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Extinction Memory Is Impaired in Schizophrenia
Open accessAbstract
Background Schizophrenia is associated with abnormalities in emotional processing and social cognition, which might result from disruption of the underlying neural mechanism(s) governing emotional learning and memory. To investigate this possibility, we measured the acquisition and extinction of conditioned fear responses and delayed recall of extinction in schizophrenia and control subjects.Methods Twenty-eight schizophrenia and 18 demographically matched control subjects underwent a 2-day fear conditioning, extinction learning, and extinction recall procedure, in which skin conductance response (SCR) magnitude was used as the index of conditioned responses.Results During fear acquisition, 83% of the control subjects and 57% of the patients showed autonomic responsivity ("responders"), and the patients showed larger SCRs to the stimulus that was not paired with the unconditioned stimulus (CS-) than the control subjects. Within the responder group, there was no difference between the patients and control subjects in levels of extinction learning; however, the schizophrenia patients showed significant impairment, relative to the control subjects, in context-dependent recall of the extinction memory. In addition, delusion severity in the patients correlated with baseline skin conductance levels.Conclusions These data are consistent with prior evidence for a heightened neural response to innocuous stimuli in schizophrenia and elevated arousal levels in psychosis. The finding of deficient extinction recall in schizophrenia patients who showed intact extinction learning suggests that schizophrenia is associated with a disturbance in the neural processes supporting emotional memory.
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“Consistent with this possibility, altered fear learning, and related activity of the PFC and amygdala, has been reported in subjects with SZ (Holt et al., 2012; Holt et al., 2009).”
From Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia (2015) · cites this paper as Holt et al., 2009
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Cites
The Positive and Negative Syndrome Scale (PANSS) for schizophrenia.
Kay, S. R., Fiszbein, A., & Opler, L. A. (1987) · Schizophrenia Bulletin · doi:10.1093/schbul/13.2.261 · Cited by 21,378
LeDoux, J. E. (2000) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.23.1.155 · Cited by 8,444
Structured Clinical Interview for DSM-IV Axis I Disorders
Spitzer, R. L., First, M. B., & Gibbon, M. (1997) · Medical Entomology and Zoology · Cited by 3,582
Kapur, S. (2003) · American Journal of Psychiatry · doi:10.1176/appi.ajp.160.1.13 · Cited by 2,813
Neurons in medial prefrontal cortex signal memory for fear extinction
Milad, M. R., & Quirk, G. J. (2002) · Nature · doi:10.1038/nature01138 · Cited by 1,836
Self-citationEffects of an expanding-spaced vs massed exposure schedule on fear reduction and return of fear
Rowe, M. K., & Craske, M. G. (1998) · Behaviour Research and Therapy · doi:10.1016/s0005-7967(97)10016-x · Cited by 1,782
Phelps, E. A., Delgado, M. R., Nearing, K. I., & LeDoux, J. E. (2004) · Neuron · doi:10.1016/j.neuron.2004.08.042 · Cited by 1,753
Meta-analysis of regional brain volumes in schizophrenia
Wright, I. C., Rabe-Hesketh, S., Woodruff, P. W. R., David, A. S., Murray, R. M., & Bullmore, E. T. (2000) · American Journal of Psychiatry · doi:10.1176/ajp.157.1.16 · Cited by 1,662
Neural Mechanisms of Extinction Learning and Retrieval
Quirk, G. J., & Mueller, D. (2008) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301555 · Cited by 1,645
Rauch, S. L., Shin, L. M., & Phelps, E. A. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.06.004 · Cited by 1,397
Self-citation
Research works printed but not linked: 1
- Holt, 2007, Abnormal neural responses to ambiguous social information in psychosis, Schizophr Bull, 33, 524
Cited by
Sorted by citations
Hölzel, B. K., Lazar, S. W., Gard, T., Schuman-Olivier, Z., Vago, D. R., & Ott, U. (2011) · Perspectives on Psychological Science · doi:10.1177/1745691611419671 · Cited by 3,024
“, 2009), schizophrenia (Holt et al., 2009), and depression (Anand et al.”
The Neuroscience of Mindfulness Meditation
Tang, Y.-Y., Hölzel, B. K., & Posner, M. I. (2015) · Nature reviews. Neuroscience · doi:10.1038/nrn3916 · Cited by 2,889
Fear Extinction as a Model for Translational Neuroscience: Ten Years of Progress
Milad, M. R., & Quirk, G. J. (2012) · Annual Review of Psychology · doi:10.1146/annurev.psych.121208.131631 · Cited by 1,466
“Similar observations have been made for schizophrenic subjects (Holt et al. 2009), which suggests that dysfunction in fear extinction circuits might cut across disorders (Graham & Milad 2011, Insel et al.”
BackgroundResultSelf-citationWamsley, E. J., Tucker, M. A., Shinn, A. K., Ono, K. E., McKinley, S. K., Ely, A. V., Goff, D. C., Stickgold, R., & Manoach, D. S. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.08.008 · Cited by 492
From Pavlov to PTSD: The extinction of conditioned fear in rodents, humans, and anxiety disorders
VanElzakker, M. B., Kathryn Dahlgren, M., Caroline Davis, F., Dubois, S., & Shin, L. M. (2014) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2013.11.014 · Cited by 482
“Consistent with this strategic plan, researchers have begun to examine fear conditioning and extinction measures across diagnostic categories (e.g., Holt et al., 2009; Lissek et al., 2005).”
BackgroundThe hippocampal–prefrontal pathway: The weak link in psychiatric disorders?
Godsil, B. P., Kiss, J., Spedding, M., & Jay, T. M. (2013) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2012.10.018 · Cited by 459
“Importantly, these responder patients displayed normal extinction learning, but impaired context-dependent recall of extinction (Holt et al., 2009).”
Toward a neurobiology of delusions
Corlett, P. R., Taylor, J. R., Wang, X.-J., Fletcher, P. C., & Krystal, J. H. (2010) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2010.06.007 · Cited by 394
“The top-down instantiation of extinction learning is particularly interesting in this respect; the dopaminergic and GABAergic mechanisms that override old fear learning with new extinction learning (Bissiere et al., 2003) may be impaired in schizophrenia (Holt et al., 2008).”
BackgroundInfluentialMilad, M. R., Furtak, S. C., Greenberg, J. L., Keshaviah, A., Im, J. J., Falkenstein, M. J., Jenike, M., Rauch, S. L., & Wilhelm, S. (2013) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2013.914 · Cited by 308
Bussey, T. J., Holmes, A., Lyon, L., Mar, A. C., McAllister, K. A. L., Nithianantharajah, J., Oomen, C. A., & Saksida, L. M. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.04.011 · Cited by 299
Synaptic scaffold evolution generated components of vertebrate cognitive complexity
Nithianantharajah, J., Komiyama, N. H., McKechanie, A., Johnstone, M., Blackwood, D. H., Clair, D. S., Emes, R. D., van de Lagemaat, L. N., Saksida, L. M., Bussey, T. J., et al. (2013) · Nature Neuroscience · doi:10.1038/nn.3276 · Cited by 251
Erasing Fear Memories with Extinction Training: Figure 1.
Quirk, G. J., Paré, D., Richardson, R., Herry, C., Monfils, M., Schiller, D., & Vicentic, A. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.4268-10.2010 · Cited by 233
“Impairments in extinction have also been reported in a subset of schizophrenia patients who showed a general inability to retrieve safety signals (Holt et al., 2009).”
BackgroundHDAC1 Regulates Fear Extinction in Mice
Bahari‐Javan, S., Maddalena, A., Kerimoglu, C., Wittnam, J. L., Held, T., Bähr, M., Burkhardt, S., Delalle, I., Kügler, S., Fischer, A., et al. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.0079-12.2012 · Cited by 195
“Thus, we decided to investigate fear extinction learning, a specific form of emotional memory that is also affected in patients suffering from schizophrenia (Holt et al., 2009).”
BackgroundExtracellular matrix abnormalities in schizophrenia
Berretta, S. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.08.010 · Cited by 179
“Notably, abnormal fear conditioning and extinction has been observed in subjects with SZ (Holt et al., 2009).”
BackgroundBerretta, S., Pantazopoulos, H., Markota, M., Brown, C., & Batzianouli, E. T. (2015) · Schizophrenia Research · doi:10.1016/j.schres.2014.12.040 · Cited by 152
Marin, M., Zsido, R. G., Song, H., Lasko, N. B., Killgore, W. D. S., Rauch, S. L., Simon, N. M., & Milad, M. R. (2017) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2017.0329 · Cited by 151
Tanaka, M., Szabó, Á., Spekker, E., Polyák, H., Tóth, F., & Vécsei, L. (2022) · Cells · doi:10.3390/cells11162607 · Cited by 164
“Hypoactivation in the ventromedial PFC with hyperactivation in the dorsal anterior cingulate cortex are reported in patients with PTSD and SCZ [133,134].”
BackgroundNeuroimaging of fear-associated learning
Greco, J. A., & Liberzon, I. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2015.255 · Cited by 145
Corlett, P. R. (2009) · Frontiers in Human Neuroscience · doi:10.3389/neuro.09.012.2009 · Cited by 146
Rabinak, C. A., Angstadt, M., Lyons, M., Mori, S., Milad, M. R., Liberzon, I., & Phan, K. L. (2013) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2013.09.009 · Cited by 148
Infralimbic D2 Receptors Are Necessary for Fear Extinction and Extinction-Related Tone Responses
Mueller, D. T., Bravo-Rivera, C., & Quirk, G. J. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.08.014 · Cited by 139
Failure of Neural Responses to Safety Cues in Schizophrenia
Holt, D. J., Coombs, G., Zeidan, M. A., Goff, D. C., & Milad, M. R. (2012) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2011.2310 · Cited by 121
“Previously, we examined fear and extinction learning and memory in patients with schizophrenia by measuring skin conductance responses (SCRs) using a validated 2-day Pavlovian fear conditioning and extinction paradigm.(17) We found that both healthy control subjects and schizophrenic patients were able to successfully…”
MethodResultIs Altered BDNF Biosynthesis a General Feature in Patients with Cognitive Dysfunctions?
Carlino, D., Vanna, M. D., & Tongiorgi, E. (2012) · The Neuroscientist · doi:10.1177/1073858412469444 · Cited by 117
Ketamine effects on memory reconsolidation favor a learning model of delusions
Corlett, P. R., Cambridge, V., Gardner, J. M., Piggot, J. S., Turner, D. C., Everitt, J. C., Arana, F. S., Morgan, H. L., Milton, A. L., Lee, J. L., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0065088 · Cited by 105
“Indeed, extinction learning fails to consolidate in patients with schizophrenia [101].”
BackgroundLinnman, C., Zeidan, M. A., Furtak, S. C., Pitman, R. K., Quirk, G. J., & Milad, M. R. (2012) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2011.10121780 · Cited by 107
Wilson, C., Vazdarjanova, A. I., & Terry, A. V. (2012) · Behavioural Brain Research · doi:10.1016/j.bbr.2012.10.003 · Cited by 99
Barkus, C., Sanderson, D. J., Rawlins, J. N. P., Walton, M. E., Harrison, P. J., & Bannerman, D. M. (2014) · Molecular Psychiatry · doi:10.1038/mp.2014.91 · Cited by 92
Anderson, E., Siegel, E. H., White, D. A., & Barrett, L. F. (2012) · Emotion · doi:10.1037/a0027514 · Cited by 92
“Neuroimaging results suggest that these findings may be due to impaired functioning of paralimbic midline structures (Holt, Lakshmanan, et al., 2009) that are involved in regulating somatovisceral aspects of the body and representing those changes as affect.”
BackgroundFear Extinction Retention: Is It What We Think It Is?
Lonsdorf, T. B., Merz, C. J., & Fullana, M. A. (2019) · Biological Psychiatry · doi:10.1016/j.biopsych.2019.02.011 · Cited by 83
Barkus, C., Feyder, M. J., Graybeal, C., Wright, T., Wiedholz, L. M., Izquierdo, A., Kiselycznyk, C., Schmitt, W. B., Sanderson, D. J., Rawlins, J. N. P., et al. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.06.005 · Cited by 82
“With regards to the pattern of cognitive and executive alterations we found in these mice, the apparently impaired operant extinction could be reminiscent of the deficient extinction of fear responses in schizophrenia (Holt et al., 2009), although it could also simply reflect stronger initial acquisition of the operan…”
BackgroundMotivational Deficits in Schizophrenia and the Representation of Expected Value
Waltz, J. A., & Gold, J. M. (2015) · Current topics in behavioral neurosciences · doi:10.1007/7854_2015_385 · Cited by 84
“In this study Holt and colleagues (2012) used a paradigm similar to the one described above in their behavior study (Holt et al., 2009).”
MethodIs the mTOR‐signalling cascade disrupted in Schizophrenia?
Gururajan, A., & van den Buuse, M. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12622 · Cited by 81
Caballero, A., Flores-Barrera, E., Thomases, D. R., & Tseng, K. Y. (2020) · Neuropsychopharmacology · doi:10.1038/s41386-020-0709-9 · Cited by 81
Sterzer, P., Mishara, A. L., Voss, M., & Heinz, A. (2016) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2016.00502 · Cited by 76
“Another example of reduced context effects in learning is the observation that in people with schizophrenia the recall of extinction learning following fear conditioning is impaired, with a reduced effect of the context that was learned during extinction on conditioned responses (Holt et al., 2009).”
BackgroundEpisodic Memory in Schizophrenia
Leavitt, V. M., & Goldberg, T. E. (2009) · Neuropsychology Review · doi:10.1007/s11065-009-9107-0 · Cited by 80
“…important to note that while a number of excellent investigations of memory have employed classical conditioning paradigms (e.g., emotional memory, Holt et al. 2009); we have chosen not to include these here, as we believe that these may be tapping processing networks not explicitly involved in…”
D-cycloserine facilitation of cognitive behavioral therapy for delusions in schizophrenia
Gottlieb, J. D., Cather, C., Shanahan, M., Creedon, T., Macklin, E. A., & Goff, D. C. (2011) · Schizophrenia Research · doi:10.1016/j.schres.2011.05.029 · Cited by 73
“Consistent with a defect in NMDA receptor function, individuals with schizophrenia exhibit deficits inmemory consolidationwhen tested 24 h after both procedural memory training (Manoach et al., 2004) and conditioned fear extinction training (Holt et al., 2009) compared to healthy controls.”
BackgroundSelf-citationCotinine: Beyond that Expected, More than a Biomarker of Tobacco Consumption
Echeverrı́a, V. (2012) · Frontiers in Pharmacology · doi:10.3389/fphar.2012.00173 · Cited by 73
d-Cycloserine augmentation of cognitive remediation in schizophrenia
Cain, C. K., McCue, M. G., Bello, I., Creedon, T. B., Tang, D., LASKA, E. M., & GOFF, D. C. (2014) · Schizophrenia Research · doi:10.1016/j.schres.2014.01.016 · Cited by 75
“We have found deficits in fear extinction in subjects with schizophrenia (Holt et al., 2009; Holt et al., 2012), and numerous studies have demonstrated facilitation of fear extinction with DCS (Davis, 2011).”
BackgroundCamp, M., Norcross, M. A., Whittle, N., Feyder, M. J., D’Hanis, W., Yilmazer‐Hanke, D., Singewald, N., & Holmes, A. (2009) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2009.00519.x · Cited by 69
“Fear extinction, the learned inhibition of a conditioned fear response (Pavlov 1927), is impaired in anxiety disorders such as phobias and post-traumatic stress disorder (PTSD), as well as schizophrenia (Holt et al. 2008).”
BackgroundCognitive enhancers for anxiety disorders
Hofmann, S. G., Smits, J. A. J., Asnaani, A., Gutner, C. A., & Otto, M. W. (2010) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2010.11.020 · Cited by 69
“For example, deficits in extinction retention have been found in schizophrenia (Holt et al., 2009), and animal studies suggests that DCS may help overcome specific extinction retention deficits, at least those that occur developmentally (e.”
BackgroundPitts, M. W., Raman, A. V., Hashimoto, A. C., Todorovic, C., Nichols, R. A., & Berry, M. J. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.02.017 · Cited by 67
Kredlow, M. A., Pineles, S. L., Inslicht, S. S., Marin, M., Milad, M. R., Otto, M. W., & Orr, S. P. (2017) · Psychophysiology · doi:10.1111/psyp.12909 · Cited by 66
“Samples 4a and 4b—Sample 4a (AA, n = 14; non-AA, n = 28) and 4b (AA, n = 13; nonAA, n = 26) consists of group data from multiple studies conducted by Milad and colleagues that examined fear conditioning in a range of clinical and healthy populations (Holt, Coombs, Zeidan, Goff, & Milad, 2012; Holt et al., 2009; Hwang…”
BackgroundMethodInfluentialSevinc, G., Hölzel, B. K., Greenberg, J., Gard, T., Brunsch, V., Hashmi, J. A., Vangel, M. G., Orr, S. P., Milad, M. R., & Lazar, S. W. (2019) · Biological Psychiatry · doi:10.1016/j.biopsych.2019.05.017 · Cited by 66
D-Cycloserine: An Evolving Role in Learning and Neuroplasticity in Schizophrenia
GOFF, D. C. (2012) · Schizophrenia Bulletin · doi:10.1093/schbul/sbs012 · Cited by 65
Test–Retest Reliability during Fear Acquisition and Fear Extinction in Humans
Zeidan, M. A., Lebrón‐Milad, K., Thompson‐Hollands, J., Im, J. J. Y., Dougherty, D. D., Holt, D. J., Orr, S. P., & Milad, M. R. (2011) · CNS Neuroscience & Therapeutics · doi:10.1111/j.1755-5949.2011.00238.x · Cited by 64
“Studies using the 2-day fear conditioning procedure demonstrated that patients diagnosed with schizophrenia and posttraumatic stress disorder (PTSD) exhibited deficits in fear extinction memory recall[11,12].”
Neurobiological advances of learned fear in humans
Battaglia, S. (2022) · Advances in Clinical and Experimental Medicine · doi:10.17219/acem/146756 · Cited by 65
Cognition-Emotion Dysinteraction in Schizophrenia
Anticevic, A., & Corlett, P. R. (2012) · Frontiers in Psychology · doi:10.3389/fpsyg.2012.00392 · Cited by 66
Naert, A., Callaerts‐Vegh, Z., & D’Hooge, R. (2011) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2011.03.027 · Cited by 63
MicroRNAs in the Onset of Schizophrenia
Thomas, K. T., & Zakharenko, S. S. (2021) · Cells · doi:10.3390/cells10102679 · Cited by 64
Lebrón‐Milad, K., Tsareva, A., Ahmed, N., & Milad, M. R. (2013) · Behavioural Brain Research · doi:10.1016/j.bbr.2013.07.024 · Cited by 58
“Failure to extinguish conditioned fears has been reported to possibly contribute to the etiology and/or maintenance of elevated fear across psychiatric disorders such PTSD [3–5], OCD [6], and schizophrenia [7].”
BackgroundGalatzer‐Levy, I. R., Andero, R., Sawamura, T., Jovanović, T., Papini, S., Ressler, K. J., & Norrholm, S. D. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.12.023 · Cited by 55
“, 2011) and other mental disorders (Holt et al., 2009; Ressler andMayberg, 2007), supporting the assertion that extinction learning represents a key dimension underlying stress pathology.”
BackgroundPapaleo, F., Yang, F., Paterson, C., Palumbo, S., Carr, G. V., Wang, Y., Floyd, K., Huang, W., Thomas, C. J., Chen, J., et al. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.4632-15.2016 · Cited by 55
“…is a multifactorial brain disorder with complex genetic, neurodevelopmental, and environmental origins (Weinberger, 1987; Rapoport et al., 2012; Howes and Murray, 2014; Schizophrenia Working Group of the Psychiatric Genomics Received Dec. 24, 2015; revised March 3, 2016; accepted March 22,…”
BackgroundHasan, A., Mitchell, A., Schneider, A., Halene, T. B., & Akbarian, S. (2013) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-013-0395-2 · Cited by 52
“Fear extinction can be considered as a certain kind of emotional memory which has been shown to be affected in schizophrenia patients [10, 63].”
BackgroundPedraza, C., Sánchez-López, J., Castilla‐Ortega, E., Rosell‐Valle, C., Zambrana-Infantes, E. N., Garcia‐Fernandez, M. I., de Fonseca, F. R., Chun, J. J. M., Santín, L. J., & Estivill‐Torrús, G. (2013) · Brain Structure and Function · doi:10.1007/s00429-013-0592-9 · Cited by 53
Mindfulness-Based Stress Reduction, Fear Conditioning, and The Uncinate Fasciculus: A Pilot Study
Hölzel, B. K., Brunsch, V., Gard, T., Greve, D. N., Koch, K., Sorg, C., Lazar, S. W., & Milad, M. R. (2016) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2016.00124 · Cited by 56
“Recent research has shown that successful extinction memory reliably differentiates healthy from pathological conditions (Milad et al., 2008; Holt et al., 2009; Graham and Milad, 2011).”
BackgroundHolt, D. J., Boeke, E. A., Wolthusen, R. P. F., Nasr, S., Milad, M. R., & Tootell, R. B. H. (2014) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2014.00624 · Cited by 51
“Next, the intensity of the US was set by each participant to a level that was “highly annoying but not painful” (Milad et al., 2005; Holt et al., 2009).”
Cortical stress regulation is disrupted in schizophrenia but not in clinical high risk for psychosis
Schifani, C., Tseng, H., Kenk, M., Tagore, A., Kiang, M., Wilson, A. A., Houle, S., Rusjan, P., & Mizrahi, R. (2018) · Brain · doi:10.1093/brain/awy133 · Cited by 47
Resolving the Delusion Paradox
Petrović, P., & Sterzer, P. (2023) · Schizophrenia Bulletin · doi:10.1093/schbul/sbad084 · Cited by 45
“71,72 As in reward learning, these differences are largely due to aberrant responses to stimuli not associated with fear learning, an effect that also was related to delusion severity.”
BackgroundDysfunction of a Cortical Midline Network During Emotional Appraisals in Schizophrenia
Holt, D. J., Lakshmanan, B. M., Freudenreich, O., GOFF, D. C., Rauch, S. L., & Kuperberg, G. R. (2009) · Schizophrenia Bulletin · doi:10.1093/schbul/sbp067 · Cited by 45
Characterization of fear conditioning and fear extinction by analysis of electrodermal activity
Faghih, R. T., Stokes, P. A., Marin, M., Zsido, R. G., Zorowitz, S., Rosenbaum, B. L., Song, H., Milad, M. R., Dougherty, D. D., Eskandar, E. N., et al. (2015) · Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC) · doi:10.1109/embc.2015.7320204 · Cited by 43
Piantadosi, P. T., & Floresco, S. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.99 · Cited by 43
“This exacerbated fear response is reminiscent of deficient extinction learning in schizophrenia, whereby individuals do not recall extinction memories as strongly as controls and continuing to display elevated conditioned responses despite extinction training (Holt et al, 2009, 2012).”
GOFF, D. C. (2016) · Current Neuropharmacology · doi:10.2174/1570159x14666160225154812 · Cited by 40
“Of note, contextual fear conditioning is relatively intact in schizophrenia, as is immediate recall of fear extinction [115, 116].”
Amodio, A., Quarantelli, M., Mucci, A., Prinster, A., Soricelli, A., Vignapiano, A., Giordano, G. M., Merlotti, E., Nicita, A., & Galderisi, S. (2017) · Clinical EEG and Neuroscience · doi:10.1177/1550059417745934 · Cited by 41
“In fact, the circuit including NAcc and OFC is critical for encoding prediction about future outcome (expected value) for reward-guided decision making.(96,114,115,118-122) Two previous studies found WM abnormalities within rNAcc and mOFC pathways, already in the early stage of the disease, and reported correlations w…”
BackgroundAbsence of conditioned responding in humans: A bad measure or individual differences?
Marin, M., Barbey, F. M., Rosenbaum, B. L., Hammoud, M. Z., Orr, S. P., & Milad, M. R. (2019) · Psychophysiology · doi:10.1111/psyp.13350 · Cited by 41
Lack of insula reactivity to aversive stimuli in schizophrenia
Linnman, C., Coombs, G., GOFF, D. C., & Holt, D. J. (2012) · Schizophrenia Research · doi:10.1016/j.schres.2012.10.038 · Cited by 37
“Using a Pavlovian fear-conditioning protocol (Milad et al., 2007; Holt et al., 2009) we examined neural and autonomic responses to conditioned (CS+) and unconditioned stimulus (US, an electrical shock) presentations in a partial reinforcement paradigm.”
MethodChalkiadaki, K., Velli, A., Kyriazidis, E., Stavroulaki, V., Vouvoutsis, V., Chatzaki, E., Aivaliotis, M., & Sidiropoulou, K. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.10.026 · Cited by 33
The relationship of perceptual discrimination to neural mechanisms of fear generalization
Tuominen, L. J., Boeke, E. A., DeCross, S. N., Wolthusen, R. P. F., Nasr, S., Milad, M. R., Vangel, M. G., Tootell, R. B. H., & Holt, D. J. (2018) · NeuroImage · doi:10.1016/j.neuroimage.2018.12.034 · Cited by 34
“Before the scan, the intensity of the electric shock was set by each subject at a level that was “ highly annoying but not painful ” (Holt et al., 2009, 2014; Milad et al., 2005).”
Maksymetz, J., Joffe, M. E., Moran, S. P., Stansley, B. J., Li, B., Temple, K. J., Engers, D. W., Lawrence, J. J., Lindsley, C. W., & Conn, P. J. (2019) · Biological Psychiatry · doi:10.1016/j.biopsych.2019.02.020 · Cited by 36
“Dysfunctional connectivity between the hippocampus, amygdala, and PFC (46, 65) and impaired fear extinction (66) are present in many psychiatric disorders therefore these results and potential translatability may be relevant to disorders other than PTSD.”
BackgroundThe effect of ketamine on the consolidation and extinction of contextual fear memory
Clifton, N. E., Thomas, K. L., & Hall, J. (2018) · Journal of Psychopharmacology · doi:10.1177/0269881117748903 · Cited by 33
“These findings are consistent with impaired extinction learning in schizophrenia (Holt et al., 2009) and parallel the selective impact of schizophrenia-related copy number variants on molecular processes engaged during extinction learning (Clifton et al., 2017).”
de Bruin, N. M. W. J., Drimmelen, M. V., Kops, M. S., van Elk, J., de Wetering, M. M.-V., & Schwienbacher, I. (2013) · Behavioural Brain Research · doi:10.1016/j.bbr.2013.01.035 · Cited by 34
Impairment in acquisition of conditioned fear in schizophrenia
Tuominen, L. J., Romaniuk, L., Milad, M. R., GOFF, D. C., Hall, J., & Holt, D. J. (2021) · Neuropsychopharmacology · doi:10.1038/s41386-021-01193-1 · Cited by 30
Wellman, C. L., & Moench, K. M. (2018) · Psychopharmacology · doi:10.1007/s00213-018-5023-4 · Cited by 33
A mechanism-oriented approach to psychopathology: The role of Pavlovian conditioning
Nees, F., Heinrich, A., & Flor, H. (2015) · International Journal of Psychophysiology · doi:10.1016/j.ijpsycho.2015.05.005 · Cited by 36
Sangha, S., Greba, Q., Robinson, P., Ballendine, S., & Howland, J. (2014) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2014.00168 · Cited by 33
“Patients with schizophrenia show impaired fear inhibition after extinction of cued fear (Holt et al., 2009), an effect that may be due to altered activation of the ventromedial prefrontal cortex (Holt et al., 2012).”
BackgroundNeuregulin 3 Knockout Mice Exhibit Behaviors Consistent with Psychotic Disorders
Hayes, L. N., Shevelkin, A. V., Zeledón, M., Steel, G., Chen, P., Obie, C., Pulver, A. E., Avramopoulos, D., Valle, D. L., Sawa, A., et al. (2016) · Complex Psychiatry · doi:10.1159/000445836 · Cited by 31
Amygdala subnucleus volumes in psychosis high-risk state and first-episode psychosis
Armio, R.-L., Laurikainen, H., Ilonen, T., Walta, M., Salokangas, R. K. R., Koutsouleris, N., Hietala, J. A., & Tuominen, L. J. (2019) · Schizophrenia Research · doi:10.1016/j.schres.2019.10.014 · Cited by 32
Predicting Impaired Extinction of Traumatic Memory and Elevated Startle
Nalloor, R. I., Bunting, K. M., & Vazdarjanova, A. I. (2011) · PLoS ONE · doi:10.1371/journal.pone.0019760 · Cited by 29
“Such impairments are not unique to PTSD; for example, impaired fear extinction is also common in depression and schizophrenia [35].”
BackgroundGraybeal, C., Kiselycznyk, C., & Holmes, A. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.02.042 · Cited by 30
“Fear extinction is not a measure of executive function but is very salient to the current discussion given the importance of the mPFC to fear extinction (Quirk and Mueller, 2008) and clinical evidence of deficient fear extinction in diseases such as schizophrenia, where PFC dysfunction is prominent (Holt et al., 2008).”
BackgroundHaan, N., Westacott, L. J., Carter, J., Owen, M. J., Gray, W. P., Hall, J., & Wilkinson, L. S. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01415-6 · Cited by 29
Ago, Y., Hayata‐Takano, A., Kawanai, T., Yamauchi, R., Takeuchi, S., Cushman, J. D., Rajbhandari, A. K., Fanselow, M. S., Hashimoto, H., & Waschek, J. A. (2017) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2017.10.010 · Cited by 28
“However, dysfunction in the fear system can produce inappropriate and excessive fear responses that lead to psychiatric diseases, such as anxiety disorders (Dymond, Dunsmoor, Vervliet, Roche, & Hermans, 2015), post-traumatic stress disorder (PTSD) (Maren, Phan, & Liberzon, 2013), autism spectrum disorder (Evans, Canav…”
Temporal factors in the extinction of fear in inbred mouse strains differing in extinction efficacy
MacPherson, K. P., Whittle, N., Camp, M., Gunduz‐Cinar, O., Singewald, N., & Holmes, A. (2013) · Biology of Mood & Anxiety Disorders · doi:10.1186/2045-5380-3-13 · Cited by 31
“Various neuropsychiatric conditions, including posttraumatic stress disorder (PTSD) [2] and schizophrenia [3], are characterized by deficient fear extinction.”
BackgroundAgo, Y., Condro, M. C., Tan, Y., Ghiani, C. A., Colwell, C. S., Cushman, J. D., Fanselow, M. S., Hashimoto, H., & Waschek, J. A. (2015) · Psychopharmacology · doi:10.1007/s00213-014-3848-z · Cited by 28
“…during early postnatal development on fear learning (conditioning, retrieval, and extinction), alterations of which represent an endophenotype that has been documented in schizophrenic patients and recapitulated in multiple mouse models of schizophrenia (Amann et al. 2010; Holt et al. 2009, 2012).”
BackgroundSugar glues for broken neurons
Swarup, V. P., Mencio, C. P., Hlady, V., & Kuberan, B. (2013) · BioMolecular Concepts · doi:10.1515/bmc-2012-0042 · Cited by 27
“This may be directly influenced by alterations in the PNN present in the amygdala, as previous studies have shown that enzymatic degradation of this structure disrupted fear learning (122, 123) .”
Impairment in Long-Term Retention of Preference Conditioning in Schizophrenia
Herbener, E. S. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.01.020 · Cited by 27
Yan, P., Qiao, X., Wu, H., Yin, F., Zhang, J., Ji, Y., Wei, S., & Lai, J. (2016) · Journal of Molecular Neuroscience · doi:10.1007/s12031-016-0751-6 · Cited by 27
“development and influences neuronal morphology through cell–cell interactions (Tepass et al. 2000; Holt et al. 2009; Deans et al. 2011).”
BackgroundTrent, S., Abdullah, M. H., Parwana, K., Valdivieso, M. A., Hassan, Z., & Müller, C. P. (2025) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2025.111310 · Cited by 31
“Additionally, clinical studies have shown that schizophrenia patients have impaired recall of fear memory (Holt et al., 2009, 2012), whilst schizophrenia risk genes overlap with extinction genes (Clifton et al., 2017).”
Perez, D. L., Pan, H., Weisholtz, D. S., Root, J. C., Tüscher, O., Fischer, D. B., Butler, T., Vago, D. R., Isenberg, N., Epstein, J., et al. (2015) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2015.06.002 · Cited by 25
“Schizophrenic patients show associative learning deficits exemplified by heightened CS- related autonomic activity and impaired extinction learning(Holt et al., 2009).”
BackgroundThe Mechanisms and Boundary Conditions of Drug Memory Reconsolidation
Chen, L., He, Y., Wang, Y., He, Z., Leng, Q., Huang, S., Wu, F., Feng, X., & Yan, J. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.717956 · Cited by 23
Sleep dysfunctions in schizophrenia: A practical review
Waters, F., & Manoach, D. S. (2012) · Open Journal of Psychiatry · doi:10.4236/ojpsych.2012.224054 · Cited by 24
“solidation across multiple domains [50].”
Hippocampal circuits underlie improvements in self‐reported anxiety following mindfulness training
Sevinc, G., Greenberg, J., Hölzel, B. K., Gard, T., Calahan, T., Brunsch, V., Hashmi, J. A., Vangel, M. G., Orr, S. P., Milad, M. R., et al. (2020) · Brain and Behavior · doi:10.1002/brb3.1766 · Cited by 24
“Similarly, longitudinal studies investigating mindfulness interventions have demonstrated increased hippocampal gray matter density (Holzel et al., 2011) as well as alterations in hippocampal functioning and increased connectivity between the hippocampus and other brain regions, both during and…”
BackgroundResultInfluentialLesions to the ventral, but not the dorsal, medial prefrontal cortex enhance latent inhibition
George, D. N., Duffaud, A. M., Pothuizen, H. H. J., Haddon, J. E., & Killcross, S. (2010) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2010.07178.x · Cited by 27
“…those seen in patients with schizophrenia: an enhanced latent inhibition effect has been observed in patients with chronic schizophrenia (Rascle et al., 2001; Gal et al., 2009), and Holt et al. (2009) have recently shown that schizophrenic patient fail to recall extinction of fear conditioning.”
BackgroundRenewal in human fear conditioning: A systematic review and meta-analysis
Wang, Y., Olsson, S., Lipp, O. V., & Ney, L. J. (2024) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2024.105606 · Cited by 23
“In another study, patients with schizophrenia did not show renewal, while a healthy control group displayed renewal (Holt et al., 2009).”
Pollard, M., Varin, C., Hrupka, B. J., Pemberton, D. J., Steckler, T., & Shaban, H. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.10.050 · Cited by 22
Johnson, J. (2024) · Brain Circulation · doi:10.4103/bc.bc_86_23 · Cited by 22
“[48] There is a piece of evidence provided by neurotrophins such as Brain Derived Neurotropic factor (BDNF) for the explanation of the framework.”
BackgroundSchizophrenia copy number variants and associative learning
Clifton, N. E., Pocklington, A. J., Scholz, B., Rees, E., Walters, J., Kirov, G., O’Donovan, M. C., Owen, M. J., Wilkinson, L. S., Thomas, K. L., et al. (2016) · Molecular Psychiatry · doi:10.1038/mp.2016.227 · Cited by 22
“15,25,26 It is not known, however, which components of associative learning are affected by genes in schizophrenia-associated CNVs.”
BackgroundMíguez‐Burbano, M. J., Espinoza, L. A., Whitehead, N. E., Bryant, V., Vargas, M., Cook, R. L., Quiros, C., Lewis, J. E., & Asthana, D. (2014) · Current HIV Research · doi:10.2174/1570162x12666140721121238 · Cited by 21
“Similarly to studies among the general medical literature that have observed a relationship between BDNF levels and screening dementia tests, such as the Global Cognitive Score and Mini Mental State Examination score [60], a relationship between BDNF levels and the HIV dementia scoring was evident.”
ResultCalcyon upregulation in adolescence impairs response inhibition and working memory in adulthood
Vazdarjanova, A., Bunting, K., Muthusamy, N., & Bergson, C. (2011) · Molecular Psychiatry · doi:10.1038/mp.2011.14 · Cited by 20
Bhardwaj, S. K., Tse, Y. C., Ryan, R., Wong, T. P., & Srivastava, L. K. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.142 · Cited by 21
“Further, while impaired fear extinction is common in conditions of altered adrenergic responsivity, such as posttraumatic stress disorder and stress (Holmes and Wellman 2008), a deficit in fear extinction memory has also been shown in individuals suffering from schizophrenia (Holt et al. 2009).”
Harb, M., Jagusch, J., Durairaja, A., Endres, T., Leßmann, V., & Fendt, M. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01365-z · Cited by 23
Dean, B. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107510 · Cited by 20
Beyond the γ-aminobutyric acid hypothesis of schizophrenia
Fujihara, K. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1161608 · Cited by 20
Metadata
- Authors
- Holt, D. J., Lebron-Milad, K., Milad, M. R., Rauch, S. L., Pitman, R. K., Orr, S. P., Cassidy, B. S., Walsh, J. P., & Goff, D. C.
- Affiliations
- Harvard University (US)
- McLean Hospital (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Holt, Daphne J.
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2009-03
- Volume
- 65
- Issue
- 6
- Pages
- 455-463
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC3740529
- OpenAlex
- W2076938137
- Cited by
- 170
- References
- 93
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 9 · 2023: 8 · 2022: 8 · 2021: 8 · 2020: 7 · 2019: 10 · 2018: 15 · 2017: 8 · 2016: 11 · 2015: 10 · 2014: 8 · 2013: 16 · 2012: 19
- FWCI
- 5.62
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (K23MH076054, K24MH002025)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- schizophrenia, memory extinction, fear conditioning, extinction learning, extinction recall, emotional memory, emotional learning, skin conductance response, delusions, contextual memory
- MeSH terms
- Adult, Conditioning, Psychological, Extinction, Psychological, Fear, Female, Galvanic Skin Response, Humans, Male, Memory, Schizophrenic Psychology, Case-Control Studies
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