Advertisement

Angiotensin II regulates the neural expression of subjective fear in humans - precision pharmaco-neuroimaging approach

  • Ran Zhang
    Affiliations
    Center of Psychosomatic Medicine, Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China

    MOE Key Laboratory for Neuroinformation, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
    Search for articles by this author
  • Weihua Zhao
    Affiliations
    MOE Key Laboratory for Neuroinformation, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
    Search for articles by this author
  • Ziyu Qi
    Affiliations
    Center of Psychosomatic Medicine, Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China

    MOE Key Laboratory for Neuroinformation, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
    Search for articles by this author
  • Ting Xu
    Affiliations
    Center of Psychosomatic Medicine, Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China

    MOE Key Laboratory for Neuroinformation, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
    Search for articles by this author
  • Feng Zhou
    Correspondence
    Correspondence to Feng Zhou, Southwest University, Tian Sheng RD, No.2, Beibei, ChongQing, 400715, China
    Affiliations
    Faculty of Psychology, Southwest University, ChongQing, China

    Key Laboratory of Cognition and Personality, Ministry of Education, ChongQing, China
    Search for articles by this author
  • Benjamin Becker
    Correspondence
    Correspondence to Benjamin Becker, University of Electronic Science and Technology, Xiyuan Avenue 2006, 611731 Chengdu, China
    Affiliations
    Center of Psychosomatic Medicine, Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China

    MOE Key Laboratory for Neuroinformation, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
    Search for articles by this author
Published:September 26, 2022DOI:https://doi.org/10.1016/j.bpsc.2022.09.008

      Abstract

      Background

      Rodent models and pharmacological neuroimaging studies in humans have been employed to test novel pharmacological agents to reduce fear. However, these strategies are limited with respect to determining process-specific effects on the actual subjective experience of fear which represents the key symptom why patients seek treatment. We here employed a novel precision pharmacological fMRI approach that is based on process-specific neuro affective signatures to determine effects of the selective angiotensin II type 1 receptor (ATR1) antagonist losartan on the subjective experience of fear.

      Methods

      In a double-blind, placebo-controlled randomized pharmacological fMRI design n = 87 healthy participants were administered 50mg losartan or placebo before they underwent an oddball paradigm which included neutral, novel and fear oddballs. Losartan effects on brain activity and connectivity as well as on process-specific multivariate neural signatures were examined.

      Results

      AT1R blockade selectively reduces the neurofunctional reactivity to fear-inducing visual oddballs in terms of attenuating dorsolateral prefrontal activity and amygdala-ventral anterior cingulate (vACC) communication. Neurofunctional decoding further demonstrates fear-specific effects given that ATR1 blockade (
      • Kessler R.C.
      • Berglund P.
      • Demler O.
      • Jin R.
      • Merikangas K.R.
      • Walters E.E.
      Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication.
      ) reduces the neural expression of subjective fear, but not threat or non-specific negative expressions, and (
      • Correll C.U.
      • Solmi M.
      • Veronese N.
      • Bortolato B.
      • Rosson S.
      • Santonastaso P.
      • et al.
      Prevalence, incidence and mortality from cardiovascular disease in patients with pooled and specific severe mental illness: a large‐scale meta‐analysis of 3,211,768 patients and 113,383,368 controls.
      ) does not affect reactivity to novel oddballs.

      Conclusions

      These results show a specific role of the AT1R in regulating subjective fear experience and demonstrate the feasibility of a precision pharmacological fMRI approach to the affective characterization of novel receptor targets for fear in humans.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      References

        • Kessler R.C.
        • Berglund P.
        • Demler O.
        • Jin R.
        • Merikangas K.R.
        • Walters E.E.
        Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication.
        Archives of general psychiatry. 2005; 62: 593-602
        • Correll C.U.
        • Solmi M.
        • Veronese N.
        • Bortolato B.
        • Rosson S.
        • Santonastaso P.
        • et al.
        Prevalence, incidence and mortality from cardiovascular disease in patients with pooled and specific severe mental illness: a large‐scale meta‐analysis of 3,211,768 patients and 113,383,368 controls.
        World Psychiatry. 2017; 16: 163-180
        • Santomauro D.F.
        • Herrera A.M.M.
        • Shadid J.
        • Zheng P.
        • Ashbaugh C.
        • Pigott D.M.
        • et al.
        Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic.
        The Lancet. 2021; 398: 1700-1712
        • Farach F.J.
        • Pruitt L.D.
        • Jun J.J.
        • Jerud A.B.
        • Zoellner L.A.
        • Roy-Byrne P.P.
        Pharmacological treatment of anxiety disorders: Current treatments and future directions.
        Journal of anxiety disorders. 2012; 26: 833-843
        • Insel T.R.
        • Wang P.S.
        The STAR* D trial: revealing the need for better treatments.
        Psychiatric services. 2009; 60: 1466-1467
      1. Liu X, Klugah-Brown B, Zhang R, Zhang J, Becker B. Distinct neurostructural signatures of anxiety-, fear-related and depressive disorders: a comparative voxel-based meta-analysis. medRxiv. 2021.

        • Garcia R.
        Neurobiology of fear and specific phobias.
        Learning & Memory. 2017; 24: 462-471
        • Milad M.R.
        • Rauch S.L.
        • Pitman R.K.
        • Quirk G.J.
        Fear extinction in rats: implications for human brain imaging and anxiety disorders.
        Biological psychology. 2006; 73: 61-71
      2. Becker B, Zhou F. Neural Processing of Fear–From Animal Models to Human Research. 2022.

        • Paulus M.P.
        • Stein M.B.
        Role of functional magnetic resonance imaging in drug discovery.
        Neuropsychology review. 2007; 17: 179-188
        • Marvar P.J.
        • Andero R.
        • Hurlemann R.
        • Lago T.R.
        • Zelikowsky M.
        • Dabrowska J.
        Limbic neuropeptidergic modulators of emotion and their therapeutic potential for anxiety and post-traumatic stress disorder.
        Journal of neuroscience. 2021; 41: 901-910
        • Quintana D.S.
        • Lischke A.
        • Grace S.
        • Scheele D.
        • Ma Y.
        • Becker B.
        Advances in the field of intranasal oxytocin research: lessons learned and future directions for clinical research.
        Molecular Psychiatry. 2021; 26: 80-91
        • Reinecke A.
        • Browning M.
        • Breteler J.K.
        • Kappelmann N.
        • Ressler K.J.
        • Harmer C.J.
        • et al.
        Angiotensin regulation of amygdala response to threat in high-trait-anxiety individuals.
        Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. 2018; 3: 826-835
        • Chrissobolis S.
        • Luu A.N.
        • Waldschmidt R.A.
        • Yoakum M.E.
        • D'Souza M.S.
        Targeting the renin angiotensin system for the treatment of anxiety and depression.
        Pharmacology Biochemistry and Behavior. 2020; 199173063
        • Morrison F.G.
        • Ressler K.J.
        From the neurobiology of extinction to improved clinical treatments.
        Depression and anxiety. 2014; 31: 279-290
        • Seligowski A.V.
        • Duffy L.A.
        • Merker J.B.
        • Michopoulos V.
        • Gillespie C.F.
        • Marvar P.J.
        • et al.
        The renin–angiotensin system in PTSD: a replication and extension.
        Neuropsychopharmacology. 2021; 46: 750-755
        • Marvar P.J.
        • Goodman J.
        • Fuchs S.
        • Choi D.C.
        • Banerjee S.
        • Ressler K.J.
        Angiotensin type 1 receptor inhibition enhances the extinction of fear memory.
        Biological psychiatry. 2014; 75: 864-872
        • Zhou F.
        • Geng Y.
        • Xin F.
        • Li J.
        • Feng P.
        • Liu C.
        • et al.
        Human extinction learning is accelerated by an angiotensin antagonist via ventromedial prefrontal cortex and its connections with basolateral amygdala.
        Biological psychiatry. 2019; 86: 910-920
      3. Xu T, Zhou X, Jiao G, Zeng Y, Zhao W, Li J, et al. Angiotensin antagonist inhibits preferential negative memory encoding via decreasing hippocampus activation and its coupling with amygdala. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. 2022.

        • Mihov Y.
        • Kendrick K.M.
        • Becker B.
        • Zschernack J.
        • Reich H.
        • Maier W.
        • et al.
        Mirroring fear in the absence of a functional amygdala.
        Biological Psychiatry. 2013; 73: e9-e11
        • Janak P.H.
        • Tye K.M.
        From circuits to behaviour in the amygdala.
        Nature. 2015; 517: 284-292
        • LeDoux J.E.
        • Pine D.S.
        Using neuroscience to help understand fear and anxiety: a two-system framework.
        American journal of psychiatry. 2016;
        • Zhou F.
        • Zhao W.
        • Qi Z.
        • Geng Y.
        • Yao S.
        • Kendrick K.M.
        • et al.
        A distributed fMRI-based signature for the subjective experience of fear.
        Nature communications. 2021; 12: 1-16
        • Woo C.-W.
        • Chang L.J.
        • Lindquist M.A.
        • Wager T.D.
        Building better biomarkers: brain models in translational neuroimaging.
        Nature neuroscience. 2017; 20: 365-377
        • Taschereau-Dumouchel V.
        • Michel M.
        • Lau H.
        • Hofmann S.G.
        • LeDoux J.E.
        Putting the “mental” back in “mental disorders”: a perspective from research on fear and anxiety.
        Molecular Psychiatry. 2022; : 1-9
        • Poldrack R.A.
        • Baker C.I.
        • Durnez J.
        • Gorgolewski K.J.
        • Matthews P.M.
        • Munafò M.R.
        • et al.
        Scanning the horizon: towards transparent and reproducible neuroimaging research.
        Nature reviews neuroscience. 2017; 18: 115-126
        • Xin F.
        • Zhou X.
        • Dong D.
        • Zhao Z.
        • Yang X.
        • Wang Q.
        • et al.
        Oxytocin Differentially Modulates Amygdala Responses during Top‐Down and Bottom‐Up Aversive Anticipation.
        Advanced Science. 2020; 72001077
        • Paulus M.P.
        • Stein M.B.
        • Simmons A.N.
        • Risbrough V.B.
        • Halter R.
        • Chaplan S.R.
        The effects of FAAH inhibition on the neural basis of anxiety-related processing in healthy male subjects: a randomized clinical trial.
        Neuropsychopharmacology. 2021; 46: 1011-1019
        • Geng Y.
        • Zhao W.
        • Zhou F.
        • Ma X.
        • Yao S.
        • Becker B.
        • et al.
        Oxytocin facilitates empathic-and self-embarrassment ratings by attenuating amygdala and anterior insula responses.
        Frontiers in endocrinology. 2018; : 572
        • Ma X.
        • Zhao W.
        • Luo R.
        • Zhou F.
        • Geng Y.
        • Xu L.
        • et al.
        Sex-and context-dependent effects of oxytocin on social sharing.
        Neuroimage. 2018; 183: 62-72
        • Becker B.
        • Mihov Y.
        • Scheele D.
        • Kendrick K.M.
        • Feinstein J.S.
        • Matusch A.
        • et al.
        Fear processing and social networking in the absence of a functional amygdala.
        Biological psychiatry. 2012; 72: 70-77
        • Anderson A.K.
        • Phelps E.A.
        Is the human amygdala critical for the subjective experience of emotion? Evidence of intact dispositional affect in patients with amygdala lesions.
        Journal of cognitive neuroscience. 2002; 14: 709-720
        • Zhao Z.
        • Yao S.
        • Li K.
        • Sindermann C.
        • Zhou F.
        • Zhao W.
        • et al.
        Real-time functional connectivity-informed neurofeedback of amygdala-frontal pathways reduces anxiety.
        Psychotherapy and psychosomatics. 2019; 88: 5-15
        • Diemer J.
        • Zwanzger P.
        • Fohrbeck I.
        • Zavorotnyy M.
        • Notzon S.
        • Silling K.
        • et al.
        Influence of single-dose quetiapine on fear network activity–A pharmaco-imaging study.
        Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2017; 76: 80-87
        • Kragel P.A.
        • Koban L.
        • Barrett L.F.
        • Wager T.D.
        Representation, pattern information, and brain signatures: from neurons to neuroimaging.
        Neuron. 2018; 99: 257-273
        • Wager T.D.
        • Atlas L.Y.
        • Lindquist M.A.
        • Roy M.
        • Woo C.-W.
        • Kross E.
        An fMRI-based neurologic signature of physical pain.
        New England Journal of Medicine. 2013; 368: 1388-1397
        • Chang L.J.
        • Gianaros P.J.
        • Manuck S.B.
        • Krishnan A.
        • Wager T.D.
        A sensitive and specific neural signature for picture-induced negative affect.
        PLoS biology. 2015; 13e1002180
        • Reddan M.C.
        • Wager T.D.
        • Schiller D.
        Attenuating neural threat expression with imagination.
        Neuron. 2018; 100 (e4): 994-1005
        • Huettel S.A.
        • McCarthy G.
        What is odd in the oddball task?: Prefrontal cortex is activated by dynamic changes in response strategy.
        Neuropsychologia. 2004; 42: 379-386
        • Genaro K.
        • Juliano M.A.
        • Prado W.A.
        • Brandão M.L.
        • Martins A.R.
        Effects of angiotensin (5-8) microinfusions into the ventrolateral periaqueductal gray on defensive behaviors in rats.
        Behavioural brain research. 2013; 256: 537-544
        • Swiercz A.P.
        • Iyer L.
        • Yu Z.
        • Edwards A.
        • Prashant N.
        • Nguyen B.N.
        • et al.
        Evaluation of an angiotensin Type 1 receptor blocker on the reconsolidation of fear memory.
        Translational psychiatry. 2020; 10: 1-12
        • Winter A.
        • Ahlbrand R.
        • Sah R.
        Recruitment of central angiotensin II type 1 receptor associated neurocircuits in carbon dioxide associated fear.
        Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2019; 92: 378-386
        • Pulcu E.
        • Shkreli L.
        • Holst C.G.
        • Woud M.L.
        • Craske M.G.
        • Browning M.
        • et al.
        The effects of the angiotensin II receptor antagonist losartan on appetitive versus aversive learning: a randomized controlled trial.
        Biological psychiatry. 2019; 86: 397-404
        • Lo M.W.
        • Goldberg M.R.
        • McCrea J.B.
        • Lu H.
        • Furtek C.I.
        • Bjornsson T.D.
        Pharmacokinetics of losartan, an angiotensin II receptor antagonist, and its active metabolite EXP3174 in humans.
        Clinical Pharmacology & Therapeutics. 1995; 58: 641-649
        • Ohtawa M.
        • Takayama F.
        • Saitoh K.
        • Yoshinaga T.
        • Nakashima M.
        Pharmacokinetics and biochemical efficacy after single and multiple oral administration of losartan, an orally active nonpeptide angiotensin II receptor antagonist, in humans.
        British journal of clinical pharmacology. 1993; 35: 290-297
        • Marchewka A.
        • Ł Żurawski
        • Jednoróg K.
        • Grabowska A.
        The Nencki Affective Picture System (NAPS): Introduction to a novel, standardized, wide-range, high-quality, realistic picture database.
        Behavior research methods. 2014; 46: 596-610
      4. Penny W, Henson R. Analysis of variance. Statistical parametric mapping: The analysis of functional brain images. 2006: 166-177.

        • LeDoux J.E.
        Coming to terms with fear.
        Proceedings of the National Academy of Sciences. 2014; 111: 2871-2878
        • McLaren D.G.
        • Ries M.L.
        • Xu G.
        • Johnson S.C.
        A generalized form of context-dependent psychophysiological interactions (gPPI): A comparison to standard approaches.
        NeuroImage. 2012; 61: 1277-1286
        • Beauregard M.
        • Lévesque J.
        • Bourgouin P.
        Neural correlates of conscious self-regulation of emotion.
        Journal of Neuroscience. 2001; 21: RC165-RC
        • Ochsner K.N.
        • Bunge S.A.
        • Gross J.J.
        • Gabrieli J.D.
        Rethinking feelings: an FMRI study of the cognitive regulation of emotion.
        Journal of cognitive neuroscience. 2002; 14: 1215-1229
        • Lévesque J.
        • Eugene F.
        • Joanette Y.
        • Paquette V.
        • Mensour B.
        • Beaudoin G.
        • et al.
        Neural circuitry underlying voluntary suppression of sadness.
        Biological psychiatry. 2003; 53: 502-510
        • Ochsner K.N.
        • Ray R.D.
        • Cooper J.C.
        • Robertson E.R.
        • Chopra S.
        • Gabrieli J.D.
        • et al.
        For better or for worse: neural systems supporting the cognitive down-and up-regulation of negative emotion.
        Neuroimage. 2004; 23: 483-499
        • Phan K.L.
        • Taylor S.F.
        • Welsh R.C.
        • Ho S.-H.
        • Britton J.C.
        • Liberzon I.
        Neural correlates of individual ratings of emotional salience: a trial-related fMRI study.
        Neuroimage. 2004; 21: 768-780
        • Kim S.H.
        • Hamann S.
        Neural correlates of positive and negative emotion regulation.
        Journal of cognitive neuroscience. 2007; 19: 776-798
        • Delgado M.R.
        • Nearing K.I.
        • LeDoux J.E.
        • Phelps E.A.
        Neural circuitry underlying the regulation of conditioned fear and its relation to extinction.
        Neuron. 2008; 59: 829-838
        • Zhuang Q.
        • Xu L.
        • Zhou F.
        • Yao S.
        • Zheng X.
        • Zhou X.
        • et al.
        Segregating domain-general from emotional context-specific inhibitory control systems-ventral striatum and orbitofrontal cortex serve as emotion-cognition integration hubs.
        NeuroImage. 2021; 238118269
        • Liu C.
        • Dai J.
        • Chen Y.
        • Qi Z.
        • Xin F.
        • Zhuang Q.
        • et al.
        Disorder-and emotional context-specific neurofunctional alterations during inhibitory control in generalized anxiety and major depressive disorder.
        NeuroImage: Clinical. 2021; 30102661
        • Sagliano L.
        • D’Olimpio F.
        • Izzo L.
        • Trojano L.
        The effect of bicephalic stimulation of the dorsolateral prefrontal cortex on the attentional bias for threat: A transcranial direct current stimulation study.
        Cognitive, Affective, & Behavioral Neuroscience. 2017; 17: 1048-1057
        • Peers P.V.
        • Simons J.S.
        • Lawrence A.D.
        Prefrontal control of attention to threat.
        Frontiers in human neuroscience. 2013; 7: 24
        • Clarke P.J.
        • Van Bockstaele B.
        • Marinovic W.
        • Howell J.A.
        • Boyes M.E.
        • Notebaert L.
        The effects of left DLPFC tDCS on emotion regulation, biased attention, and emotional reactivity to negative content.
        Cognitive, Affective, & Behavioral Neuroscience. 2020; 20: 1323-1335
        • Kroes M.C.
        • Dunsmoor J.E.
        • Hakimi M.
        • Oosterwaal S.
        • collaboration N.P.
        • Meager M.R.
        • et al.
        Patients with dorsolateral prefrontal cortex lesions are capable of discriminatory threat learning but appear impaired in cognitive regulation of subjective fear.
        Social cognitive and affective neuroscience. 2019; 14: 601-612
        • Ironside M.
        • O’Shea J.
        • Cowen P.J.
        • Harmer C.J.
        Frontal cortex stimulation reduces vigilance to threat: implications for the treatment of depression and anxiety.
        Biological psychiatry. 2016; 79: 823-830
        • Deng J.
        • Fang W.
        • Gong Y.
        • Bao Y.
        • Li H.
        • Su S.
        • et al.
        Augmentation of fear extinction by theta-burst transcranial magnetic stimulation of the prefrontal cortex in humans.
        Journal of Psychiatry and Neuroscience. 2021; 46: E292-E302
        • Kober H.
        • Barrett L.F.
        • Joseph J.
        • Bliss-Moreau E.
        • Lindquist K.
        • Wager T.D.
        Functional grouping and cortical–subcortical interactions in emotion: a meta-analysis of neuroimaging studies.
        NeuroImage. 2008; 42: 998-1031
        • Toyoda H.
        • Li X.-Y.
        • Wu L.-J.
        • Zhao M.-G.
        • Descalzi G.
        • Chen T.
        • et al.
        Interplay of amygdala and cingulate plasticity in emotional fear.
        Neural plasticity. 2011; 2011
        • Etkin A.
        • Egner T.
        • Peraza D.M.
        • Kandel E.R.
        • Hirsch J.
        Resolving emotional conflict: a role for the rostral anterior cingulate cortex in modulating activity in the amygdala.
        Neuron. 2006; 51: 871-882
        • Etkin A.
        • Egner T.
        • Kalisch R.
        Emotional processing in anterior cingulate and medial prefrontal cortex.
        Trends in cognitive sciences. 2011; 15: 85-93
        • Genaro K.
        • Fabris D.
        • Fachim H.A.
        • Prado W.A.
        Angiotensin AT1 receptors modulate the anxiogenic effects of angiotensin (5–8) injected into the rat ventrolateral periaqueductal gray.
        Peptides. 2017; 96: 8-14
        • Marinzalda MdlA.
        • Pérez P.A.
        • Gargiulo P.A.
        • Casarsa B.S.
        • Bregonzio C.
        • Baiardi G.
        Fear-Potentiated behaviour is modulated by central amygdala angiotensin II receptors stimulation.
        BioMed research international. 2014; 2014
      5. Zhou X, Xu T, Zeng Y, Zhang R, Qi Z, Zhao W, et al. The angiotensin antagonist Losartan modulates social reward motivation and punishment sensitivity via modulating midbrain-striato-frontal circuits. bioRxiv. 2022: 2021.07. 19.452920.

        • Zhou F.
        • Li J.
        • Zhao W.
        • Xu L.
        • Zheng X.
        • Fu M.
        • et al.
        Empathic pain evoked by sensory and emotional-communicative cues share common and process-specific neural representations.
        Elife. 2020; 9e56929
        • Li Z.
        • Bains J.S.
        • Ferguson A.V.
        Functional evidence that the angiotensin antagonist losartan crosses the blood-brain barrier in the rat.
        Brain research bulletin. 1993; 30: 33-39
        • Culman J.
        • von Heyer C.
        • Piepenburg B.
        • Rascher W.
        • Unger T.
        Effects of systemic treatment with irbesartan and losartan on central responses to angiotensin II in conscious, normotensive rats.
        Eur J Pharmacol. 1999; 367: 255-265
        • Thöne-Reineke C.
        • Steckelings U.M.
        • Unger T.
        Angiotensin receptor blockers and cerebral protection in stroke.
        J Hypertens Suppl. 2006; 24: S115-S121
        • Samyuktha M.
        • Vasanth P.
        • Suresh K.
        • Ramesh T.
        • Ramesh M.
        Formulation and evaluation of gastroretentive floating tablets of losartan potassium.
        Int J Biopharm. 2013; 4: 18-26
        • Sica D.A.
        • Gehr T.W.
        • Ghosh S.
        Clinical pharmacokinetics of losartan.
        Clinical pharmacokinetics. 2005; 44: 797-814