Neural Correlates of Inhibition and Contextual Cue Processing Related to Treatment Response in PTSD
Open accessAbstract
Thirty to fifty percent of posttraumatic stress disorder (PTSD) patients do not respond to treatment. Understanding the neural mechanisms underlying treatment response could contribute to improve response rates. PTSD is often associated with decreased inhibition of fear responses in a safe environment. Importantly, the mechanism of effective treatment (psychotherapy) relies on inhibition and so-called contextual cue processing. Therefore, we investigate inhibition and contextual cue processing in the context of treatment. Forty-one male war veterans with PTSD and 22 healthy male war veterans (combat controls) were scanned twice with a 6- to 8-month interval, in which PTSD patients received treatment (psychotherapy). We distinguished treatment responders from nonresponders on the base of percentage symptom decrease. Inhibition and contextual cue processing were assessed with the stop-signal anticipation task. Behavioral and functional MRI measures were compared between PTSD patients and combat controls, and between responders and nonresponders using repeated measures analyses. PTSD patients showed behavioral and neural deficits in inhibition and contextual cue processing at both time points compared with combat controls. These deficits were unaffected by treatment; therefore, they likely represent vulnerability factors or scar aspects of PTSD. Second, responders showed increased pretreatment activation of the left inferior parietal lobe (IPL) during contextual cue processing compared with nonresponders. Moreover, left IPL activation predicted percentage symptom improvement. The IPL has an important role in contextual cue processing, and may therefore facilitate the effect of psychotherapy. Hence, increased left IPL activation may represent a potential predictive biomarker for PTSD treatment response.
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Frontostriatal circuits are known to support inhibition of fear responses to stimuli similar to the feared stimulus in generalization of extinction learning.
“Frontostriatal circuits are known to support the inhibition of fear responses to stimuli similar to the feared stimulus (e.g., masked pictures of it) in the generalization of extinction learning (Peters, Dunlop & Downar, 2016; van Rooij et al. 2015).”
From Advancing the treatment of anxiety disorders in transition‐age youth: a review of the therapeutic effects of unconscious exposure. (2025) · cites this paper as van Rooij et al. 2015
The Introduction and Discussion link fear inhibition in PTSD to contextual cues and report reduced right inferior frontal gyrus activation during a cognitive inhibition task. They do not establish that frontostriatal circuits inhibit fear responses to similar stimuli during generalization of extinction learning; the study deliberately used a task unrelated to trauma rather than testing such stimuli. (LLM, conf=0.88)
Experimental — accuracy not yet measuredFrontostriatal circuits comprise a neuroregulatory system that supports extinction of stimulus generalization-fear responses to stimuli resembling the phobic stimulus.
“Frontostriatal circuits comprise a neuroregulatory system that supports the extinction of stimulus generalization -- fear responses to stimuli that resemble the phobic stimulus, such as masked pictures of it; Peters et al. 2016; van Rooij et al. 2015).”
From Advancing the treatment of anxiety disorders in transition‐age youth: a review of the therapeutic effects of unconscious exposure. (2025) · cites this paper as van Rooij et al. 2015
The Introduction (page unavailable) links fear extinction to inhibition in a safe context, and the Results (page unavailable) associate right inferior frontal gyrus activation with contextual cue processing in veterans with PTSD. The paper does not establish that frontostriatal circuits extinguish generalized fear responses to phobic-stimulus lookalikes or masked pictures; its task used cues about whether a stop signal could occur. (LLM, conf=0.87)
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Self-citationMcDermott, T. J., Kirlić, N., Akeman, E., Touthang, J., Cosgrove, K. T., DeVille, D. C., Clausen, A. N., White, E. J., Kuplicki, R., & Aupperle, R. L. (2020) · NeuroImage · doi:10.1016/j.neuroimage.2020.117077 · Cited by 20 · see citing works
Biological predictors of pharmacological therapy in anxiety disorders
Maron, E., & Nutt, D. (2015) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2015.17.3/emaron · Cited by 24 · see citing works
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López, C. M., Lancaster, C. L., Wilkerson, A. K., Grös, D. F., Ruggiero, K. J., & Acierno, R. E. (2019) · Behavior Therapy · doi:10.1016/j.beth.2019.01.006 · Cited by 22 · see citing works
Neural Mechanisms of Spatial Attention Deficits in Trauma
Block, S. R., Weissman, D. H., Sripada, C., Angstadt, M., Duval, E. R., King, A. P. J., & Liberzon, I. (2019) · Biological Psychiatry Cognitive Neuroscience and Neuroimaging · doi:10.1016/j.bpsc.2019.05.014 · Cited by 16 · see citing works
Bryant, R. A., Williamson, T., Erlinger, M., Felmingham, K. L., Malhi, G. S., Hinton, M., Williams, L. M., & Korgaonkar, M. S. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01340-8 · Cited by 20 · see citing works
Powers, A. D., Hinojosa, C. A., Stevens, J. S., Harvey, B., Pas, P., ROTHBAUM, B. O., Ressler, K. J., Jovanović, T., & van Rooij, S. J. H. (2022) · European Journal of Psychotraumatology · doi:10.1080/20008198.2022.2059993 · Cited by 13 · see citing works
“Sixth, because the main goal of this study is to replicate and extend prior fi ndings, we used ROIs that were previously de fi ned (Jovanovic et al., 2012; van Rooij et al., 2016; Zandbelt et al., 2010) and used (Stevens et al., 2021; Van Rooij et al., 2015, 2014, 2016, 2018) in earlier studies.”
BackgroundMethodWhite matter anisotropy and response to cognitive behavior therapy for posttraumatic stress disorder
Korgaonkar, M. S., Felmingham, K. L., Klimova, A., Erlinger, M., Williams, L. M., & Bryant, R. A. (2021) · Translational Psychiatry · doi:10.1038/s41398-020-01143-3 · Cited by 14 · see citing works
Bryant, R. A., Erlinger, M., Felmingham, K. L., Malhi, G. S., O'Donnell, M. L., Williams, L. M., & Korgaonkar, M. S. (2020) · Depression and Anxiety · doi:10.1002/da.23061 · Cited by 16 · see citing works
Brain Mechanisms of Stress and Depression in Coronary Artery Disease
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Latent Profiles of Comorbid Depression as Predictors of PTSD Treatment Outcome
Burton, M. S., Cooper, A. A., Mello, P. G., Feeny, N. C., & Zoellner, L. A. (2021) · Behavior Therapy · doi:10.1016/j.beth.2020.12.005 · Cited by 17 · see citing works
McDermott, T. J., Kirlić, N., & Aupperle, R. L. (2018) · Neurobiology of Stress · doi:10.1016/j.ynstr.2018.05.001 · Cited by 14 · see citing works
“For example, with PTSD measures, the practitioner is likely to use normatively defined cutoffs to establish whether the person screens positive for potential PTSD diagnosis or whether they score in the mild, moderate, or severe range (Weathers et al., 2013).”
BackgroundSadeh, N., Spielberg, J. M., & Hayes, J. P. (2017) · Journal of Anxiety Disorders · doi:10.1016/j.janxdis.2017.11.001 · Cited by 13 · see citing works
“In terms of context processing, research indicates that failures to process contextual information is deficient in PTSD, including in situations that require inhibition (van Rooij et al., 2014, 2015).”
BackgroundHinojosa, C. A., VanElzakker, M. B., Kaur, N., Felicione, J. M., Charney, M. E., Bui, É., Marques, L. M., D, P. S. M., Rauch, S. L., Simon, N. M., et al. (2023) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2023.1198244 · Cited by 13 · see citing works
Short-term meditation modulates EEG activity in subjects with post-traumatic residual disabilities
Hata, M., Hayashi, N., Ishii, R., Canuet, L., Pascual-Marqui, R. D., Aoki, Y., Ikeda, S., Sakamoto, T., Iwata, M., Kimura, K., et al. (2019) · Clinical Neurophysiology Practice · doi:10.1016/j.cnp.2019.01.003 · Cited by 12 · see citing works
Visual false memories in posttraumatic stress disorder.
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Smits, F., de Kort, G. J., & Geuze, E. (2021) · BMC Psychiatry · doi:10.1186/s12888-021-03086-5 · Cited by 12 · see citing works
Self-citationBremner, J. D., Ortega, R. A., Campanella, C., Nye, J. A., Davis, L. L., Fani, N., & Vaccarino, V. (2023) · Journal of Affective Disorders Reports · doi:10.1016/j.jadr.2023.100615 · Cited by 10 · see citing works
Maron, E., Lan, C.-C., & Nutt, D. (2018) · Current Topics in Behavioral Neurosciences · doi:10.1007/7854_2018_49 · Cited by 9 · see citing works
Defining the r factor for post-trauma resilience and its neural predictors
van Rooij, S. J. H., Santos, J. L., Hinojosa, C. A., Ely, T. D., Harnett, N. G., Murty, V. P., Lebois, L. A. M., Jovanović, T., House, S. L., Bruce, S. E., et al. (2024) · Nature Mental Health · doi:10.1038/s44220-024-00242-0 · Cited by 16 · see citing works
“However, neurobiological research in the field of trauma, including our own work, has predominantly studied resilience as the absence of posttraumatic stress disorder (PTSD) or other traumarelated disorders in the after math of trauma or have used a traitlike resilience measure, such as the Connor–Davidson Resilie…”
InfluentialPierce, Z. P., Johnson, E. R., Kim, I. A., Lear, B. E., Mast, A. M., & Black, J. M. (2023) · Frontiers in Psychology · doi:10.3389/fpsyg.2023.1074972 · Cited by 10 · see citing works
RetractedZukerman, G., Pinhas, M., Ben‐Itzchak, E., & Fostick, L. (2019) · Neuropsychologia · doi:10.1016/j.neuropsychologia.2019.107226 · Cited by 11 · see citing works
Korgaonkar, M. S., Felmingham, K. L., Malhi, G. S., Williamson, T. H., Williams, L. M., & Bryant, R. A. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02375-9 · Cited by 9 · see citing works
Bound Together: How Psychoanalysis Diminishes Inter-generational DNA Trauma
Colangeli, R. (2020) · The American Journal of Psychoanalysis · doi:10.1057/s11231-020-09247-x · Cited by 7 · see citing works
“…number of studies have focused on establishing a link between psychoanalysis, trauma and epigenetics (Yehuda et al., 2009; Yehuda et al., 2013; Yehuda et al., 2014; Yehuda et al., 2015; Bishop et al., 2018; van Rooij et al., 2015; Ready et al., 2012; Richardson et al., 2014; King et al., 2013).”
BackgroundAltered anticipatory brain responses in eating disorders: A neuroimaging meta‐analysis
Yu, X., & Desriviéres, S. (2023) · European eating disorders review · doi:10.1002/erv.2967 · Cited by 7 · see citing works
“Beyond ED, the left IPL has been proposed as a potential predictive biomarker for PTSD treatment response in a study (van Rooij et al., 2015) that reported increased pre‐treatment activation of this region in treat-ment responders compared with non‐responders during the stop‐signal anticipation…”
BackgroundAdams, Z. W., Meinzer, M. C., Mandel, H., Voltin, J. R., Caughron, B., Sallee, F. R., Hamner, M. B., & Wang, Z. (2017) · Journal of Anxiety Disorders · doi:10.1016/j.janxdis.2017.08.003 · Cited by 8 · see citing works
A System Computational Model of Implicit Emotional Learning
Puviani, L., & Rama, S. (2016) · Frontiers in Computational Neuroscience · doi:10.3389/fncom.2016.00054 · Cited by 7 · see citing works
“As a matter of fact, in some forms of PTSD and panic disorders the mere repetitive exposure to cues related to a traumatic event does not lead to an extinction of emotional responses or results in a very slow extinction (Paunovic, 1999; Van Rooij et al., 2015; Perusini et al., 2016).”
BackgroundSheynin, J., Lokshina, Y., Ahrari, S., Nickelsen, T., Duval, E. R., Ben‐Zion, Z., Shalev, A. Y., Hendler, T., & Liberzon, I. (2023) · Biological Psychiatry Cognitive Neuroscience and Neuroimaging · doi:10.1016/j.bpsc.2023.07.002 · Cited by 10 · see citing works
van Lutterveld, R., Varkevisser, T., Kouwer, K., van Rooij, S. J. H., Kennis, M., Hueting, M., van Montfort, S. J. T., van Dellen, E., & Geuze, E. (2022) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2022.730745 · Cited by 5 · see citing works
Self-citationWeber, S., Kemp, S. A., & Hinder, M. R. (2026) · Cognitive Affective & Behavioral Neuroscience · doi:10.3758/s13415-026-01440-2 · Cited by 1 · see citing works
“ARI tasks have been used to assess changes to inhibitory networks in clinical populations (Van Rooij et al., 2015; Zandbelt et al., 2011) and during development (Van Hulst et al., 2018; Vink et al., 2014).”
Mo, X., He, M.-R., Zhou, L., Liu, Y., Zhu, H., Huang, X., Zeng, G., Zhang, J., & Li, L. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.923572 · Cited by 3 · see citing works
“indicated decreased withinDMN connectivity of PCC in adolescents with PTSD (71), so the decreased structural connectivity in the visual cortex (left ITG) and DMN regions (right IPL) is known for their roles in visual mental imagery and contextual cue processing (67, 72) with the left PCC and the increased structural c…”
BackgroundWeisholtz, D. S., Silbersweig, D., Pan, H., Cloître, M., LeDoux, J. E., & Stern, E. R. (2020) · Journal of Neuropsychiatry · doi:10.1176/appi.neuropsych.20030058 · Cited by 5 · see citing works
“Studies utilizing behavioral inhibition tasks have shown that greater activation of dorsal striatum, pre-frontal networks (11) and inferior parietal lobule (12) were associated with better response to treatment.”
Puviani, L., Rama, S., & Vitetta, G. M. (2016) · arXiv (Cornell University) · doi:10.48550/arxiv.1601.07766 · Cited by 5 · see citing works
“As a matter of fact, in some forms of PTSD and panic disorders the mere repetitive exposure to cues related to a traumatic event does not lead to an extinction of emotional responses or results in a very slow extinction [210, 70, 211].”
BackgroundBehavior, neuropsychology and fMRI
Bennett, M. R., Hatton, S. N., Hermens, D. F., & Lagopoulos, J. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.07.001 · Cited by 4 · see citing works
Davey, D. K., Caudle, M. M., Hoffman, S. N., Jak, A. J., Bomyea, J. A., & Crocker, L. D. (2024) · Psychological Medicine · doi:10.1017/s0033291724003106 · Cited by 2 · see citing works
“Studies also reveal that functioning of frontoparietal substrates relevant to EF predict treatment response in trauma-focused CBT (Bryant et al., 2021; Falconer et al., 2013; van Rooij, Geuze, Kennis, Rademaker, & Vink, 2015).”
Zhang, J., Buchanan, G. J. R., Monn, A. R., & Gewirtz, A. H. (2021) · Journal of Traumatic Stress · doi:10.1002/jts.22724 · Cited by 3 · see citing works
A Hippocampal Signature of Posttraumatic Stress Disorder Vulnerability.
Mayo, L., & Heilig, M. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2018.04.015 · Cited by 2 · see citing works
Siegel, P., & Peterson, B. S. (2025) · Journal of Child Psychology and Psychiatry · doi:10.1111/jcpp.14037 · Cited by 1 · see citing works
Ericksonian hypnotherapy versus cognitive behavioral therapy for post-traumatic stress disorder
Çınaroğlu, M., Ülker, S. V., Yılmazer, E., Ahlatcıoğlu, E. N., & Sayar, G. H. (2026) · American Journal of Clinical Hypnosis · doi:10.1080/00029157.2026.2640622 · Cited by 1 · see citing works
“Both EH and CBT were associated with normalization of neural and autonomic indices, including reduced hyperarousal and improved attentional processing of trauma-related cues (Butt et al., 2019; van Rooij et al., 2015).”
van Lutterveld, R., Sterk, M., Spitoni, C., Kennis, M., van Rooij, S. J. H., & Geuze, E. (2025) · Chronic Stress · doi:10.1177/24705470241311285 · Cited by 1 · see citing works
Self-citationNeurobiology of Posttraumatic Stress Disorder
Carletto, S., Panero, M., Cavallo, M., & Pagani, M. (2020) · Springer eBooks · doi:10.1007/978-3-030-57231-0_11 · Cited by 3 · see citing works
Peyvandi, A., Pigoni, A., Anastasi, A., Nosari, G., Borghi, L., Vegni, E. A. M., Brambilla, P., & Delvecchio, G. (2026) · Journal of Affective Disorders · doi:10.1016/j.jad.2026.122054
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“…functioning and PTSD psychotherapy outcomes, most have been small, non-controlled studies largely focusing on memory impairment (Haaland et al., 2016; Nijdam et al., 2015; Tanev et al., 2019; Wild & Gur, 2008) or fMRI correlates of inhibition (Falconer et al., 2013; Van Rooij et al., 2015).”
Bremner, J. D., Wittbrodt, M. T., Gurel, N. Z., Nye, J. A., Shandhi, M. M. H., Gazi, A. H., Shah, A. J., Amorim, V., Pearce, B. D., Vaccarino, V., et al. (2025) · Journal of Affective Disorders Reports · doi:10.1016/j.jadr.2025.101014
Inhibitory control impairments underlie associative memory deficits in posttraumatic stress disorder
Guez, J., Saar-Ashkenazy, R., Keha, E., & Shalev, H. (2025) · PLoS ONE · doi:10.1371/journal.pone.0329810
Targeting the Hippocampus in the Context of Trauma
van Rooij, S. V. (2024) · Biological Psychiatry Global Open Science · doi:10.1016/j.bpsgos.2024.100335
“Interest-ingly, the left inferior parietal lobe has been implicated separately in PTSD trauma-focused therapy outcomes, such that lower left inferior parietal lobe engagement during contextual cue processing predicted poorer PTSD treatment outcomes (6).”
BackgroundAn opportunity for multivariate pattern analysis in psychiatry - Authors' reply.
Siegel, P., & Peterson, B. (2021) · Lancet psychiatry · doi:10.1016/s2215-0366(20)30563-0
The significate of IGF-1 and IGF-1R in reducing PTSD cognitive function symptoms
Zhang, Y., Hao, P., Yuan, X., Zhang, G., & Dong, Y. (2017) · Annales Médico-psychologiques revue psychiatrique · doi:10.1016/j.amp.2016.03.023
- Authors
- van Rooij, S. J., Geuze, E., Kennis, M., Rademaker, A. R., & Vink, M.
- Affiliations
- University Medical Center Utrecht (NL)
- Ministry of Defence (NL)
- Venue
- Neuropsychopharmacology
- Published
- 2014-08-26
- Volume
- 40
- Issue
- 3
- Pages
- 667-675
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC4289955
- OpenAlex
- W2006486060
- Cited by
- 94
- References
- 0
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 6 · 2023: 7 · 2022: 4 · 2021: 11 · 2020: 12 · 2019: 6 · 2018: 13 · 2017: 9 · 2016: 13 · 2015: 6
- FWCI
- 11.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Funders
- Ministerie van Defensie
- Topics
- Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Social Sciences › Psychology › Clinical Psychology › Psychoanalysis and Psychopathology Research
- Keywords
- post-traumatic stress disorder, treatment response prediction, inhibition, inferior parietal lobule, war veterans, fear extinction, predictive biomarkers, psychotherapy, combat exposure
- MeSH terms
- Adult, Cues, Humans, Inhibition, Psychological, Magnetic Resonance Imaging, Male, Parietal Lobe, Psychotherapy, Stress Disorders, Post-Traumatic, Veterans, Case-Control Studies, Treatment Outcome, Young Adult, Anticipation, Psychological, Functional Neuroimaging
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