Inhibiting Human Aversive Memory by Transcranial Theta-Burst Stimulation to the Primary Sensory Cortex

  • Author Footnotes
    1 KEO and MS contributed equally to this work.
    Karita E. Ojala
    Address correspondence to Karita E. Ojala, Ph.D.
    1 KEO and MS contributed equally to this work.
    Computational Psychiatry Research, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zürich, Zürich, Switzerland

    Neuroscience Centre Zurich, University of Zürich, Zürich, Switzerland
    Search for articles by this author
  • Author Footnotes
    1 KEO and MS contributed equally to this work.
    Matthias Staib
    1 KEO and MS contributed equally to this work.
    Computational Psychiatry Research, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zürich, Zürich, Switzerland

    Neuroscience Centre Zurich, University of Zürich, Zürich, Switzerland
    Search for articles by this author
  • Samuel Gerster
    Computational Psychiatry Research, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zürich, Zürich, Switzerland
    Search for articles by this author
  • Christian C. Ruff
    Neuroscience Centre Zurich, University of Zürich, Zürich, Switzerland

    Zurich Center for Neuroeconomics, Department of Economics, University of Zürich, Zürich, Switzerland
    Search for articles by this author
  • Dominik R. Bach
    Dominik R. Bach, Ph.D.
    Computational Psychiatry Research, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zürich, Zürich, Switzerland

    Neuroscience Centre Zurich, University of Zürich, Zürich, Switzerland

    Wellcome Centre for Human Neuroimaging and Max-Planck UCL Centre for Computational Psychiatry and Ageing Research, University College London, London, United Kingdom
    Search for articles by this author
  • Author Footnotes
    1 KEO and MS contributed equally to this work.
Open AccessPublished:February 09, 2022DOI:



      Predicting adverse events from past experience is fundamental for many biological organisms. However, some individuals suffer from maladaptive memories that impair behavioral control and well-being, e.g., after psychological trauma. Inhibiting the formation and maintenance of such memories would have high clinical relevance. Previous preclinical research has focused on systemically administered pharmacological interventions, which cannot be targeted to specific neural circuits in humans. Here, we investigated the potential of noninvasive neural stimulation on the human sensory cortex in inhibiting aversive memory in a laboratory threat conditioning model.


      We build on an emerging nonhuman literature suggesting that primary sensory cortices may be crucially required for threat memory formation and consolidation. Immediately before conditioning innocuous somatosensory stimuli (conditioned stimuli [CS]) to aversive electric stimulation, healthy human participants received continuous theta-burst transcranial magnetic stimulation (cTBS) to individually localized primary somatosensory cortex in either the CS-contralateral (experimental) or CS-ipsilateral (control) hemisphere. We measured fear-potentiated startle to infer threat memory retention on the next day, as well as skin conductance and pupil size during learning.


      After overnight consolidation, threat memory was attenuated in the experimental group compared with the control cTBS group. There was no evidence that this differed between simple and complex CS or that CS identification or initial learning were affected by cTBS.


      Our results suggest that cTBS to the primary sensory cortex inhibits threat memory, likely by an impact on postlearning consolidation. We propose that noninvasive targeted stimulation of the sensory cortex may provide a new avenue for interfering with aversive memories in humans.


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


        • Duits P.
        • Cath D.C.
        • Lissek S.
        • Hox J.J.
        • Hamm A.O.
        • Engelhard I.M.
        • et al.
        Updated meta-analysis of classical fear conditioning in the anxiety disorders.
        Depress Anxiety. 2015; 32: 239-253
        • Dunsmoor J.E.
        • Paz R.
        Fear generalization and anxiety: Behavioral and neural mechanisms.
        Biol Psychiatry. 2015; 78: 336-343
        • Craske M.G.
        • Stein M.B.
        • Eley T.C.
        • Milad M.R.
        • Holmes A.
        • Rapee R.M.
        • Wittchen H.U.
        Anxiety disorders [published correction appears in Nat Rev Dis Primers 2017; 3:17100].
        Nat Rev Dis Primers. 2017; 3: 17024
        • Phelps E.A.
        • Hofmann S.G.
        Memory editing from science fiction to clinical practice.
        Nature. 2019; 572: 43-50
        • Maren S.
        • Quirk G.J.
        Neuronal signalling of fear memory.
        Nat Rev Neurosci. 2004; 5: 844-852
        • Tovote P.
        • Fadok J.P.
        • Lüthi A.
        Neuronal circuits for fear and anxiety [published correction appears in Nat Rev Neurosci 2015; 16:439].
        Nat Rev Neurosci. 2015; 16: 317-331
        • McDonald A.J.
        Cortical pathways to the mammalian amygdala.
        Prog Neurobiol. 1998; 55: 257-332
        • Amaral D.G.
        • Behniea H.
        • Kelly J.L.
        Topographic organization of projections from the amygdala to the visual cortex in the macaque monkey.
        Neuroscience. 2003; 118: 1099-1120
        • Abivardi A.
        • Bach D.R.
        Deconstructing white matter connectivity of human amygdala nuclei with thalamus and cortex subdivisions in vivo.
        Hum Brain Mapp. 2017; 38: 3927-3940
        • Sacco T.
        • Sacchetti B.
        Role of secondary sensory cortices in emotional memory storage and retrieval in rats.
        Science. 2010; 329: 649-656
        • Galván V.V.
        • Weinberger N.M.
        Long-term consolidation and retention of learning-induced tuning plasticity in the auditory cortex of the guinea pig.
        Neurobiol Learn Mem. 2002; 77: 78-108
        • Campeau S.
        • Davis M.
        Involvement of subcortical and cortical afferents to the lateral nucleus of the amygdala in fear conditioning measured with fear-potentiated startle in rats trained concurrently with auditory and visual conditioned stimuli.
        J Neurosci. 1995; 15: 2312-2327
        • Romanski L.M.
        • LeDoux J.E.
        Bilateral destruction of neocortical and perirhinal projection targets of the acoustic thalamus does not disrupt auditory fear conditioning.
        Neurosci Lett. 1992; 142: 228-232
        • Romanski L.M.
        • LeDoux J.E.
        Equipotentiality of thalamo-amygdala and thalamo-cortico-amygdala circuits in auditory fear conditioning.
        J Neurosci. 1992; 12: 4501-4509
        • Peter M.
        • Scheuch H.
        • Burkard T.R.
        • Tinter J.
        • Wernle T.
        • Rumpel S.
        Induction of immediate early genes in the mouse auditory cortex after auditory cued fear conditioning to complex sounds.
        Genes Brain Behav. 2012; 11: 314-324
        • Moczulska K.E.
        • Tinter-Thiede J.
        • Peter M.
        • Ushakova L.
        • Wernle T.
        • Bathellier B.
        • Rumpel S.
        Dynamics of dendritic spines in the mouse auditory cortex during memory formation and memory recall.
        Proc Natl Acad Sci U S A. 2013; 110: 18315-18320
        • Banerjee S.B.
        • Gutzeit V.A.
        • Baman J.
        • Aoued H.S.
        • Doshi N.K.
        • Liu R.C.
        • Ressler K.J.
        Perineuronal nets in the adult sensory cortex are necessary for fear learning.
        Neuron. 2017; 95: 169-179.e3
        • Gillet S.N.
        • Kato H.K.
        • Justen M.A.
        • Lai M.
        • Isaacson J.S.
        Fear learning regulates cortical sensory representations by suppressing habituation.
        Front Neural Circuits. 2018; 11: 112
        • Yang Y.
        • Liu D.Q.
        • Huang W.
        • Deng J.
        • Sun Y.
        • Zuo Y.
        • Poo M.M.
        Selective synaptic remodeling of amygdalocortical connections associated with fear memory [published correction appears in Nat Neurosci 2018; 21:1137.
        Nat Neurosci. 2016; 19: 1348-1355
        • Dalmay T.
        • Abs E.
        • Poorthuis R.B.
        • Hartung J.
        • Pu D.L.
        • Onasch S.
        • et al.
        A critical role for neocortical processing of threat memory.
        Neuron. 2019; 104: 1180-1194.e7
        • Wigestrand M.B.
        • Schiff H.C.
        • Fyhn M.
        • LeDoux J.E.
        • Sears R.M.
        Primary auditory cortex regulates threat memory specificity.
        Learn Mem. 2017; 24: 55-58
        • Antunes R.
        • Moita M.A.
        Discriminative auditory fear learning requires both tuned and nontuned auditory pathways to the amygdala.
        J Neurosci. 2010; 30: 9782-9787
        • Aizenberg M.
        • Mwilambwe-Tshilobo L.
        • Briguglio J.J.
        • Natan R.G.
        • Geffen M.N.
        Bidirectional regulation of innate and learned behaviors that rely on frequency discrimination by cortical inhibitory neurons.
        PLoS Biol. 2015; 13e1002308
        • Letzkus J.J.
        • Wolff S.B.E.
        • Meyer E.M.M.
        • Tovote P.
        • Courtin J.
        • Herry C.
        • Lüthi A.
        A disinhibitory microcircuit for associative fear learning in the auditory cortex.
        Nature. 2011; 480: 331-335
        • Kraus M.
        • Schicknick H.
        • Wetzel W.
        • Ohl F.
        • Staak S.
        • Tischmeyer W.
        Memory consolidation for the discrimination of frequency-modulated tones in Mongolian gerbils is sensitive to protein-synthesis inhibitors applied to the auditory cortex.
        Learn Mem. 2002; 9: 293-303
        • Zhang G.W.
        • Sun W.J.
        • Zingg B.
        • Shen L.
        • He J.
        • Xiong Y.
        • et al.
        A non-canonical reticular-limbic central auditory pathway via medial septum contributes to fear conditioning.
        Neuron. 2018; 97: 406-417.e4
        • Keil A.
        • Stolarova M.
        • Moratti S.
        • Ray W.J.
        Adaptation in human visual cortex as a mechanism for rapid discrimination of aversive stimuli.
        Neuroimage. 2007; 36: 472-479
        • Miskovic V.
        • Keil A.
        Perceiving threat in the face of safety: Excitation and inhibition of conditioned fear in human visual cortex.
        J Neurosci. 2013; 33: 72-78
        • Petro N.M.
        • Gruss L.F.
        • Yin S.
        • Huang H.
        • Miskovic V.
        • Ding M.
        • Keil A.
        Multimodal imaging evidence for a frontocortical modulation of visual cortex during the selective processing of conditioned threat.
        J Cogn Neurosci. 2017; 29: 953-967
        • Li W.
        • Howard J.D.
        • Parrish T.B.
        • Gottfried J.A.
        Aversive learning enhances perceptual and cortical discrimination of indiscriminable odor cues.
        Science. 2008; 319: 1842-1845
        • Apergis-Schoute A.M.
        • Schiller D.
        • LeDoux J.E.
        • Phelps E.A.
        Extinction resistant changes in the human auditory association cortex following threat learning.
        Neurobiol Learn Mem. 2014; 113: 109-114
        • Staib M.
        • Bach D.R.
        Stimulus-invariant auditory cortex threat encoding during fear conditioning with simple and complex sounds.
        Neuroimage. 2018; 166: 276-284
        • Staib M.
        • Abivardi A.
        • Bach D.R.
        Primary auditory cortex representation of fear-conditioned musical sounds.
        Hum Brain Mapp. 2020; 41: 882-891
        • You Y.
        • Brown J.
        • Li W.
        Human sensory cortex contributes to the long-term storage of aversive conditioning.
        J Neurosci. 2021; 41: 3222-3233
        • Huang Y.Z.
        • Edwards M.J.
        • Rounis E.
        • Bhatia K.P.
        • Rothwell J.C.
        Theta burst stimulation of the human motor cortex.
        Neuron. 2005; 45: 201-206
        • Gazzaniga M.S.
        Cerebral specialization and interhemispheric communication: Does the corpus callosum enable the human condition?.
        Brain. 2000; 123: 1293-1326
        • Harvie D.S.
        • Meulders A.
        • Madden V.J.
        • Hillier S.L.
        • Peto D.K.
        • Brinkworth R.
        • Moseley G.L.
        When touch predicts pain: Predictive tactile cues modulate perceived intensity of painful stimulation independent of expectancy.
        Scand J Pain. 2016; 11: 11-18
        • Harvie D.S.
        • Meulders A.
        • Reid E.
        • Camfferman D.
        • Brinkworth R.S.A.
        • Moseley G.L.
        Selectivity of conditioned fear of touch is modulated by somatosensory precision.
        Psychophysiology. 2016; 53: 921-929
        • Korn C.W.
        • Staib M.
        • Tzovara A.
        • Castegnetti G.
        • Bach D.R.
        A pupil size response model to assess fear learning.
        Psychophysiology. 2017; 54: 330-343
        • Polanía R.
        • Nitsche M.A.
        • Ruff C.C.
        Studying and modifying brain function with non-invasive brain stimulation.
        Nat Neurosci. 2018; 21: 174-187
        • Siebner H.R.
        • Rothwell J.
        Transcranial magnetic stimulation: New insights into representational cortical plasticity.
        Exp Brain Res. 2003; 148: 1-16
        • Huang Y.Z.
        • Chen R.S.
        • Rothwell J.C.
        • Wen H.Y.
        The after-effect of human theta burst stimulation is NMDA receptor dependent.
        Clin Neurophysiol. 2007; 118: 1028-1032
        • Li C.T.
        • Huang Y.Z.
        • Bai Y.M.
        • Tsai S.J.
        • Su T.P.
        • Cheng C.M.
        Critical role of glutamatergic and GABAergic neurotransmission in the central mechanisms of theta-burst stimulation.
        Hum Brain Mapp. 2019; 40: 2001-2009
        • Stagg C.J.
        • Wylezinska M.
        • Matthews P.M.
        • Johansen-Berg H.
        • Jezzard P.
        • Rothwell J.C.
        • Bestmann S.
        Neurochemical effects of theta burst stimulation as assessed by magnetic resonance spectroscopy [published correction appears in J Neurophysiol 2011; 105:3114].
        J Neurophysiol. 2009; 101: 2872-2877
        • Baltaci S.B.
        • Mogulkoc R.
        • Baltaci A.K.
        Molecular mechanisms of early and late LTP.
        Neurochem Res. 2019; 44: 281-296
        • Dudai Y.
        The neurobiology of consolidations, or, how stable is the engram?.
        Annu Rev Psychol. 2004; 55: 51-86
        • Bach D.R.
        • Melinscak F.
        Psychophysiological modelling and the measurement of fear conditioning.
        Behav Res Ther. 2020; 127: 103576
        • Khemka S.
        • Tzovara A.
        • Gerster S.
        • Quednow B.B.
        • Bach D.R.
        Modeling startle eyeblink electromyogram to assess fear learning.
        Psychophysiology. 2017; 54: 204-214
        • Ojala K.E.
        • Bach D.R.
        Measuring learning in human classical threat conditioning: Translational, cognitive and methodological considerations.
        Neurosci Biobehav Rev. 2020; 114: 96-112
        • 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
        • Staib M.
        • Castegnetti G.
        • Bach D.R.
        Optimising a model-based approach to inferring fear learning from skin conductance responses.
        J Neurosci Methods. 2015; 255: 131-138
        • R Core Team
        R: A language and environment for statistical computing.
        (Available at:)
        Date accessed: March 16, 2022
        • Lenth R.V.
        • Buerkner P.
        • Herve M.
        • Love J.
        • Miguez F.
        • Riebl H.
        • Singmann H.
        emmeans: Estimated marginal means, aka least-squares means.
        (Available at:)
        Date accessed: March 16, 2022
        • Ben-Shachar M.S.
        • Lüdecke D.
        • Makowski D.
        effectsize: Estimation of effect size indices and standardized parameters.
        J Open Source Softw. 2020; 5: 2815
        • Morey R.D.
        Confidence intervals from normalized data: A correction to Cousineau (2005).
        Tutor Quant Methods Psychol. 2008; 4: 61-64
        • Borgomaneri S.
        • Battaglia S.
        • Garofalo S.
        • Tortora F.
        • Avenanti A.
        • di Pellegrino G.
        State-dependent TMS over prefrontal cortex disrupts fear-memory reconsolidation and prevents the return of fear.
        Curr Biol. 2020; 30: 3672-3679.e4
        • Hamm A.O.
        • Weike A.I.
        • Schupp H.T.
        • Treig T.
        • Dressel A.
        • Kessler C.
        Affective blindsight: Intact fear conditioning to a visual cue in a cortically blind patient.
        Brain. 2003; 126: 267-275
        • Badura-Brack A.S.
        • Becker K.M.
        • McDermott T.J.
        • Ryan T.J.
        • Becker M.M.
        • Hearley A.R.
        • et al.
        Decreased somatosensory activity to non-threatening touch in combat veterans with posttraumatic stress disorder.
        Psychiatry Res. 2015; 233: 194-200
        • Gdalyahu A.
        • Tring E.
        • Polack P.O.
        • Gruver R.
        • Golshani P.
        • Fanselow M.S.
        • et al.
        Associative fear learning enhances sparse network coding in primary sensory cortex.
        Neuron. 2012; 75: 121-132
        • Joachimsthaler B.
        • Brugger D.
        • Skodras A.
        • Schwarz C.
        Spine loss in primary somatosensory cortex during trace eyeblink conditioning.
        J Neurosci. 2015; 35: 3772-3781
        • Tokarski K.
        • Urban-Ciecko J.
        • Kossut M.
        • Hess G.
        Sensory learning-induced enhancement of inhibitory synaptic transmission in the barrel cortex of the mouse.
        Eur J Neurosci. 2007; 26: 134-141
        • Weinberger N.M.
        Associative representational plasticity in the auditory cortex: A synthesis of two disciplines.
        Learn Mem. 2007; 14: 1-16
        • Kholodar-Smith D.B.
        • Allen T.A.
        • Brown T.H.
        Fear conditioning to discontinuous auditory cues requires perirhinal cortical function.
        Behav Neurosci. 2008; 122: 1178-1185
        • Bach D.R.
        • Tzovara A.
        • Vunder J.
        Blocking human fear memory with the matrix metalloproteinase inhibitor doxycycline.
        Mol Psychiatry. 2018; 23: 1584-1589
        • Bach D.R.
        • Melinščak F.
        • Fleming S.M.
        • Voelkle M.C.
        Calibrating the experimental measurement of psychological attributes.
        Nat Hum Behav. 2020; 4: 1229-1235
        • Vlachos A.
        • Müller-Dahlhaus F.
        • Rosskopp J.
        • Lenz M.
        • Ziemann U.
        • Deller T.
        Repetitive magnetic stimulation induces functional and structural plasticity of excitatory postsynapses in mouse organotypic hippocampal slice cultures.
        J Neurosci. 2012; 32: 17514-17523
        • Nitsche M.A.
        • Müller-Dahlhaus F.
        • Paulus W.
        • Ziemann U.
        The pharmacology of neuroplasticity induced by non-invasive brain stimulation: Building models for the clinical use of CNS active drugs.
        J Physiol. 2012; 590: 4641-4662
        • Fritsch B.
        • Reis J.
        • Martinowich K.
        • Schambra H.M.
        • Ji Y.
        • Cohen L.G.
        • Lu B.
        Direct current stimulation promotes BDNF-dependent synaptic plasticity: Potential implications for motor learning.
        Neuron. 2010; 66: 198-204
        • Cheeran B.
        • Talelli P.
        • Mori F.
        • Koch G.
        • Suppa A.
        • Edwards M.
        • et al.
        A common polymorphism in the brain-derived neurotrophic factor gene (BDNF) modulates human cortical plasticity and the response to rTMS.
        J Physiol. 2008; 586: 5717-5725
        • Ueyama E.
        • Ukai S.
        • Ogawa A.
        • Yamamoto M.
        • Kawaguchi S.
        • Ishii R.
        • Shinosaki K.
        Chronic repetitive transcranial magnetic stimulation increases hippocampal neurogenesis in rats.
        Psychiatry Clin Neurosci. 2011; 65: 77-81
        • Suppa A.
        • Huang Y.Z.
        • Funke K.
        • Ridding M.C.
        • Cheeran B.
        • Di Lazzaro V.
        • et al.
        Ten years of theta burst stimulation in humans: Established knowledge, unknowns and prospects.
        Brain Stimul. 2016; 9: 323-335
        • Silvanto J.
        • Bona S.
        • Marelli M.
        • Cattaneo Z.
        On the mechanisms of transcranial magnetic stimulation (TMS): How brain state and baseline performance level determine behavioral effects of TMS.
        Front Psychol. 2018; 9: 741
        • Bestmann S.
        • Feredoes E.
        Combined neurostimulation and neuroimaging in cognitive neuroscience: Past, present, and future.
        Ann N Y Acad Sci. 2013; 1296: 11-30
        • Valchev N.
        • Curčić-Blake B.
        • Renken R.J.
        • Avenanti A.
        • Keysers C.
        • Gazzola V.
        • Maurits N.M.
        cTBS delivered to the left somatosensory cortex changes its functional connectivity during rest.
        Neuroimage. 2015; 114: 386-397
        • Kroes M.C.W.
        • Schiller D.
        • LeDoux J.E.
        • Phelps E.A.
        Translational approaches targeting reconsolidation.
        Curr Top Behav Neurosci. 2016; 28: 197-230

      Linked Article

      • The High Road to Inhibiting Fear Memories
        Biological PsychiatryVol. 92Issue 2
        • Preview
          In an elegant study in the current issue of Biological Psychiatry, Ojala et al. (1) interrupt the consolidation of an acquired aversive memory via careful stimulation of sensory cortex—an approach that holds promise as a novel avenue of attenuating disruptive memories in clinical populations in the future.
        • Full-Text
        • PDF
      • Erratum
        Biological Psychiatry
        • Preview
          Erratum to: “Inhibiting Human Aversive Memory by Transcranial Theta-Burst Stimulation to the Primary Sensory Cortex”, by Ojala et al. (Biol Psychiatry 2022; 92:149-157); .
        • Full-Text
        • PDF
        Open Access