1. Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:593–602.
Molecular Psychiatry (2022) 27:1322 – 1330
V. Taschereau-Dumouchel et al.
2. LeDoux JE. The emotional brain: the mysterious underpinnings of emotional life. Simon and Schuster; 1996.
3. LeDoux JE. Anxious: using the brain to understand and treat fear and anxiety. Penguin; 2015.
4. Morrison FG, Ressler KJ. From the neurobiology of extinction to improved clinical treatments. Depress Anxiety. 2014;31:279–90.
5. Perusini JN, Fanselow MS. Neurobehavioral perspectives on the distinction between fear and anxiety. Learn Mem. 2015;22:417–25.
6. File SE. Factors controlling measures of anxiety and responses to novelty in the mouse. Behav Brain Res. 2001;125:151–7.
7. Lang PJ, Davis M. Emotion, motivation, and the brain: reflex foundations in animal and human research. Prog Brain Res. 2006;156:3–29.
8. Gray JA, McNaughton N. The psychology of anxiety and enquiry in to the func- tions of the septo hippocampus system. New York: Oxford University Press; 2000.
9. Hartley CA, Phelps EA. Changing fear: the neurocircuitry of emotion regulation.
10. Büchel C, Dolan RJ. Classical fear conditioning in functional neuroimaging. Curr
Opin Neurobiol. 2000;10:219–23.
11. Grupe DW, Nitschke JB. Uncertainty and anticipation in anxiety: an integrated
neurobiological and psychological perspective. Nat Rev Neurosci. 2013;14:
12. Krystal JH, Deutsch DN, Charney DS. The biological basis of panic disorder. J Clin
Psychiatry 1996;57:23–31. Discussion 32–33
13. Maren S, Phan KL, Liberzon I. The contextual brain: implications for fear con-
ditioning, extinction and psychopathology. Nat Rev Neurosci. 2013;14:417–28.
14. Craske MG, Kircanski K, Zelikowsky M, Mystkowski J, Chowdhury N, Baker A. Optimizing inhibitory learning during exposure therapy. Behav Res Ther.
15. Ehlers A, Bisson J, Clark DM, Creamer M, Pilling S, Richards D, et al. Do all
psychological treatments really work the same in posttraumatic stress disorder?
Clin Psychol Rev. 2010;30:269–76.
16. Barlow DH, Raffa SD, Cohen EM. Psychosocial treatments for panic disorders,
phobias, and generalized anxiety disorder. In: Nathan PE, Gorman JM, editors. A
guide to treatments that work, Oxford University Press; 2002.
17. Hofmann SG, Asmundson GJG, Beck AT. The science of cognitive therapy. Behav
18. Milad MR, Quirk GJ. Fear extinction as a model for translational neuroscience:
ten years of progress. Annu Rev Psychol. 2012;63:129–51.
19. Mathew SJ, Coplan JD, Gorman JM. Neurobiological mechanisms of social
anxiety disorder. Am J Psychiatry. 2001;158:1558–67.
20. Griebel G, Holmes A. 50 years of hurdles and hope in anxiolytic drug discovery.
Nat Rev Drug Discov. 2013;12:667–87.
21. LeDoux JE, Pine DS. Using neuroscience to help understand fear and anxiety: a
two-system framework. Am J Psychiatry. 2016;173:1083–93.
22. LeDoux JE, Hofmann SG. The subjective experience of emotion: a fearful view.
Curr Opin Behav Sci. 2018;19:67–72.
23. Hyman SE. Revolution stalled. Sci Transl Med. 2012;4:155cm11.
24. Miller G. Is pharma running out of brainy ideas? Science 2010;329:502–4.
25. Darwin C. The expression of the emotions in man and animals. London: John
26. James W. What is an emotion? Mind 1884;9:188–205.
27. Cannon WB. Organization for physiological homeostasis. Physiol Rev.
28. Keller FS. The definition of psychology. 2nd ed. Appleton-Century-Crofts; 1973.
29. Boring EG. A history of introspection. Psychol Bull. 1953;50:169–89.
30. Watson JB. Psychology as the behaviorist views it. Psychol Rev. 1913;20:158–77.
31. Stellar E. The physiology of motivation. Psychol Rev. 1954;61:5–22.
32. Olds J. Pleasure centers in the brain. Sci Am. 1956;195:105–17.
33. Weiskrantz L. Behavioral changes associated with ablation of the amygdaloid
complex in monkeys. J Comp Physiol Psychol. 1956;49:381–91.
34. Goddard GV. Functions of the amygdala. Psychol Bull. 1964;62:89–109.
35. Miller GA, Galanter E, Pribram KH. Plans and the structure of behavior. Martino
Fine Books; 2013.
36. Wolpe J. Psychotherapy by reciprocal inhibition. Stanford, CA: Stanford Uni-
versity Press; 1958.
37. Bandura A. Psychotherapy as a learning process. Psychol Bull. 1961;58:143–59.
38. Braslow JT, Marder SR. History of psychopharmacology. Annu Rev Clin Psychol.
39. Valenstein E. Blaming the brain. New York: Free Press; 1999.
40. Wittenborn JR. The clinical psychopharmacology of anxiety. Springfield: C.C.
41. Ellis A. Rational psychotherapy and individual psychology. J Individ Psychol.
42. Beck AT. Thinking and depression. II. Theory and therapy. Arch Gen Psychiatry.
43. Insel T, Cuthbert B, Garvey M, Heinssen R, Pine DS, Quinn K, et al. Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry. 2010;167:748–51.
44. Kozak MJ, Cuthbert BN. The NIMH Research Domain Criteria Initiative: back- ground, issues, and pragmatics. Psychophysiology 2016;53:286–97.
45. Lieberman MD. Boo! The consciousness problem in emotion. Cogn Emot. 2019;33:24–30.
46. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-5®). American Psychiatric Pub; 2013.
47. Moncrieff J. The myth of the chemical cure: a critique of psychiatric drug treatment. Springer; 2016.
48. Harrington A. Mind fixers: psychiatry's troubled search for the biology of mental illness. W. W. Norton & Company; 2019.
49. Ivanov I, Schwartz JM. Why psychotropic drugs don't cure mental illness—but should they? Front Psychiatry. 2021;12.
50. Greenberg G. The psychiatric drug crisis. New Yorker. 2013;3.
51. Hyman SE. Psychiatric drug development: diagnosing a crisis. Cerebrum
52. Braslow JT, Brekke JS, Levenson J. Psychiatry's myopia-reclaiming the social, cul-
tural, and psychological in the psychiatric gaze. JAMA Psychiatry. 2020;78:349. 53. Michel M. Consciousness science underdetermined: a short history of endless
debates. Ergo. 2019;6.
54. LeDoux JE. Coming to terms with fear. Proc Natl Acad Sci USA. 2014;111:2871–8. 55. LeDoux JE. Semantics, surplus meaning, and the science of fear. Trends Cogn
56. Tolman EC. Purposive behavior in animals and man. New York: Century; 1932. 57. Brown JS, Farber IE. Emotions conceptualized as intervening variables—with
suggestions toward a theory of frustration. Psychol Bull. 1951;48:465–95.
58. Kozak MJ, Miller GA. Hypothetical constructs versus intervening variables: a re- appraisal of the three-systems model of anxiety assessment. Behav Assess.
59. Marx MH. Intervening variable or hypothetical construct? Psychol Rev. 1951;
60. Tinbergen N. The study of instinct. New York: Oxford University Press; 1951. 61. Miller NE. Studies of fear as an acquirable drive fear as motivation and fear-
reduction as reinforcement in the learning of new responses. J Exp Psychol.
62. Mowrer OH. Anxiety-reduction and learning. J Exp Psychol. 1940;27:497–516. 63. Mowrer OH. A stimulus-response analysis of anxiety and its role as a reinforcing
agent. Psychol Rev. 1939;46:553–65.
64. Mowrer OH, Lamoreaux RR. Fear as an intervening variable in avoidance con-
ditioning. J Comp Psychol. 1946;39:29–50.
65. Rescorla RA, Solomon RL. Two-process learning theory: relationships between
Pavlovian conditioning and instrumental learning. Psychol Rev. 1967;74:151–82. 66. Solomon RL, Wynne LC. Traumatic avoidance learning: the principles of anxiety
conservation and partial irreversibility. Psychol Rev. 1954;61:353–85.
67. LeDoux JE, Moscarello J, Sears R, Campese V. The birth, death and resurrection of avoidance: a reconceptualization of a troubled paradigm. Mol Psychiatry.
68. Mineka S. The role of fear in theories of avoidance learning, flooding, and
extinction. Psychol Bull. 1979;86:985–1010.
69. McAllister WR, McAllister DE. Behavioral measurement of conditioned fear.
Aversive conditioning and learning, Elsevier; 1971. p. 105–79.
70. Bolles RC. Theory of motivation. Harper and Row, New York; 1967.
71. Mowrer OH. Learning theory and behavior. Wiley; 1960.
72. Mowrer OH. Learning theory and the neurotic paradox. Am J Orthopsychiatry.
73. Dollard J, Miller NE. Personality and psychotherapy; an analysis in terms of
learning, thinking, and culture. Vol. 488. New York: McGraw-Hill; 1950.
74. Beck AT. Cognitive therapy: nature and relation to behavior therapy. Behav Ther.
75. Levis DJ. The case for a return to a two-factor theory of avoidance: the failure of
non-fear interpretations. In: Klein SB, Mowrer RR, editors. Contemporary learning theories: pavlovian conditioning and the status of traditional learning theory. Hillsdale: Lawrence Erlbaum Assn.; 1989.
76. Beckers T, Craske MG. Avoidance and decision making in anxiety: an intro- duction to the special issue. Behav Res Ther. 2017;96:1.
77. Dykman RA, Ackerman PT, Newton JE. Posttraumatic stress disorder: a sensiti- zation reaction. Integr Physiol Behav Sci. 1997;32:9–18.
78. Ekman P. Universals and cultural differences in facial expressions of emotions. In: Cole J, editor. Nebraska symposium on motivation, vol. 19, University of Nebraska Press; 1972. p. 207–83.
79. Izard CE. The face of emotion New York. New York: Appleton-Century-Crofts; 1971.
80. Panksepp J. Toward a general psychobiological theory of emotions. Behav Brain
1964;10:561–71. Sci. 1982;5:407–22.
81. Panksepp J. Affective neuroscience. Oxford University Press; 1998.
82. Fanselow MS, Pennington ZT. A return to the psychiatric dark ages with a two-
system framework for fear. Behav Res Ther. 2018;100:24–29.
83. Ressler KJ. Translating across circuits and genetics toward progress in fear- and
anxiety-related disorders. Am J Psychiatry. 2020;177:214–22.
84. Lang PJ, Lazovik AD, Reynolds DJ. Desensitization, suggestibility, and pseu-
dotherapy. J Abnorm Psychol. 1965;70:395–402.
85. Lacey JI. Psychophysiological approaches to the evaluation of psychotherapeutic
process and outcome. In: Rubinstein EA, Parloff MB. editors. Research in psy-
chotherapy. Washington, DC: American Psychological Association; 1959. p. 160–208.
86. Lang PJ. The mechanics of desensitization and the laboratory study of human fear. In: Franks C, editor. Assessment and status of the behavior therapies, New
York: McGraw-Hill; 1969. p. 160–91.
87. Lang PJ, Miller GA, Levin DN. Anxiety and fear. In: Davidson RJ, Schwartz GE,
Shapiro D, editors. Consciousness and self-regulation: Vol. 3: Advances in
research and theory. Boston, MA: Springer US; 1983. p. 123–51.
88. Miller GA, Kozak MJ. Three-systems assessment and the construct of emotion. In: Birbaumer N, Öhman A, editors. The structure of emotion: physiological, cog-
nitive and clinical aspects. Hogrefe & Huber Kirkland, WA; 1993. p. 31–47.
89. Rachman S. The passing of the two-stage theory of fear and avoidance: fresh
possibilities. Behav Res Ther. 1976;14:125–31.
90. Rachman S, Hodgson RI. Synchrony and desynchrony in fear and avoidance.
Behav Res Ther. 1974;12:311–8.
91. Borkovec TD. Physiological and cognitive processes in the regulation of anxiety.
In: Schwartz GE, Shapiro D, editors. Consciousness and self-regulation: advances
in research. Vol. 1. Boston, MA: Springer US; 1976. p. 261–312.
92. Hugdahl K. The three-systems-model of fear and emotion—a critical examina-
tion. Behav Res Ther. 1981;19:75–83.
93. Zinbarg RE. Concordance and synchrony in measures of anxiety and panic recon-
sidered: a hierarchical model of anxiety and panic. Behav Ther. 1998;29:301–23.
94. Foa EB, Kozak MJ. Emotional processing of fear: exposure to corrective infor-
mation. Psychol Bull. 1986;99:20–35.
95. Romer AS. The vertebrate as a dual animal—somatic and visceral. In: Dobzhansky
T, Hecht MK, Steere WC, editors. Evolutionary biology, Springer; 1972. p. 121–56.
96. LeDoux JE, Daw ND. Surviving threats: neural circuit and computational implications of a new taxonomy of defensive behaviour. Nat Rev Neurosci.
97. Hollenstein T, Lanteigne D. Models and methods of emotional concordance. Biol
98. Davidson RJ, Schwartz GE. The psychobiology of relaxation and related states: a
multi-process theory. In: Mostoesky DI, editor. Behavior control and modification
of physiological activity. Englewood Cliffs, NJ: Prentice-Hall; 1976. p. 399–442.
99. Lang PJ. Physiological assessment of anxiety and fear. In: Cone JD, Hawkins RP, editors. Behavioral assessment: new directions in clinical psychology. New York:
Brunner-Mazel; 1977. p. 178–95.
100. Michelson L. The role of individual differences, response profiles, and treatment
consonance in anxiety disorders. J Behav Assess. 1984;6:349–67.
101. Ost LG, Jerremalm A, Johansson J. Individual response patterns and the effects of different behavioral methods in the treatment of social phobia. Behav Res
102. Ost LG, Johansson J, Jerremalm A. Individual response patterns and the effects
of different behavioral methods in the treatment of claustrophobia. Behav Res
103. Gerrans P, Scherer K. Wired for despair the neurochemistry of emotion and the
phenomenology of depression. J Conscious Stud. 2013;20:254–68.
104. Steenen SA, van Wijk AJ, van der Heijden GJMG, van Westrhenen R, de Lange J, de Jongh A. Propranolol for the treatment of anxiety disorders: systematic
review and meta-analysis. J Psychopharmacol. 2016;30:128–39.
105. Lang PJ, Lazovik AD. Experimental desensitization of phobia. J Abnorm Soc
106. Gray JA. The psychology of fear and stress. London: Weidenfeld & Nicolson; 1971.
107. LeDoux JE. Rethinking the emotional brain. Neuron 2012;73:653–76.
108. Hilton SM, Zbrozyna AW. Amygdaloid region for defence reactions and its
efferent pathway to the brain stem. J Physiol. 1963;165:160–73.
109. Cohen DH, Obrist PA. Interactions between behavior and the cardiovascular
system. Circ Res. 1975;37:693–706.
110. Balleine BW, Dickinson A. Goal-directed instrumental action: contingency and
incentive learning and their cortical substrates. Neuropharmacology 1998;37:407–19.
111. Cronbach LJ, Meehl PE. Construct validity in psychological tests. Psychol Bull.
112. Barrett LF. Variety is the spice of life: a psychological construction approach to
understanding variability in emotion. Cogn Emot. 2009;23:1284–306.
113. Friedman BH, Stephens CL, Thayer JF. Redundancy analysis of autonomic and
self-reported, responses to induced emotions. Biol Psychol. 2014;98:19–28.
114. Schaffner KF. A comparison of two neurobiological models of fear and anxiety: a 'construct validity' application? Perspect Psychol Sci. 2020;2020. https://doi.org/ 10.1177/1745691620920860.
115. Lonsdorf TB, Merz CJ, Fullana MA. Fear extinction retention: is it what we think it is? Biol Psychiatry. 2019;85:1074–82.
116. LeDoux JE, Brown R. A higher-order theory of emotional consciousness. Proc Natl Acad Sci USA. 2017;114:E2016–E2025.
117. LeDoux JE. What emotions might be like in other animals. Curr Biol. 2021;31: R824–R829.
118. LeDoux JE. Thoughtful feelings. Curr Biol. 2020;30:R619–R623.
119. Schachter S, Singer JE. Cognitive, social, and physiological determinants of
emotional state. Psychol Rev. 1962;69:379–99.
120. Ortony A, Clore GL. Emotions, moods, and conscious awareness; comment on
johnson-laird and oatley's 'the language of emotions: an analysis of a semantic
field'. Cognition Emot. 1989;3:125–37.
121. Barrett LF, Russell JA, editors. The psychological construction of emotions.
Guilford Press; 2015.
122. Rosenthal D. Consciousness and mind. Oxford University Press; 2005.
123. LeDoux JE. How does the non-conscious become conscious? Curr Biol. 2020;30:
124. LeDoux JE, Brown R, Pine D, Hofmann SG. Know thyself: well-being and sub-
jective experience. Cerebrum. 2018;2018.
125. Damasio AR. The somatic marker hypothesis and the possible functions of the
prefrontal cortex. Philos Trans R Soc Lond B Biol Sci. 1996;351:1413–20.
126. Danziger K. The history of introspection reconsidered. J Hist Behav Sci.
127. Johansson P, Hall L, Sikström S, Olsson A. Failure to detect mismatches between
intention and outcome in a simple decision task. Science 2005;310:116–9. 128. Nisbett RE, Wilson TD. Telling more than we can know: verbal reports on mental
processes. Psychol Rev. 1977;84:231–59.
129. Jerolmack C, Khan S. Talk is cheap. Sociol Methods Res. 2014;43:178–209.
130. Carruthers P. The opacity of mind: an integrative theory of self-knowledge.
Oxford University Press; 2011.
131. Robinson MD, Clore GL. Belief and feeling: evidence for an accessibility model of
emotional self-report. Psychol Bull. 2002;128:934–60.
132. Walentynowicz M, Schneider S, Stone AA. The effects of time frames on self-
report. PLoS ONE. 2018;13:e0201655.
133. Chirimuuta M. Psychophysical methods and the evasion of introspection. Philos
134. Quigley KS, Lindquist KA, Barrett LF. Inducing and measuring emotion and
affect: tips, tricks, and secrets. In: Reis HT, Judd CM, editors. Handbook of research methods in social and personality psychology. Cambridge University Press; 2014. p. 220–52.
135. Borsboom D, Mellenbergh GJ. The concept of validity. Psychol Rev. 2004;111: 1061–71.
136. Cohen JA, Mannarino AP, Deblinger E. Treating trauma and traumatic grief in children and adolescents, 2nd ed. Guilford Publications; 2016.
137. Schneider KJ, Krug OT. Existential-humanistic therapy. American Psychological Association Washington, DC; 2010.
138. Hofmann SG, Gómez AF. Mindfulness-based interventions for anxiety and depression. Psychiatric Clin. 2017;40:739–49.
139. Zoellner LA, Foa EB. Applying Research Domain Criteria (RDoC) to the study of fear and anxiety: a critical comment. Psychophysiology. 2016;53:332–5.
140. Constantinou E, Purves KL, McGregor T, Lester KJ, Barry TJ, Treanor M, et al. Measuring fear: association among different measures of fear learning. J Behav Ther Exp Psychiatry. 2021;70:101618.
141. Nord CL, Barrett LF, Lindquist KA, Ma Y, Marwood L, Satpute AB, et al. Neural effects of antidepressant medication and psychological treatments: a quanti- tative synthesis across three meta-analyses. Br J Psychiatry. 2021;219:1–5.
142. Taschereau-Dumouchel V, Kawato M, Lau H. Multivoxel pattern analysis reveals dissociations between subjective fear and its physiological correlates. Mol Psychiatry. 2020;25:2342–54.
143. FeldmanHall O, Glimcher P, Baker AL, PROSPEC NYU Collaboration, Phelps EA. The functional roles of the amygdala and prefrontal cortex in processing uncertainty. J Cogn Neurosci. 2019;31:1742–54.
144. Hofmann SG, Curtiss JE, Hayes SC. Beyond linear mediation: toward a dynamic network approach to study treatment processes. Clin Psychol Rev. 2020;76:101824. 145. LeDoux JE, Lau H. A new vista in psychiatric treatment: using individualized func-
tional connectivity to track symptoms. Proc Natl Acad Sci USA. 2020;117:4450–2. 146. Sylvester CM, Yu Q, Srivastava AB, Marek S, Zheng A, Alexopoulos D, et al. Individual-specific functional connectivity of the amygdala: a substrate for
precision psychiatry. Proc Natl Acad Sci USA. 2020;117:3808–18.
147. Allen JG, Haccoun DM. Sex differences in emotionality: a multidimensional
Molecular Psychiatry (2022) 27:1322 – 1330
V. Taschereau-Dumouchel et al.
approach. Hum Relat. 1976;29:711–22.
148. Gard MG, Kring AM. Sex differences in the time course of emotion. Emotion 2007;7:429–37.
149. Zhou F, Zhao W, Qi Z, Geng Y, Yao S, Kendrick KM, et al. A distributed fMRI-based signature for the subjective experience of fear. Nat Commun. 2021;12:6643.
150. Ekman P. An argument for basic emotions. Cognition Emot. 1992;6:169–200.
151. Scherer KR. The dynamic architecture of emotion: evidence for the component
process model. Cognition Emot. 2009;23:1307–51.
152. Barrett LF. How emotions are made: the secret life of the brain. Houghton Mifflin
153. Mashour GA, Roelfsema P, Changeux J-P, Dehaene S. Conscious processing and
the global neuronal workspace hypothesis. Neuron 2020;105:776–98.
154. Apkarian AV. Definitions of nociception, pain, and chronic pain with implications
regarding science and society. Neurosci Lett. 2019;702:1–2.
155. Krueger RF, Hobbs KA. An overview of the DSM-5 alternative model of per-
sonality disorders. Psychopathology 2020;53:126–32.
156. Michel M, Lau H. On the dangers of conflating strong and weak versions of a
theory of consciousness. Philos. Mind Sci. 2020;1.
157. Dretske F. Naturalizing the mind. Cambridge, MA: Bradford; 1995.
158. Lamme VAF. How neuroscience will change our view on consciousness. Cogn
159. Tye M. Consciousness, color, and content (representation and mind). MIT Press;
160. Block N. Empirical science meets higher order views of consciousness: reply to
Hakwan Lau and Richard Brown. Blockheads! Essays on Ned block's philosophy
of mind and consciousness. MIT Press Cambridge, MA; 2019. p. 199–213.
161. Panksepp J. What is an emotional feeling? Lessons about affective origins from
cross-species neuroscience. Motiv Emot. 2012;36:4–15.
162. Lau H, Rosenthal D. Empirical support for higher-order theories of conscious
awareness. Trends Cogn Sci. 2011;15:365–73.
163. Brown R, Lau H, LeDoux JE. Understanding the higher-order approach to con-
sciousness. Trends Cogn Sci. 2019;23:754–68.
164. Fleming SM, Daw ND. Self-evaluation of decision-making: a general Bayesian
framework for metacognitive computation. Psychol Rev. 2017;124:91–114.
V.T-D, M.M., H.L., S.G.H., and J.E.L. wrote and edited the manuscript.
SGH receives financial support from the Alexander von Humboldt Foundation and the James S. McDonnell Foundation 21st Century Science Initiative in
Understanding Human Cognition—Special Initiative. HL received financial support from the US National Institute of Mental Health (R61MH113772) and The Templeton World Charity Foundation (RA537-01). JELD receives financial support from the National Institute of Drug Abuse, The Templeton World Charity Foundation, New York University, and private donors. VT-D received the financial support from the Canadian Institute of Health Research (CIHR).
SGH receives compensation for his work as editor from SpringerNature and the Association for Psychological Science, and as an advisor from the Palo Alto Health Sciences Otsuka Pharmaceuticals, and for his work as a Subject Matter Expert from John Wiley & Sons, Inc. and SilverCloud Health, Inc. He also receives royalties and payments for his editorial work from various publishers. JELD receives royalties from his books. The remaining authors declare no competing interests.