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
-
- Computational and Systems Biology
- Genetics and Genomics
Root causal gene expression levels – or root causal genes for short – correspond to the initial changes to gene expression that generate patient symptoms as a downstream effect. Identifying root causal genes is critical towards developing treatments that modify disease near its onset, but no existing algorithms attempt to identify root causal genes from data. RNA-sequencing (RNA-seq) data introduces challenges such as measurement error, high dimensionality and non-linearity that compromise accurate estimation of root causal effects even with state-of-the-art approaches. We therefore instead leverage Perturb-seq, or high-throughput perturbations with single-cell RNA-seq readout, to learn the causal order between the genes. We then transfer the causal order to bulk RNA-seq and identify root causal genes specific to a given patient for the first time using a novel statistic. Experiments demonstrate large improvements in performance. Applications to macular degeneration and multiple sclerosis also reveal root causal genes that lie on known pathogenic pathways, delineate patient subgroups and implicate a newly defined omnigenic root causal model.
-
- Computational and Systems Biology
Artificial intelligence (AI) models have been used to study the compositional regularities of proteins in nature, enabling it to assist in protein design to improve the efficiency of protein engineering and reduce manufacturing cost. However, in industrial settings, proteins are often required to work in extreme environments where they are relatively scarce or even non-existent in nature. Since such proteins are almost absent in the training datasets, it is uncertain whether AI model possesses the capability of evolving the protein to adapt extreme conditions. Antibodies are crucial components of affinity chromatography, and they are hoped to remain active at the extreme environments where most proteins cannot tolerate. In this study, we applied an advanced large language model (LLM), the Pro-PRIME model, to improve the alkali resistance of a representative antibody, a VHH antibody capable of binding to growth hormone. Through two rounds of design, we ensured that the selected mutant has enhanced functionality, including higher thermal stability, extreme pH resistance, and stronger affinity, thereby validating the generalized capability of the LLM in meeting specific demands. To the best of our knowledge, this is the first LLM-designed protein product, which is successfully applied in mass production.