Advertisement

The Neurofunctional Basis of Affective Startle Modulation in Humans: Evidence From Combined Facial Electromyography and Functional Magnetic Resonance Imaging

      Abstract

      Background

      The startle eye-blink is the cross-species translational tool to study defensive behavior in affective neuroscience with relevance to a broad range of neuropsychiatric conditions. It makes use of the startle reflex, a defensive response elicited by an immediate, unexpected sensory event, which is potentiated when evoked during threat and inhibited during safety. In contrast to skin conductance responses or pupil dilation, modulation of the startle reflex is valence specific. Rodent models implicate a modulatory pathway centering on the brainstem (i.e., nucleus reticularis pontis caudalis) and the centromedial amygdala as key hubs for flexibly integrating valence information into differential startle magnitude. Technical advances now allow for the investigation of this pathway using combined facial electromyography and functional magnetic resonance imaging in humans.

      Methods

      We employed a multimethodological approach combining trial-by-trial facial eye-blink startle electromyography and brainstem- and amygdala-specific functional magnetic resonance imaging in humans. Validating the robustness and reproducibility of our findings, we provide evidence from two different paradigms (fear-potentiated startle, affect-modulated startle) in two independent studies (N = 43 and N = 55).

      Results

      We provide key evidence for a conserved neural pathway for acoustic startle modulation between humans and rodents. Furthermore, we provide the crucial direct link between electromyography startle eye-blink magnitude and neural response strength. Finally, we demonstrate a dissociation between arousal-specific amygdala responding and triggered valence-specific amygdala responding.

      Conclusions

      We provide neurobiologically based evidence for the strong translational value of startle responding and argue that startle-evoked amygdala responding and its affective modulation may hold promise as an important novel tool for affective neuroscience and its clinical translation.

      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'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • LeDoux J.
        Rethinking the emotional brain.
        Neuron. 2012; 73: 653-676
        • Mobbs D.
        • Hagan C.C.
        • Dalgleish T.
        • Silston B.
        • Prévost C.
        The ecology of human fear: Survival optimization and the nervous system.
        Front Neurosci. 2015; 9: 55
        • Brown P.
        • Rothwell J.C.
        • Thompson P.D.
        • Britton T.C.
        • Day B.L.
        • Marsden C.D.
        New observations on the normal auditory startle reflex in man.
        Brain. 1991; 114: 1891-1902
        • Hamm A.O.
        Fear-potentiated startle.
        in: Wright J.D. International Encyclopedia of the Social and Behavioral Sciences. Elsevier, New York2015: 860-867
        • Anthony B.J.
        In the blink of an eye: Implications of reflex modification for information processing.
        in: Ackles P.K. Jennings J.R. Coles M.G.H. Advances in Psychophysiology. JAI Press, Greenwich, CT1985: 167-218
        • Blumenthal T.D.
        • Cuthbert B.N.
        • Filion D.L.
        • Hackley S.
        • Lipp O.V.
        • van Boxtel A.
        Committee report: Guidelines for human startle eyeblink electromyographic studies.
        Psychophysiology. 2005; 42: 1-15
        • Davis M.
        • Walker D.L.
        • Miles L.
        • Grillon C.
        Phasic vs sustained fear in rats and humans: Role of the extended amygdala in fear vs anxiety.
        Neuropsychopharmacology. 2010; 35: 105-135
        • Romero M.
        • Williams W.C.
        • New A.S.
        • Siever L.J.
        • Speiser L.J.
        • Hazlett E.A.
        • et al.
        Exaggerated affect-modulated startle during unpleasant stimuli in borderline personality disorder.
        Biol Psychiatry. 2007; 62: 250-255
        • Allen N.B.
        • Trinder J.
        • Brennan C.
        Affective startle modulation in clinical depression: Preliminary findings.
        Biol Psychiatry. 1999; 46: 542-550
        • Quednow B.B.
        • Frommann I.
        • Berning J.
        • Kühn K.U.
        • Maier W.
        • Wagner M.
        Impaired sensorimotor gating of the acoustic startle response in the prodrome of schizophrenia.
        Biol Psychiatry. 2008; 64: 766-773
        • Conzelmann A.
        • Mucha R.F.
        • Jacob C.P.
        • Weyers P.
        • Romanos J.
        • Gerdes A.B.M.
        • et al.
        Abnormal affective responsiveness in attention-deficit/hyperactivity disorder: Subtype differences.
        Biol Psychiatry. 2009; 65: 578-585
        • Schmidt U.
        • Kaltwasser S.F.
        • Wotjak C.T.
        Biomarkers in posttraumatic stress disorder: Overview and implications for future research.
        Dis Markers. 2013; 35: 43-54
        • Moberg C.A.
        • Bradford D.E.
        • Kaye J.T.
        • Curtin J.J.
        Increased startle potentiation to unpredictable stressors in alcohol dependence: Possible stress neuroadaptation in humans.
        J Abnorm Psychol. 2017; 126: 441-453
        • Winslow J.T.
        • Parr L.A.
        • Davis M.
        Acoustic startle, prepulse inhibition, and fear-potentiated startle measured in rhesus monkeys.
        Biol Psychiatry. 2002; 51: 859-866
        • Glover E.M.
        • Phifer J.E.
        • Crain D.F.
        • Norrholm S.D.
        • Davis M.
        • Bradley B.
        • et al.
        Tools for translational neuroscience: PTSD is associated with heightened fear responses using acoustic startle but not skin conductance measures.
        Depress Anxiety. 2011; 28: 1058-1066
        • Jovanovic T.
        • Blanding N.Q.
        • Norrholm S.D.
        • Duncan E.
        • Bradley B.
        • Ressler K.J.
        Childhood abuse is associated with increased startle reactivity in adulthood.
        Depress Anxiety. 2009; 26: 1018-1026
        • Lang P.J.
        • Bradley M.M.
        • Cuthbert B.N.
        Emotion, attention, and the startle reflex.
        Psychol Rev. 1990; 97: 377-395
        • Davis M.
        • Walker D.L.
        • Lee Y.
        Neurophysiology and neuropharmacology of startle and its affective modulation.
        in: Dawson M.E. Schell A.M. Bohmelt A.H. Startle Modification: Implications for Neuroscience, Cognitive Science, and Clinical Science. Cambridge University Press, Cambridge, MA1999: 95-113
        • Hamm A.O.
        • Vaitl D.
        Affective learning: Awareness and aversion.
        Psychophysiology. 1996; 33: 698-710
        • Bradley M.M.
        • Miccoli L.
        • Escrig M.A.
        • Lang P.J.
        The pupil as a measure of emotional arousal and autonomic activation.
        Psychophysiology. 2008; 45: 602-607
        • van Well S.
        • Visser R.M.
        • Scholte H.S.
        • Kindt M.
        Neural substrates of individual differences in human fear learning: Evidence from concurrent fMRI, fear-potentiated startle, and US-expectancy data.
        Cogn Affect Behav Neurosci. 2012; 12: 499-512
        • Lindner K.
        • Neubert J.
        • Pfannmöller J.
        • Lotze M.
        • Hamm A.O.
        • Wendt J.
        Fear-potentiated startle processing in humans: Parallel fMRI and orbicularis EMG assessment during cue conditioning and extinction.
        Int J Psychophysiol. 2015; 98: 535-545
        • Yeomans J.S.
        • Frankland P.W.
        The acoustic startle reflex: Neurons and connections.
        Brain Res Rev. 1995; 21: 301-314
        • Koch M.
        The neurobiology of startle.
        Prog Neurobiol. 1999; 59: 107-128
        • Lee Y.
        • López D.E.
        • Meloni E.G.
        • Davis M.
        A primary acoustic startle pathway: Obligatory role of cochlear root neurons and the nucleus reticularis pontis caudalis.
        J Neurosci. 1996; 16: 3775-3789
        • Gómez-Nieto R.
        • de Horta-Júnior J. de AC.
        • Castellano O.
        • Millian-Morell L.
        • Rubio M.E.
        • López D.E.
        Origin and function of short-latency inputs to the neural substrates underlying the acoustic startle reflex.
        Front Neurosci. 2014; 8: 216
        • Hitchcock J.M.
        • Davis M.
        Lesions of the amygdala, but not of the cerebellum or red nucleus, block conditioned fear as measured with the potentiated startle paradigm.
        Behav Neurosci. 1986; 100: 11-22
        • Hitchcock J.M.
        • Davis M.
        Efferent pathway of the amygdala involved in conditioned fear as measured with the fear-potentiated startle paradigm.
        Behav Neurosci. 1991; 105: 826-842
        • Rosen J.B.
        • Hitchcock J.M.
        • Sananes C.B.
        • Miserendino M.J.D.
        • Davis M.
        A Direct Projection from the central nucleus of the amygdala to the acoustic startle pathway: Anterograde and retrograde tracing studies.
        Behav Neurosci. 1991; 105: 817-825
        • LeDoux J.E.
        • Iwata J.
        • Cicchetti P.
        • Reis D.J.
        Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear.
        J Neurosci. 1988; 8: 2517-2529
        • de Haan M.I.C.
        • van Well S.
        • Visser R.M.
        • Scholte H.S.
        • van Wingen G.A.
        • Kindt M.
        The influence of acoustic startle probes on fear learning in humans.
        Sci Rep. 2018; 8: 14552
        • Wendt J.
        • Löw A.
        • Weymar M.
        • Lotze M.
        • Hamm A.O.
        Active avoidance and attentive freezing in the face of approaching threat.
        Neuroimage. 2017; 158: 196-204
        • Sclocco R.
        • Beissner F.
        • Bianciardi M.
        • Polimeni J.R.
        • Napadow V.
        Challenges and opportunities for brainstem neuroimaging with ultrahigh field MRI.
        Neuroimage. 2018; 168: 412-426
        • Beissner F.
        Functional MRI of the brainstem: Common problems and their solutions.
        Clin Neuroradiol. 2015; 25: 251-257
        • Lang P.J.
        • Bradley M.M.
        • Cuthbert B.N.
        International Affective Picture System (IAPS): Technical Manual and Affective Ratings.
        NIMH Center for the Study of Emotion and Attention, Gainesville, FL1997
        • Wessa M.
        • Kanske P.
        • Neumeister P.
        • Bode K.
        • Heissler J.
        • Schönfelder S.
        EmoPics: Subjektive und psychophysiologische Evaluationen neuen Bildmaterials für die klinisch-bio-psychologische Forschung.
        Z Klin Psychol Psychother. 2010; 39: 77
        • Bradley M.M.
        • Lang P.J.
        Measuring emotion: The self-assessment manikin and the semantic differential.
        J Behav Ther Exp Psychiatry. 1994; 25: 49-59
        • Sjouwerman R.
        • Niehaus J.
        • Kuhn M.
        • Lonsdorf T.B.
        Don’t startle me—Interference of startle probe presentations and intermittent ratings with fear acquisition.
        Psychophysiology. 2016; 53: 1889-1899
        • Boucsein W.
        • Fowles D.C.
        • Grimnes S.
        • Ben-Shakhar G.
        • Roth W.T.
        • Dawson M.E.
        • Filion D.L.
        Publication recommendations for electrodermal measurements.
        Psychophysiology. 2012; 49: 1017-1034
        • R Developement Core Team
        R: A Language and Environment for Statistical Computing.
        R Found Stat Comput. 2015; 1: 409
        • Costa V.D.
        • Lang P.J.
        • Sabatinelli D.
        • Bradley M.M.
        • Keil A.
        The timing of emotional discrimination in human amygdala and ventral visual cortex.
        J Neurosci. 2009; 29: 14864-14868
        • Heller A.S.
        • Lapate R.C.
        • Mayer K.E.
        • Davidson R.J.
        The face of negative affect: trial-by-trial corrugator responses to negative pictures are positively associated with amygdala and negatively associated with ventromedial prefrontal cortex activity.
        J Cogn Neurosci. 2014; 26: 2102-2110
        • Weike A.I.
        • Hamm A.O.
        • Schupp H.T.
        • Runge U.
        • Schroeder H.S.W.
        • Kessler C.
        Fear conditioning following unilateral temporal lobectomy: Dissociation of conditioned startle potentiation and autonomic learning.
        J Neurosci. 2005; 25: 11117-11124
        • Klumpers F.
        • Morgan B.
        • Terburg D.
        • Stein D.J.
        • van Honk J.
        Impaired acquisition of classically conditioned fear-potentiated startle reflexes in humans with focal bilateral basolateral amygdala damage.
        Soc Cogn Affect Neurosci. 2014; 10: 1161-1168
        • Angrilli A.
        • Mauri A.
        • Palomba D.
        • Flor H.
        • Birbaumer N.
        • Sartori G.
        • Di Paola F.
        Startle reflex and emotion modulation impairment after a right amygdala lesion.
        Brain. 1996; 119: 1991-2000
        • Pissiota A.
        • Frans O.
        • Fredrikson M.
        • Langstrom B.
        • Flaten M.A.
        The human startle reflex and pons activation: A regional cerebral blood flow study.
        Eur J Neurosci. 2002; 15: 395-398
        • Pissiota A.
        • Frans Ö.
        • Michelgård Å.
        • Appel L.
        • Långström B.
        • Flaten M.A.
        • Fredrikson M.
        Amygdala and anterior cingulate cortex activation during affective startle modulation: A PET study of fear.
        Eur J Neurosci. 2003; 18: 1325-1331
        • Balaban M.T.
        • Taussig H.N.
        Salience of fear/threat in the affective modulation of the human startle blink.
        Biol Psychol. 1994; 38: 117-131
        • Dal Monte O.
        • Costa V.D.
        • Noble P.L.
        • Murray E.A.
        • Averbeck B.B.
        Amygdala lesions in rhesus macaques decrease attention to threat.
        Nat Commun. 2015; 6: 10161
        • Dolan R.J.
        • Vuilleumier P.
        Amygdala automaticity in emotional processing.
        Ann N Y Acad Sci. 2006; 985: 348-355
        • Vuilleumier P.
        • Pourtois G.
        Distributed and interactive brain mechanisms during emotion face perception: Evidence from functional neuroimaging.
        Neuropsychologia. 2007; 45: 174-194
        • Wendt J.
        • Weike A.I.
        • Lotze M.
        • Hamm A.O.
        The functional connectivity between amygdala and extrastriate visual cortex activity during emotional picture processing depends on stimulus novelty.
        Biol Psychol. 2011; 86: 203-209
        • Stevens J.S.
        • Hamann S.
        Sex differences in brain activation to emotional stimuli: A meta-analysis of neuroimaging studies.
        Neuropsychologia. 2012; 50: 1578-1593
        • Anders S.
        • Eippert F.
        • Weiskopf N.
        • Veit R.
        The human amygdala is sensitive to the valence of pictures and sounds irrespective of arousal: An fMRI study.
        Soc Cogn Affect Neurosci. 2008; 3: 233-243
        • Tye K.M.
        Neural circuit motifs in valence processing.
        Neuron. 2018; 100: 436-452
        • Calder A.J.
        • Goodyer I.M.
        • Stobbe Y.
        • van Goozen S.H.M.
        • Fairchild G.
        Facial expression recognition, fear conditioning, and startle modulation in female subjects with conduct disorder.
        Biol Psychiatry. 2010; 68: 272-279
        • Patrick C.J.
        • Berthot B.D.
        • Moore J.D.
        Diazepam blocks fear-potentiated startle in humans.
        J Abnorm Psychol. 1996; 105: 89-96
        • Deckert J.
        • Weber H.
        • Villmann C.
        • Lonsdorf T.B.
        • Richter J.
        • Andreatta M.
        • et al.
        GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: A potential neurogenetic pathway to panic disorder.
        Mol Psychiatry. 2017; 22: 1431-1439
        • Roelofs K.
        Freeze for action: Neurobiological mechanisms in animal and human freezing.
        Philos Trans R Soc Lond B Biol Sci. 2017; 372: 20160206
        • Hamm A.O.
        • Richter J.
        • Pané-Farré C.
        • Westphal D.
        • Wittchen H.-U.U.
        • Vossbeck-Elsebusch A.N.
        • et al.
        Panic disorder with agoraphobia from a behavioral neuroscience perspective: Applying the research principles formulated by the Research Domain Criteria (RDoC) initiative.
        Psychophysiology. 2016; 53: 312-322
        • Insel T.R.
        • Cuthbert B.
        • Garvey M.
        • Heinssen R.
        • Pine D.S.
        • Quinn K.
        • et al.
        Research Domain Criteria (RDoC): Toward a new classification framework for research on mental disorders.
        Am J Psychiatry. 2010; 167: 748-751
        • Lonsdorf T.B.
        • Richter J.
        Challenges of fear conditioning research in the age of RDoC.
        Zeitschrift fur Psychol / J Psychol. 2017; 225: 189-199
        • Naidich T.P.
        • Duvernoy H.M.
        • Delman B.N.
        • Sorensen A.G.
        • Kollias S.S.
        • Haacke E.M.
        Duvernoy’s Atlas of the Human Brain Stem and Cerebellum: High-Field MRI, Surface Anatomy, Internal Structure, Vascularization and 3 D Sectional Anatomy.
        Springer Science & Business Media, New York2009
        • Edlow B.L.
        • Takahashi E.
        • Wu O.
        • Benner T.
        • Dai G.
        • Bu L.
        • et al.
        Neuroanatomic connectivity of the human ascending arousal system critical to consciousness and its disorders.
        J Neuropathol Exp Neurol. 2012; 71: 531-546

      Linked Article

      • Advances in Mapping the Startle Eye-Blink Response Onto Neural Circuits
        Biological PsychiatryVol. 87Issue 6
        • Preview
          Cross-species translational research allows us to further knowledge regarding the biological mechanisms underlying psychiatric symptoms (1,2). In neuroscience, such research can bridge the precise probing of neural circuits in animal models with the less invasive work performed in humans using neuroimaging, with the goal of mapping human emotions to neural functioning. Affective modulation measured with startle is a prime example of a translational paradigm that can be measured across human and nonhuman species using the eye-blink startle response measured with facial electromyography (EMG) in humans or whole-body startle in animals such as rodents.
        • Full-Text
        • PDF