Global effects in fMRI reveal brain markers of state and trait anxiety

Background To personalize the diagnosis and treatment of anxiety, there is a need to identify biological constructs that underlie self-reported symptoms. Notably, physiological responses and altered levels of arousal are constituents of anxiety and have widespread (“global”) effects on fMRI signals across the brain. Therefore, fMRI signatures of global cortical arousal and autonomic physiological responses may provide valuable neuroimaging biomarkers of anxiety. Additionally, these effects may also contribute to relationships observed between large scale network dynamics and anxiety level.

Drawing upon data from a large community sample of 543 subjects (F= 369, M=174) we examine whether the global mean fMRI signal, and a data-driven estimate of cortical arousal effects in fMRI, relate to state and trait anxiety. Additionally, we investigate if autonomic physiological measures (heart rate) in fMRI patterns relate to state and trait anxiety in a subsample of these subjects (240 subjects; F=154, M=86). Finally, we investigate if these three global fMRI effects influence the relationship between functional brain network connectivity and state and trait anxiety.

We observe that the spatial patterns of the global mean fMRI signal and the cortical arousal-related fMRI signal related to both state and trait anxiety. These results support current theories that cortical arousal is closely tied to the anxious experience. Additionally, we observe that global component regression had variable effects on the relationship between anxiety and brain networks.

These findings suggest that global effects in fMRI signals hold valuable information about both state and trait anxiety. These observations also underscore the importance of understanding global fMRI effects as a source of information as opposed to a confound. Competing Interest Statement M.W.- is a member of the advisory boards and gave presentations for the following companies: HMNC, Janssen Pharmaceutical Research, Novartis, Boehringer Ingelheim, Germany; Bayer AG, Germany; and Biologische Heilmittel Heel GmbH, Germany. MW has further conducted studies with institutional research support from HEEL and from Janssen Pharmaceutical Research for a clinical trial (IIT) on ketamine in patients with major depression unrelated to this investigation. Funding Statement This study was funded by NIH grants T32 MH064913 (KRO) and T32AG058524/F99AG079810 Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used openly available data set from the Nathan Klein Institute Rockland sample. The fMRI and heart rate measures were fully open source and available publicly. We did apply to receive participants state and trait anxiety scores. Ethics committee/IRB of Nathan Klein Institute gave ethical approval for us to download and use the state and trait data for our investigation. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced are available online at https://fcon_1000.projects.nitrc.org/indi/enhanced/access.html https://fcon_1000.projects.nitrc.org/indi/enhanced/access.html