Circuit dysregulation and circuit-based treatments in posttraumatic stress disorder

Sheynin, Jony; Liberzon, Israel

doi:10.1016/j.neulet.2016.11.014

Cited by 68Posttraumatic Stress Disorder ResearchMemory and Neural MechanismsPsychoanalysis and Psychopathology Research

Circuit dysregulation and circuit-based treatments in posttraumatic stress disorder

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Sheynin, Jony, Liberzon, Israel·2017·Neuroscience Letters

DOI 10.1016/j.neulet.2016.11.014PMC PMC5422122

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Abstract

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that develops in some individuals in the aftermath of exposure to traumatic events, such as actual or threatened death, serious injury or sexual assault. It has been hypothesized that dysregulations in a number of specific neurocircuits, characterized by heightened responsivity of amygdala, dACC and insula, diminished responsivity of mPFC, impaired hippocampal function and deficits in cortical regions, underlie the development and expression of key PTSD symptoms. Here, we concisely describe three functional neural circuits implicated in PTSD pathophysiology and briefly review selected treatment strategies in the context of these neural circuits. We start with the commonly implicated neurocircuit model, namely, the fear learning and threat detection circuits, and then discuss the context processing circuitry, which plays an important role among others, in fear regulation. We then discuss the emotion regulation circuitry, which can further contribute to PTSD pathophysiology, and conclude with a discussion of the therapeutic approaches that might be targeting dysregulation in these circuits in PTSD patients. Specifically, we discuss how exposure-based treatments might be targeting fear learning circuits, and the pharmacological and brain-stimulation interventions aimed to augment these therapies. Finally, we discuss other pharmacological and cognitive therapeutic approaches that can augment or restore the function of the context processing and emotional regulation circuits.

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A circuit involving the amygdala, medial prefrontal cortex, and hippocampus is concerned with the processing of context, enabling what has been learned about threat to be expressed or inhibited depending on the prevailing conditions.
“Another circuit, involving the amygdala, medial prefrontal cortex, and hippocampus, is concerned with the processing of context, enabling what has been learned about threat to be expressed or inhibited depending on the prevailing conditions [34].”
From Memory and Forgetting (2018) · cites this paper as [34]

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The emerging field of emotion regulation: an integrative review
Gross, J. J. (1998) · Review of General Psychology · doi:10.1037/1089-2680.2.3.271 · Cited by 9,916 · cited 1× · see citing works
“Other cognitive regulation strategies exist, but clearly require further research, including re-allocation of attention away from emotional stimuli, suppression of expression of an emotion, distraction [50], and distancing, i.”
Background
Dissociable intrinsic connectivity networks for salience processing and executive control
Seeley, W. W., Menon, V., Schatzberg, A. F., Keller, J., Glover, G. H., Kenna, H., Reiss, A. L., & Greicius, M. D. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.5587-06.2007 · Cited by 7,426 · cited 1× · see citing works
“Two key fear learning regions – amygdala and dACC, together with insula/ operculum, also constitute important nodes in a more general salience/threat detection system [12].”
Background
Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants
Santarelli, L., Saxe, M., Gross, C., Surget, A., Battaglia, F., Dulawa, S., Weisstaub, N., Lee, J., Duman, R., Arancio, O., et al. (2003) · Science · doi:10.1126/science.1083328 · Cited by 4,321 · cited 1× · see citing works
“Interestingly, if adult neurogenesis in the dentate gyrus enhances contextual processing in hippocampus by improving one’s ability to separate harm from safety [73, 74], this might explain at least partially the therapeutic efficacy of antidepressants shown to enhance hippocampal neurogenesis [75], in treatment of PTS…”
Background
Contributions of the Amygdala to Emotion Processing: From Animal Models to Human Behavior
Phelps, E. A., & LeDoux, J. E. (2005) · Neuron · doi:10.1016/j.neuron.2005.09.025 · Cited by 3,203 · cited 1× · see citing works
“This system identifies salient cues in the environment [13], and abnormalities within this system can also contribute to PTSD pathophysiology, independent of fear learning [3, 14].”
Background
How does mindfulness meditation work? Proposing mechanisms of action from a conceptual and neural perspective
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 · see citing works
Rethinking feelings: an fMRI study of the cognitive regulation of emotion
Ochsner, K. N., Bunge, S. A., Gross, J. J., & Gabrieli, J. D. E. (2002) · Journal of Cognitive Neuroscience · doi:10.1162/089892902760807212 · Cited by 2,520 · cited 2× · see citing works
“For example, redirecting attention might involve dorsal parietal (unique) and dorsolateral PFC (common) regions, while reappraisal might involve dorsolateral PFC (common) and dorsomedial PFC (unique) regions [52].”
BackgroundResult
The Neurocircuitry of Fear, Stress, and Anxiety Disorders
Shin, L. M., & Liberzon, I. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2009.83 · Cited by 2,083 · cited 1× · see citing works
“The neurocircuitry underlying fear learning contains a number of regions [2, 3, 8, 9], with amygdala as the key structure that receives sensory input from the thalamus and orchestrates response to threatening signals by sending outputs to the hypothalamus, basal ganglia and brainstem.”
BackgroundSelf-citation
Cognitive Reappraisal of Emotion: A Meta-Analysis of Human Neuroimaging Studies
Buhle, J. T., Silvers, J. A., Wager, T. D., Lopez, R., Onyemekwu, C., Kober, H., Weber, J., & Ochsner, K. N. (2014) · Cerebral Cortex · doi:10.1093/cercor/bht154 · Cited by 1,896 · cited 1× · see citing works
“Reappraisal of negative stimuli has been associated with increased activation of dorsolateral, ventrolateral and dorsomedial prefrontal cortex (PFC), and decreased activation of medial orbitofrontal cortex and the amygdala [52] – findings that were confirmed by a recent meta-analysis [53].”
Result
Functional imaging studies of emotion regulation: a synthetic review and evolving model of the cognitive control of emotion
Ochsner, K. N., Silvers, J. A., & Buhle, J. T. (2012) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2012.06751.x · Cited by 1,879 · see citing works
Neuronal circuits for fear and anxiety
Tovote, P., Fadok, J. P., & Lüthi, A. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3945 · Cited by 1,786 · cited 1× · see citing works
“, genetic and viral tools, optogenetics and advanced in-vivo imaging techniques) to characterize cellular and molecular mechanisms and to address the role of both local microcircuits and long-range projection pathways within defined neurocircuits that are dysregulated in PTSD [84].”
Background
Prefrontal-Subcortical Pathways Mediating Successful Emotion Regulation
Wager, T. D., Davidson, M. L., Hughes, B. L., Lindquist, M. A., & Ochsner, K. N. (2008) · Neuron · doi:10.1016/j.neuron.2008.09.006 · Cited by 1,761 · see citing works
The contextual brain: implications for fear conditioning, extinction and psychopathology
Maren, S., Phan, K. L., & Liberzon, I. (2013) · Nature Reviews Neuroscience · doi:10.1038/nrn3492 · Cited by 1,547 · cited 4× · see citing works
“Dysfunction in the contextual processing circuit may lead to inflexible, rigid and inappropriate behavioral responses, contributing to development of various PTSD symptoms [3, 39, 40].”
BackgroundInfluentialSelf-citation
Biological studies of post-traumatic stress disorder
Pitman, R. K., Rasmusson, A. M., Koenen, K. C., Shin, L. M., Orr, S. P., Gilbertson, M. W., Milad, M. R., & Liberzon, I. (2012) · Nature Reviews Neuroscience · doi:10.1038/nrn3339 · Cited by 1,529 · cited 1× · see citing works
“The hypoactivation in mPFC and hyperactivation of the amygdala [19, 20] could, in turn, underlie the impaired extinction recall [3, 16, 21, 22] in PTSD.”
BackgroundSelf-citation
Neurocircuitry Models of Posttraumatic Stress Disorder and Extinction: Human Neuroimaging Research—Past, Present, and Future
Rauch, S. L., Shin, L. M., & Phelps, E. A. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.06.004 · Cited by 1,397 · cited 1× · see citing works
“Furthermore, PTSD has been associated with hyporesponsiveness of the rostral anterior cingulate cortex (rACC) and adjacent vmPFC, which could contribute, to lessened inhibitory input and subsequent hyperactivation of the amygdala [3, 5, 15, 17, 18].”
Background
Neurobiological Basis of Failure to Recall Extinction Memory in Posttraumatic Stress Disorder
Milad, M. R., Pitman, R. K., Ellis, C. B., Gold, A. L., Shin, L. M., Lasko, N. B., Zeidan, M. A., Handwerger, K., Orr, S. P., & Rauch, S. L. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.06.026 · Cited by 1,339 · cited 2× · see citing works
“The hypoactivation in mPFC and hyperactivation of the amygdala [19, 20] could, in turn, underlie the impaired extinction recall [3, 16, 21, 22] in PTSD.”
Background
Amygdala, medial prefrontal cortex, and hippocampal function in PTSD
SHIN, L. M., RAUCH, S. L., & PITMAN, R. K. (2006) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1364.007 · Cited by 1,203 · cited 1× · see citing works
“Furthermore, PTSD has been associated with hyporesponsiveness of the rostral anterior cingulate cortex (rACC) and adjacent vmPFC, which could contribute, to lessened inhibitory input and subsequent hyperactivation of the amygdala [3, 5, 15, 17, 18].”
Background
Recall of Fear Extinction in Humans Activates the Ventromedial Prefrontal Cortex and Hippocampus in Concert
Milad, M. R., Wright, C. I., Orr, S. P., Pitman, R. K., Quirk, G. J., & Rauch, S. L. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.10.011 · Cited by 1,197 · cited 1× · see citing works
“Specifically, contextual processing is required to support adaptive fear extinction and renewal, and human research has confirmed the role of the hippocampus-mPFC-amygdala circuitry in both contextual conditioning [42–44] and regulation [45, 46] of fear.”
Background
Cognitive Enhancers as Adjuncts to Psychotherapy: Use of D-Cycloserine in Phobic Individuals to Facilitate Extinctionof Fear
Ressler, K. J., Rothbaum, B. O., Tannenbaum, L., Anderson, P., Graap, K., Zimand, E., Hodges, L., & Davis, M. (2004) · Archives of General Psychiatry · doi:10.1001/archpsyc.61.11.1136 · Cited by 1,063 · cited 1× · see citing works
“Among strategies targeting fear circuits, pharmacological interventions with compounds like d-cycloserine, a partial NMDA agonist, in combination with exposure therapy, have been shown to facilitate fear extinction in phobic patients [64].”
Background
Explicit and implicit emotion regulation: a dual-process framework.
Gyurak, A., Gross, J. J., & Etkin, A. (2011) · Cognition and Emotion · doi:10.1080/02699931.2010.544160 · Cited by 1,015 · see citing works
Cognitive Emotion Regulation: Insights From Social Cognitive and Affective Neuroscience
Ochsner, K. N., & Gross, J. J. (2008) · Current Directions in Psychological Science · doi:10.1111/j.1467-8721.2008.00566.x · Cited by 988 · see citing works
The role of ventromedial prefrontal cortex in the recovery of extinguished fear
Quirk, G. J., Russo, G. K., Barron, J. L., & Lebron, K. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-16-06225.2000 · Cited by 957 · cited 1× · see citing works
“The medial prefrontal cortex (mPFC) is another key region that regulates appropriate fear/safety learning by exerting top-down control on the amygdala [10], with dorsal regions like dorsal anterior cingulate (dACC) being critical to expression of fear and ventromedial region (vmPFC), specifically, playing a key role i…”
Background
Executive function and PTSD: disengaging from trauma.
Aupperle, R. L., Melrose, A. J., Stein, M. B., & Paulus, M. P. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.02.008 · Cited by 657 · cited 1× · see citing works
“, attention, inhibitory function) that are often seen in PTSD also relate to dysfunction within dorsal prefrontal networks and are exacerbated within emotional or trauma-related context [60].”
Background
The functional neuroanatomy of PTSD: a critical review
Liberzon, I., & Sripada, C. S. (2007) · Progress in Brain Research · doi:10.1016/s0079-6123(07)67011-3 · Cited by 594 · cited 2× · see citing works
“Dysfunction in the contextual processing circuit may lead to inflexible, rigid and inappropriate behavioral responses, contributing to development of various PTSD symptoms [3, 39, 40].”
BackgroundSelf-citation
Prefrontal entrainment of amygdala activity signals safety in learned fear and innate anxiety
Likhtik, E., Stujenske, J. M., A Topiwala, M., Harris, A. Z., & Gordon, J. A. (2014) · Nature Neuroscience · doi:10.1038/nn.3582 · Cited by 577 · cited 1× · see citing works
“Specifically, a decreased connectivity between the basolateral amygdala (BLA) and the mPFC, might play a role as low synchrony between these regions was associated with fear generalization [33].”
Background
Overgeneralization of conditioned fear as a pathogenic marker of panic disorder
Lissek, S., Rabin, S., Heller, R. E., Lukenbaugh, D., Geraci, M., Pine, D. S., & Grillon, C. (2010) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2009.09030410 · Cited by 565 · see citing works
The Role of the Medial Prefrontal Cortex in the Conditioning and Extinction of Fear
Giustino, T. F., & Maren, S. (2015) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2015.00298 · Cited by 519 · cited 1× · see citing works
“The medial prefrontal cortex (mPFC) is another key region that regulates appropriate fear/safety learning by exerting top-down control on the amygdala [10], with dorsal regions like dorsal anterior cingulate (dACC) being critical to expression of fear and ventromedial region (vmPFC), specifically, playing a key role i…”
Background
Presence and acquired origin of reduced recall for fear extinction in PTSD: Results of a twin study
Milad, M. R., Orr, S. P., Lasko, N. B., Chang, Y., Rauch, S. L., & Pitman, R. K. (2008) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2008.01.017 · Cited by 512 · cited 1× · see citing works
“The hypoactivation in mPFC and hyperactivation of the amygdala [19, 20] could, in turn, underlie the impaired extinction recall [3, 16, 21, 22] in PTSD.”
Background
Neurogenesis and generalization: a new approach to stratify and treat anxiety disorders
Kheirbek, M. A., Klemenhagen, K. C., Sahay, A., & Hen, R. (2012) · Nature Neuroscience · doi:10.1038/nn.3262 · Cited by 509 · cited 1× · see citing works
“Interestingly, if adult neurogenesis in the dentate gyrus enhances contextual processing in hippocampus by improving one’s ability to separate harm from safety [73, 74], this might explain at least partially the therapeutic efficacy of antidepressants shown to enhance hippocampal neurogenesis [75], in treatment of PTS…”
Background
Immediate treatment with propranolol decreases posttraumatic stress disorder two months after trauma
Vaiva, G., Ducrocq, F., Jezequel, K., Averland, B., Lestavel, P., Brunet, A., & Marmar, C. R. (2003) · Biological Psychiatry · doi:10.1016/s0006-3223(03)00412-8 · Cited by 499 · cited 1× · see citing works
“Another avenue targeting fear-learning circuits, taken by some investigators is to try and prevent fear learning or consolidation of fear memory in the first place by the administration of agents, such as beta-blocker propranolol [68] or hydrocortisone [69] in the immediate aftermath of trauma.”
Background
Context-Dependent Human Extinction Memory Is Mediated by a Ventromedial Prefrontal and Hippocampal Network
Kalisch, R., Korenfeld, E., Stephan, K. E., Weiskopf, N., Seymour, B., & Dolan, R. J. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.2021-06.2006 · Cited by 493 · see citing works
Changing Fear: The Neurocircuitry of Emotion Regulation
Hartley, C. A., & Phelps, E. A. (2009) · Neuropsychopharmacology · doi:10.1038/npp.2009.121 · Cited by 492 · see citing works
Generalized Anxiety Disorder Is Associated With Overgeneralization of Classically Conditioned Fear
Lissek, S. M., Kaczkurkin, A. N., Rabin, S. J., Geraci, M. F., Pine, D. S., & Grillon, C. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.07.025 · Cited by 462 · see citing works
Quantitative meta-analysis of neural activity in posttraumatic stress disorder
Hayes, J. P., Hayes, S. M., & Mikedis, A. M. (2012) · Biology of Mood & Anxiety Disorders · doi:10.1186/2045-5380-2-9 · Cited by 452 · cited 1× · see citing works
“The hypoactivation in mPFC and hyperactivation of the amygdala [19, 20] could, in turn, underlie the impaired extinction recall [3, 16, 21, 22] in PTSD.”
Background
How the Neurocircuitry and Genetics of Fear Inhibition May Inform Our Understanding of PTSD
Jovanović, T., & Ressler, K. J. (2010) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2009.09071074 · Cited by 441 · cited 2× · see citing works
“Future studies could also test how environmental factors such as childhood background and trauma load interact with the discussed neurocircuits, to examine questions of vulnerability and resilience to trauma exposure [6].”
Background
Context Processing and the Neurobiology of Post-Traumatic Stress Disorder
Liberzon, I., & Abelson, J. (2016) · Neuron · doi:10.1016/j.neuron.2016.09.039 · Cited by 420 · cited 8× · see citing works
“Furthermore, PTSD has been associated with hyporesponsiveness of the rostral anterior cingulate cortex (rACC) and adjacent vmPFC, which could contribute, to lessened inhibitory input and subsequent hyperactivation of the amygdala [3, 5, 15, 17, 18].”
BackgroundInfluentialSelf-citation
Neural Dysregulation in Posttraumatic Stress Disorder: Evidence for Disrupted Equilibrium Between Salience and Default Mode Brain Networks
Sripada, R. K., King, A. P., Welsh, R. C., Garfinkel, S. N., Wang, X., Sripada, C. S., & Liberzon, I. (2012) · Psychosomatic Medicine · doi:10.1097/psy.0b013e318273bf33 · Cited by 412 · cited 1× · see citing works
“This system identifies salient cues in the environment [13], and abnormalities within this system can also contribute to PTSD pathophysiology, independent of fear learning [3, 14].”
BackgroundSelf-citation
Generalization of conditioned fear-potentiated startle in humans: experimental validation and clinical relevance
Lissek, S., Biggs, A. L., Rabin, S. J., Cornwell, B. R., Alvarez, R. P., Pine, D. S., & Grillon, C. (2008) · Behaviour Research and Therapy · doi:10.1016/j.brat.2008.02.005 · Cited by 401 · cited 1× · see citing works
“Generalization is commonly tested with generalization gradients, where healthy subjects demonstrate a weakening of the fear response to “safer” stimuli [23], while anxiety patients show a less steep degradation, i.”
Background
Hippocampus and context in classical conditioning
Holland, P. C., & Bouton, M. E. (1999) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(99)80027-0 · Cited by 377 · cited 1× · see citing works
“The hippocampus has been the focus of neurobiological studies on contextual processing [41], as well as its connection with mPFC [40].”
Background
Positron emission tomographic imaging of neural correlates of a fear acquisition and extinction paradigm in women with childhood sexual-abuse-related post-traumatic stress disorder
BREMNER, J. D., VERMETTEN, E., SCHMAHL, C., VACCARINO, V., VYTHILINGAM, M., AFZAL, N., GRILLON, C., & CHARNEY, D. S. (2005) · Psychological Medicine · doi:10.1017/s0033291704003290 · Cited by 370 · cited 1× · see citing works
“Furthermore, PTSD has been associated with hyporesponsiveness of the rostral anterior cingulate cortex (rACC) and adjacent vmPFC, which could contribute, to lessened inhibitory input and subsequent hyperactivation of the amygdala [3, 5, 15, 17, 18].”
Background
Impaired Contextual Modulation of Memories in PTSD: An fMRI and Psychophysiological Study of Extinction Retention and Fear Renewal
Garfinkel, S. N., Abelson, J. L., King, A. P. J., Sripada, R. K., Wang, X., Gaines, L. M., & Liberzon, I. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.4287-13.2014 · Cited by 361 · cited 2× · see citing works
“Our laboratory replicated extinction recall findings in vmPFC in PTSD, and further extended it by showing impairment in another context dependent function – fear renewal [34].”
BackgroundSelf-citation
Contextual fear conditioning in humans: cortical–hippocampal and amygdala contributions
Alvarez, R. P., Biggs, A., Chen, G., Pine, D. S., & Grillon, C. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.1246-08.2008 · Cited by 325 · see citing works
Disrupted amygdala-prefrontal functional connectivity in civilian women with posttraumatic stress disorder
Stevens, J. S., Jovanovic, T., Fani, N., Ely, T. D., Glover, E. M., Bradley, B., & Ressler, K. J. (2013) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2013.05.031 · Cited by 293 · see citing works
Altered Processing of Contextual Information during Fear Extinction in PTSD: An fMRI Study
Rougemont-Bücking, A., Linnman, C., Zeffiro, T. A., Zeidan, M. A., Lebron-Milad, K., Rodriguez-Romaguera, J., Rauch, S. L., Pitman, R. K., & Milad, M. R. (2011) · CNS Neuroscience & Therapeutics · doi:10.1111/j.1755-5949.2010.00152.x · Cited by 292 · cited 1× · see citing works
“PTSD patients also showed dACC hyperactivity and vmPFC hypoactivity specifically during contextual processing period [35].”
Background
High dose hydrocortisone immediately after trauma may alter the trajectory of PTSD: Interplay between clinical and animal studies
Zohar, J., Yahalom, H., Kozlovsky, N., Cwikel-Hamzany, S., Matar, M. A., Kaplan, Z., Yehuda, R., & Cohen, H. (2011) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2011.06.001 · Cited by 292 · cited 1× · see citing works
“Another avenue targeting fear-learning circuits, taken by some investigators is to try and prevent fear learning or consolidation of fear memory in the first place by the administration of agents, such as beta-blocker propranolol [68] or hydrocortisone [69] in the immediate aftermath of trauma.”
Background
Functional neuroimaging studies of post-traumatic stress disorder
Hughes, K. C., & Shin, L. M. (2011) · Expert Review of Neurotherapeutics · doi:10.1586/ern.10.198 · Cited by 290 · cited 2× · see citing works
“Furthermore, PTSD has been associated with hyporesponsiveness of the rostral anterior cingulate cortex (rACC) and adjacent vmPFC, which could contribute, to lessened inhibitory input and subsequent hyperactivation of the amygdala [3, 5, 15, 17, 18].”
Background
A causal model of post-traumatic stress disorder: disentangling predisposed from acquired neural abnormalities
Admon, R., Milad, M. R., & Hendler, T. (2013) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2013.05.005 · Cited by 269 · cited 1× · see citing works
“For instance, it is unknown whether the described changes are preexisting risk factors or they are markers of the disorder itself; longitudinal studies will be required to address this question [83].”
Background
Neural circuits in anxiety and stress disorders: a focused review
Liberzon, I., Duval, E. R., & Javanbakht, A. (2015) · Therapeutics and Clinical Risk Management · doi:10.2147/tcrm.s48528 · Cited by 262 · cited 2× · see citing works
“The neurocircuitry underlying fear learning contains a number of regions [2, 3, 8, 9], with amygdala as the key structure that receives sensory input from the thalamus and orchestrates response to threatening signals by sending outputs to the hypothalamus, basal ganglia and brainstem.”
BackgroundSelf-citation
Neural Substrates of Overgeneralized Conditioned Fear in PTSD
Kaczkurkin, A. N., Burton, P. C., Chazin, S. M., Manbeck, A. B., Espensen-Sturges, T. D., Cooper, S. E., Sponheim, S. R., & Lissek, S. M. (2016) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2016.15121549 · Cited by 255 · see citing works
A Functional Magnetic Resonance Imaging Study of Deliberate Emotion Regulation in Resilience and Posttraumatic Stress Disorder
New, A. S., Fan, J., Murrough, J. W., Liu, X., Liebman, R. E., Guise, K. G., Tang, C. Y., & Charney, D. S. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.05.020 · Cited by 252 · cited 1× · see citing works
“In a study that examined volitional regulation of emotional response to negative pictures in PTSD, all trauma- exposed subjects demonstrated diminished down-regulation of emotional response [58].”
Background
Pharmacotherapy to prevent PTSD: Results from a randomized controlled proof‐of‐concept trial in physically injured patients
Stein, M. B., Kerridge, C., Dimsdale, J. E., & Hoyt, D. B. (2007) · Journal of Traumatic Stress · doi:10.1002/jts.20270 · Cited by 249 · see citing works
Learning models of PTSD: Theoretical accounts and psychobiological evidence
Lissek, S. M., & van Meurs, B. (2014) · International Journal of Psychophysiology · doi:10.1016/j.ijpsycho.2014.11.006 · Cited by 244 · cited 1× · see citing works
“Similarly, exposure treatment might be also decreasing overgeneralized fear by reducing fear reactivity to stimuli resembling features of the traumatic encounter [28, 30].”
Background
Dissociable roles for the hippocampus and the amygdala in human cued versus context fear conditioning
Marschner, A., Kalisch, R., Vervliet, B., Vansteenwegen, D., & Büchel, C. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.1651-08.2008 · Cited by 235 · see citing works
Adult Hippocampal Neurogenesis, Fear Generalization, and Stress
Besnard, A., & Sahay, A. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.167 · Cited by 226 · see citing works
Emotion Regulation and Anxiety Disorders
Cisler, J. M., & Olatunji, B. O. (2012) · Current Psychiatry Reports · doi:10.1007/s11920-012-0262-2 · Cited by 224 · cited 1× · see citing works
“Diminished ability to properly regulate emotions might be contributing to symptomatology of PTSD, as well as other psychiatric disorders [56].”
Background
Fear learning circuitry is biased toward generalization of fear associations in posttraumatic stress disorder
Morey, R. A., Dunsmoor, J. E., Haswell, C. C., Brown, V. M., Vora, A., Weiner, J., Stjepanovic, D., Wagner, H. R., Workgroup, V. M.-A. M., Brancu, M., et al. (2015) · Translational Psychiatry · doi:10.1038/tp.2015.196 · Cited by 221 · cited 1× · see citing works
“Indeed, decreased amygdala-vmPFC connectivity has been interpreted as evidence for impaired safety learning in PTSD [29].”
Background
Hippocampal Dysfunction Effects on Context Memory: Possible Etiology for Post-traumatic Stress Disorder
Acheson, D., Gresack, J., & Risbrough, V. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.04.029 · Cited by 212 · see citing works
Sleep Promotes Generalization of Extinction of Conditioned Fear
(2009) · Sleep · doi:10.5665/sleep/32.1.19 · Cited by 196 · see citing works
Amygdala–prefrontal interactions in (mal)adaptive learning
Likhtik, E., & Paz, R. (2015) · Trends in Neurosciences · doi:10.1016/j.tins.2014.12.007 · Cited by 193 · see citing works
Neural correlates of emotion regulation in psychopathology
Taylor, S. F., & Liberzon, I. (2007) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2007.08.006 · Cited by 182 · cited 2× · see citing works
“Similarly, attentional control that re-directs attention (in mindfulness-based therapies), also engages executive function/emotional regulation constructs [61].”
BackgroundSelf-citation
Context conditioning and extinction in humans: differential contribution of the hippocampus, amygdala and prefrontal cortex
Lang, S., Kroll, A., Lipinski, S. J., Wessa, M., Ridder, S., Christmann, C., Schad, L. R., & Flor, H. (2009) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2009.06624.x · Cited by 171 · see citing works
Pharmacological blockade of memory reconsolidation in posttraumatic stress disorder: Three negative psychophysiological studies
Wood, N. E., Rosasco, M. L., Suris, A. M., Spring, J. D., Marin, M.-F., Lasko, N. B., Goetz, J. M., Fischer, A. M., Orr, S. P., & Pitman, R. K. (2015) · Psychiatry Research · doi:10.1016/j.psychres.2014.09.005 · Cited by 169 · cited 1× · see citing works
“The rational behind the use of dcycloserine and other glutamatergic modulators in conjunction with exposure therapy is that enhancing glutamatergic signal in the PFC could theoretically facilitate extinction, however, further work is required to demonstrate their efficacy in PTSD [65, 66].”
Background
Functional neuroimaging of reward circuitry responsivity to monetary gains and losses in posttraumatic stress disorder
Elman, I., Lowen, S., Frederick, B. B., Chi, W., Becerra, L., & Pitman, R. K. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.06.006 · Cited by 165 · cited 1× · see citing works
“This is not to say that aberrations in other networks might not exist (reward circuitry [82], for example); however, to date, these data are limited and it has Sheynin and Liberzon Page 6”
Background
Emotion regulation, physiological arousal and PTSD symptoms in trauma-exposed individuals
Shepherd, L., & Wild, J. (2014) · Journal of Behavior Therapy and Experimental Psychiatry · doi:10.1016/j.jbtep.2014.03.002 · Cited by 165 · cited 1× · see citing works
“For example, it has been reported that PTSD symptoms are associated with greater use of suppression and less use of reappraisal to down-regulate emotions [57].”
Background
Neuroimaging of fear-associated learning
Greco, J. A., & Liberzon, I. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2015.255 · Cited by 145 · see citing works
Self-citation
Ketamine as a new treatment for depression: A review of its efficacy and adverse effects
Katalinic, N., Lai, R., Somogyi, A. A., Mitchell, P. B., Glue, P., & Loo, C. K. A. (2013) · Australian & New Zealand Journal of Psychiatry · doi:10.1177/0004867413486842 · Cited by 129 · cited 1× · see citing works
“While the efficacy of ketamine for treatment of depression has been reported [72], its efficacy in PTSD treatment is currently being examined.”
Background
Neural circuits and mechanisms involved in fear generalization: Implications for the pathophysiology and treatment of posttraumatic stress disorder
Lopresto, D., Schipper, P., & Homberg, J. R. (2015) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2015.10.009 · Cited by 117 · cited 2× · see citing works
“Similarly, exposure treatment might be also decreasing overgeneralized fear by reducing fear reactivity to stimuli resembling features of the traumatic encounter [28, 30].”
Background
Review of the Effectiveness of Transcranial Magnetic Stimulation for Post-traumatic Stress Disorder
Karsen, E. F., Watts, B. V., & Holtzheimer, P. E. (2013) · Brain stimulation · doi:10.1016/j.brs.2013.10.006 · Cited by 109 · see citing works
Conditioned fear associated phenotypes as robust, translational indices of trauma-, stressor-, and anxiety-related behaviors
Briscione, M. A., Jovanovic, T., & Norrholm, S. D. (2014) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2014.00088 · Cited by 105 · cited 1× · see citing works
“The rational behind the use of dcycloserine and other glutamatergic modulators in conjunction with exposure therapy is that enhancing glutamatergic signal in the PFC could theoretically facilitate extinction, however, further work is required to demonstrate their efficacy in PTSD [65, 66].”
Background
Is posttraumatic stress disorder a stress‐induced fear circuitry disorder?
Shin, L. M., & Handwerger, K. (2009) · Journal of Traumatic Stress · doi:10.1002/jts.20442 · Cited by 102 · see citing works
Extinction in multiple virtual reality contexts diminishes fear reinstatement in humans
Dunsmoor, J. E., Ahs, F., Zielinski, D. J., & LaBar, K. S. (2014) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2014.02.010 · Cited by 93 · see citing works
History of Mindfulness-Based Cognitive Therapy Is Associated with Increased Cognitive Reappraisal Ability
Troy, A. S., Shallcross, A. J., Davis, T. S., & Mauss, I. B. (2012) · Mindfulness · doi:10.1007/s12671-012-0114-5 · Cited by 90 · cited 1× · see citing works
“For example, in cognitive therapy, conscious, volitional effort is used to reappraise situation [79].”
Background
Emotion Regulatory Brain Function and SSRI Treatment in PTSD: Neural Correlates and Predictors of Change
MacNamara, A., Rabinak, C. A., Kennedy, A. E., Fitzgerald, D. A., Liberzon, I., Stein, M. B., & Phan, K. L. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.190 · Cited by 90 · cited 2× · see citing works
“It was also shown that patients with less activation of prefrontal regions implicated in emotion regulation would benefit more from this first-line treatment for PTSD [80].”
BackgroundSelf-citation
FOCAL AND ABERRANT PREFRONTAL ENGAGEMENT DURING EMOTION REGULATION IN VETERANS WITH POSTTRAUMATIC STRESS DISORDER: Research Article: Prefrontal Regulation of Affect in PTSD
Rabinak, C. A., MacNamara, A., Kennedy, A. E., Angstadt, M., Stein, M. B., Liberzon, I., & Phan, K. L. (2014) · Depression and Anxiety · doi:10.1002/da.22243 · Cited by 89 · cited 1× · see citing works
“However, in a more recent study of veterans with combat-related PTSD, we reported lower dorsolateral PFC activation specifically in PTSD patients during down-regulation of negative affect, as compared to trauma-exposed controls [59].”
BackgroundSelf-citation
Neural, Psychophysiological, and Behavioral Markers of Fear Processing in PTSD: A Review of the Literature
Shvil, E., Rusch, H. L., Sullivan, G. M., & Neria, Y. (2013) · Current Psychiatry Reports · doi:10.1007/s11920-013-0358-3 · Cited by 86 · see citing works
Impaired right inferior frontal gyrus response to contextual cues in male veterans with PTSD during response inhibition
van Rooij, S. J. H., Rademaker, A. R., Kennis, M., Vink, M., Kahn, R. S., & Geuze, E. (2014) · Journal of Psychiatry and Neuroscience · doi:10.1503/jpn.130223 · Cited by 75 · cited 1× · see citing works
“Of note, reduced contextual processing was also shown during a non-fear based task, further supporting general contextual processing deficit in PTSD [47].”
Background
Behavioral and central correlates of contextual fear learning and contextual modulation of cued fear in posttraumatic stress disorder.
Steiger, F., Nees, F., Wicking, M., Lang, S., & Flor, H. (2015) · International Journal of Psychophysiology · doi:10.1016/j.ijpsycho.2015.06.009 · Cited by 64 · cited 1× · see citing works
“Recent papers have replicated the impaired contextual learning in PTSD [37], and highlighted the key role of the hippocampus in the etiology of this disorder [38].”
Background
Cannabinoid Modulation of Fear Extinction Brain Circuits: A Novel Target to Advance Anxiety Treatment
Rabinak, C. A., & Phan, K. L. (2014) · Current Pharmaceutical Design · doi:10.2174/13816128113199990437 · Cited by 46 · cited 1× · see citing works
“Interestingly, it was recently suggested that the cannabinoid system might serve as a novel promising target for facilitating extinction learning and extinction recall – an idea that warrants further development and clinical testing [67].”
Background
Generalization of Conditioned Fear and Obsessive-Compulsive Traits
Kaczkurkin, A. N. (2013) · Journal of Psychology & Psychotherapy · doi:10.4172/2161-0487.s7-003 · Cited by 40 · see citing works
Self-Distancing From Trauma Memories Reduces Physiological but Not Subjective Emotional Reactivity Among Veterans With Posttraumatic Stress Disorder
Wisco, B. E., Marx, B. P., Sloan, D. M., Gorman, K. R., Kulish, A. L., & Pineles, S. L. (2015) · Clinical Psychological Science · doi:10.1177/2167702614560745 · Cited by 34 · cited 1× · see citing works
“taking a third-person perspective [51].”
Psychopharmacological treatment for military posttraumatic stress disorder: An integrative review
Tawa, J., & Murphy, S. (2013) · Journal of the American Association of Nurse Practitioners · doi:10.1111/1745-7599.12016 · Cited by 28 · cited 1× · see citing works
“Both sertraline and paroxetine had been FDA approved for PTSD treatment [63], however, they were developed initially as “me too” products, and while some hypothetical links to specific circuits can be proposed (see below), there are no sufficient empirical data to link their efficacy to a specific neural circuitry.”
Background
Learning, memory and brain plasticity in posttraumatic stress disorder: Context matters
Flor, H., & Nees, F. (2014) · Restorative Neurology and Neuroscience · doi:10.3233/rnn-139013 · Cited by 28 · see citing works

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Research works printed but not linked: 4

[19]Patel R Spreng RN Shin LM Girard TA Neurocircuitry models of posttraumatic stress disorder and beyond: a meta-analysis of functional neuroimaging studies Neurosci Biobehav Rev 36 2012 2130 2142 22766141
[27]Kaczkurkin AN Burton PC Chazin SM Lissek SM Generalization of conditioned fear in individuals with PTSD Kaczkurkin A Lissek (chairs) S Psychophysiological and Neurobiological Indices of Internalizing Psychopathology Symposium Presented at the Annual Conference of the Society for Psychophysiological Research Florence, Italy 2013
[59]Rabinak CA MacNamara A Kennedy AE Angstadt M Stein MB Liberzon I Phan KL Focal and aberrant prefrontal engagement during emotion regulation in veterans with posttraumatic stress disorder Depress Anxiety 31 2014 851 861 24677490 PMC4141895
[62]IOM (Institute of Medicine) Treatment of posttraumatic stress disorder: An assessment of the evidence Washington, DC The National Academies Press 2008

Sorted by citations

A network-based neurobiological model of PTSD: evidence from structural and functional neuroimaging studies
Akiki, T. J., Averill, C. L., & Abdallah, C. G. (2017) · Current Psychiatry Reports · doi:10.1007/s11920-017-0840-4 · Cited by 365 · see citing works
Integrating Endocannabinoid Signaling and Cannabinoids into the Biology and Treatment of Posttraumatic Stress Disorder
Hill, M. N., Campolongo, P., Yehuda, R., & Patel, S. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2017.162 · Cited by 239 · see citing works
“…elevated metabolic activity during periods of heightened symptom presentation and showing increased responsiveness to emotionally salient information, even stimuli unrelated to the trauma itself (Diamond and Zoladz, 2016; Hughes and Shin, 2011; Sheynin and Liberzon, 2016; Shin et al, 2006).”
Background
Default mode network abnormalities in posttraumatic stress disorder: A novel network-restricted topology approach
Akiki, T. J., Averill, C. L., Wrocklage, K. M., Scott, J. C., Averill, L. A., Schweinsburg, B., Alexander-Bloch, A., Martini, B., Southwick, S. M., Krystal, J. H., et al. (2018) · NeuroImage · doi:10.1016/j.neuroimage.2018.05.005 · Cited by 188 · see citing works
“Considering the increased recognition of the role of ICN alterations in psychiatric disorders, and the need for developing circuit-based treatment (Kressel, 2017; Lui et al., 2016; Ross et al., 2017; Sheynin and Liberzon, 2016), it is critical for the field to develop tools to map ICN abnormalities.”
Theta-Burst Transcranial Magnetic Stimulation for Posttraumatic Stress Disorder
Philip, N. S., Barredo, J., Aiken, E., Larson, V., Jones, R. N., Shea, M. T., Greenberg, B. D., & van ’t Wout-Frank, M. (2019) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2019.18101160 · Cited by 183 · see citing works
Theta Burst Transcranial Magnetic Stimulation for Posttraumatic Stress Disorder
Philip, N., Barredo, J., Aiken, E. M., Larson, V., Jones, R. N., Shea, M. T., Greenberg, B. D., & Wout-Frank, M. V. '. (2019) · American Journal of Psychiatry · doi:10.1016/j.brs.2018.12.279 · Cited by 151 · see citing works
Protective effects of elevated anandamide on stress and fear-related behaviors: translational evidence from humans and mice
Mayo, L. M., Asratian, A., Lindé, J., Holm, L., Nätt, D., Augier, G., Stensson, N., Vecchiarelli, H. A., Balsevich, G., Aukema, R. J., et al. (2018) · Molecular Psychiatry · doi:10.1038/s41380-018-0215-1 · Cited by 166 · see citing works
Post-Traumatic Stress Disorder after Civilian Traumatic Brain Injury: A Systematic Review and Meta-Analysis of Prevalence Rates
Praag, D. L. G. V., Cnossen, M. C., Polinder, S., Wilson, L., & Maas, A. I. R. (2019) · Journal of Neurotrauma · doi:10.1089/neu.2018.5759 · Cited by 119 · see citing works
“, pre-trauma factors, patient- or event-related factors) might play a role in the development of PTSD after TBI.(96)”
Background
Dysregulation of inflammation, neurobiology, and cognitive function in PTSD: an integrative review
Quiñones-Cordero, M. M., Gallegos, A. M., Lin, F. V., & Heffner, K. L. (2020) · Cognitive Affective & Behavioral Neuroscience · doi:10.3758/s13415-020-00782-9 · Cited by 161 · see citing works
Genomewide <scp>DNA</scp> methylation analysis in combat veterans reveals a novel locus for <scp>PTSD</scp>
Mehta, D., Bruenig, D., Carrillo‐Roa, T., Lawford, B., Harvey, W., Morris, C. P., Smith, A. K., Binder, E. B., Young, R. M., & Voisey, J. (2017) · Acta Psychiatrica Scandinavica · doi:10.1111/acps.12778 · Cited by 78 · see citing works
“The three major neural circuits implicated in PTSD include the fear learning circuitry, context processing circuitry and emotion regulation circuitry (78).”
Background
d-Serine as the gatekeeper of NMDA receptor activity: implications for the pharmacologic management of anxiety disorders
Wolosker, H., & Balu, D. T. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-00870-x · Cited by 102 · see citing works
Memory and Forgetting
Brewin, C. R. (2018) · Current Psychiatry Reports · doi:10.1007/s11920-018-0950-7 · Cited by 70 · see citing works
Neural correlates of conceptual-level fear generalization in posttraumatic stress disorder
Mid-Atlantic MIRECC Workgroup, Morey, R. A., Haswell, C. C., Stjepanović, D., Dunsmoor, J. E., & LaBar, K. S. (2020) · Neuropsychopharmacology · doi:10.1038/s41386-020-0661-8 · Cited by 62 · see citing works
“Importantly, these neural circuits have been broadly implicated in functional studies of fear conditioning, symptom provocation, and emotion regulation in PTSD[10-13] .”
Background
Longitudinal changes in brain function associated with symptom improvement in youth with PTSD
Garrett, A. S., Cohen, J. A., Zack, S., Carrión, V. G., Jo, B., Blader, J. C., Rodriguez, A., Vanasse, T. J., Reiss, A. L., & Agras, W. S. (2019) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2019.04.021 · Cited by 58 · see citing works
“The brain model of PTSD is based on human and animal studies of fear processing, with critical structures including the amygdala, hippocampus, medial prefrontal and anterior cingulate corticies (Mahan and Ressler 2012; Sheynin and Liberzon 2017).”
Method
Modelling posttraumatic stress disorders in animals
Török, B., Sipos, E., Pivac, N., & Zelena, D. (2018) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2018.11.013 · Cited by 52 · see citing works
“The mPFC is another key region that regulates appropriate fear/safety learning by exerting top-down control on amygdala (Sheynin and Liberzon, 2017).”
White matter microstructural alterations in posttraumatic stress disorder: An ROI and whole-brain based meta-analysis
Ju, Y., Ou, W., Su, J., Averill, C. L., Liu, J., Wang, M., Wang, Z., Zhang, Y., Liu, B., Li, L., et al. (2020) · Journal of Affective Disorders · doi:10.1016/j.jad.2020.01.047 · Cited by 51 · see citing works
Locus Coeruleus Phasic, But Not Tonic, Activation Initiates Global Remapping in a Familiar Environment
Grella, S. L., Neil, J. M., Edison, H. T., Strong, V., Odintsova, I. V., Walling, S. G., Martin, G. M., Marrone, D. F., & Harley, C. W. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.1956-18.2018 · Cited by 83 · see citing works
Reduced Salience and Enhanced Central Executive Connectivity Following PTSD Treatment
Abdallah, C. G., Averill, C. L., Ramage, A. E., Averill, L. A., Alkin, E., Nemati, S., Krystal, J. H., Roache, J. D., Resick, P. A., Young‐McCaughan, S., et al. (2019) · Chronic Stress · doi:10.1177/2470547019838971 · Cited by 40 · see citing works
Neuroimaging correlates and predictors of response to repeated-dose intravenous ketamine in PTSD: preliminary evidence
Norbury, A., Rutter, S., Collins, A. B., Costi, S., Jha, M. K., Horn, S. R. G.-V., Kautz, M. M., Corniquel, M. B., Collins, K. A., Glasgow, A. M., et al. (2021) · Neuropsychopharmacology · doi:10.1038/s41386-021-01104-4 · Cited by 46 · see citing works
Increased recruitment of cognitive control in the presence of traumatic stimuli in complex PTSD
Herzog, J. I., Niedtfeld, I., Rausch, S., Thome, J., Mueller-Engelmann, M., Steil, R., Priebe, K., Bohus, M., & Schmahl, C. (2019) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-017-0822-x · Cited by 40 · see citing works
Associations between resting‐state functional connectivity and treatment response in a randomized clinical trial for posttraumatic stress disorder
Sheynin, J., Duval, E. R., King, A. P. J., Angstadt, M., Phan, K. L., Simon, N. M., Rauch, S. A. M., & Liberzon, I. (2020) · Depression and Anxiety · doi:10.1002/da.23075 · Cited by 41 · see citing works
Self-citation
One-year clinical outcomes following theta burst stimulation for post-traumatic stress disorder
Petrosino, N. J., Wout‐Frank, M. V. ‘., Aiken, E., Swearingen, H. R., Barredo, J., Zandvakili, A., & Philip, N. S. (2019) · Neuropsychopharmacology · doi:10.1038/s41386-019-0584-4 · Cited by 45 · see citing works
Salience Network Disruption in U.S. Army Soldiers With Posttraumatic Stress Disorder
Abdallah, C. G., Averill, C. L., Ramage, A. E., Averill, L. A., Goktas, S., Nemati, S., Krystal, J. H., Roache, J. D., Resick, P. A., Young‐McCaughan, S., et al. (2019) · Chronic Stress · doi:10.1177/2470547019850467 · Cited by 36 · see citing works
Mapping PTSD symptoms to brain networks: a machine learning study
Zandvakili, A., Barredo, J., Swearingen, H. R., Aiken, E., Berlow, Y. A., Greenberg, B. D., Carpenter, L. L., & Philip, N. S. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-00879-2 · Cited by 46 · see citing works
Neurobiology of posttraumatic stress disorder (PTSD): A path from novel pathophysiology to innovative therapeutics
Abdallah, C. G., Southwick, S. M., & Krystal, J. H. (2017) · Neuroscience Letters · doi:10.1016/j.neulet.2017.04.046 · Cited by 35 · see citing works
Posttraumatic Stress Disorder and Depression Symptom Severities Are Differentially Associated With Hippocampal Subfield Volume Loss in Combat Veterans
Averill, C. L., Satodiya, R. M., Scott, J. C., Wrocklage, K. M., Schweinsburg, B. C., Averill, L. A., Akiki, T. J., Amoroso, T., Southwick, S. M., Krystal, J. H., et al. (2017) · Chronic Stress · doi:10.1177/2470547017744538 · Cited by 34 · see citing works
Intranasal cotinine improves memory, and reduces depressive-like behavior, and GFAP + cells loss induced by restraint stress in mice
Perez-Urrutia, N., Mendoza, C., Alvarez-Ricartes, N., Oliveros-Matus, P., Echeverria, F., Grizzell, J. A., Barreto, G. E., Iarkov, A., & Echeverrı́a, V. (2017) · Experimental Neurology · doi:10.1016/j.expneurol.2017.06.016 · Cited by 34 · see citing works
“…these conditions have been associated with functional and structural changes in several regions of the brain including the amygdala (Laugharne et al., 2016), entorhinal cortex, prefrontal cortex and hippocampus (Meng et al., 2016; Sheynin and Liberzon, 2016; Yoon et al., 2017; Zhu et al., 2016).”
Background
Increased top-down control of emotions during symptom provocation working memory tasks following a RCT of alpha-down neurofeedback in PTSD
Shaw, S. B., Nicholson, A. A., Ros, T., Harricharan, S., Terpou, B. A., Densmore, M., Théberge, J., Frewen, P., & Lanius, R. A. (2023) · NeuroImage Clinical · doi:10.1016/j.nicl.2023.103313 · Cited by 33 · see citing works
Disturbed effective connectivity patterns in an intrinsic triple network model are associated with posttraumatic stress disorder
Weng, Y., Qi, R., Zhang, L., Luo, Y., Ke, J., Xu, Q., Zhong, Y., Li, J., Chen, F., Cao, Z., et al. (2018) · Neurological Sciences · doi:10.1007/s10072-018-3638-1 · Cited by 32 · see citing works
Neuroscience Informed Prolonged Exposure Practice: Increasing Efficiency and Efficacy Through Mechanisms
Stojek, M. M., McSweeney, L. B., & Rauch, S. A. M. (2018) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2018.00281 · Cited by 36 · see citing works
Regulator of G protein signaling 14 (RGS14) is expressed pre- and postsynaptically in neurons of hippocampus, basal ganglia, and amygdala of monkey and human brain
Squires, K. E., Gerber, K. J., Paré, J., Branch, M. R., Smith, Y., & Hepler, J. R. (2017) · Brain Structure and Function · doi:10.1007/s00429-017-1487-y · Cited by 29 · see citing works
“2012), social anxiety, and PTSD (Minkova et al. 2017; Sheynin and Liberzon 2016) remains a topic of great interest for future studies.”
Background
Ketamine ameliorates post-traumatic social avoidance by erasing the traumatic memory encoded in VTA-innervated BLA engram cells
Li, M., Yang, X., Yang, J., Li, T., Cui, C., Peng, X., Lei, J., Ren, K., Ming, J., Zhang, P., et al. (2024) · Neuron · doi:10.1016/j.neuron.2024.06.026 · Cited by 33 · see citing works
Altered resting-state functional connectivity of the default mode and central executive networks following cognitive processing therapy for PTSD
Vuper, T. C., Philippi, C. L., & Bruce, S. E. (2021) · Behavioural Brain Research · doi:10.1016/j.bbr.2021.113312 · Cited by 33 · see citing works
Endocannabinoid release at ventral hippocampal-amygdala synapses regulates stress-induced behavioral adaptation
Kondev, V., Najeed, M., Yasmin, F., Morgan, A., Loomba, N., Johnson, K., Adank, D. N., Dong, A., Delpire, E. J., Li, Y., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113027 · Cited by 35 · see citing works
Norepinephrine as a spatial memory reset signal
Grella, S. L., Gomes, S. M., Lackie, R. E., Renda, B., & Marrone, D. F. (2021) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000648 · Cited by 23 · see citing works
“Furthermore, it is hypothesized that posttraumatic stress disorder (PTSD) involves impairments in memory-updating mechanisms where incorporation of new information (eg, safety signals) is not encoded at a functional level which may reflect an inability to remap hippocampal contextual representations (ie, trauma-relate…”
Background
Anxiolytic effects of γ-oryzanol in chronically- stressed mice are related to monoamine levels in the brain
Akter, S., Sasaki, H., Uddin, K. R., Ikeda, Y., Miyakawa, H., & Shibata, S. (2018) · Life Sciences · doi:10.1016/j.lfs.2018.11.042 · Cited by 21 · see citing works
Prefrontal Glutamate Neurotransmission in PTSD: A Novel Approach to Estimate Synaptic Strength in Vivo in Humans
Averill, L. A., Jiang, L., Purohit, P., Coppoli, A., Averill, C. L., Roscoe, J., Kelmendi, B., Feyter, H. M. D., de Graaf, R. A., Gueorguieva, R. V., et al. (2022) · Chronic Stress · doi:10.1177/24705470221092734 · Cited by 22 · see citing works
“While the neurobiology of trauma and stress is not fully known [2], converging evidence suggest a critical role for glutamatergic synaptic connectivity alterations that produce the dysfunction of brain networks regulating memory and emotion associated with the PTSD symptoms [3-5].”
Background
Increased Frontal Gamma and Posterior Delta Powers as Potential Neurophysiological Correlates Differentiating Posttraumatic Stress Disorder from Anxiety Disorders
Moon, S.-Y., Choi, Y. B., Jung, H. K., Lee, Y. I., & Choi, S.-H. (2018) · Psychiatry Investigation · doi:10.30773/pi.2018.09.30 · Cited by 19 · see citing works
Neural circuitry changes associated with increasing self-efficacy in Posttraumatic Stress Disorder
Titcombe, R. F., Chen, J., Rahman, N., Kouri, N. A., Qian, M., Li, M., Bryant, R. A., Marmar, C. R., & Brown, A. D. (2018) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2018.06.009 · Cited by 20 · see citing works
Neural correlates of emotional reactivity and regulation associated with treatment response in a randomized clinical trial for posttraumatic stress disorder
Joshi, S. A., Duval, E. R., Sheynin, J., King, A. P. J., Phan, K. L., Martis, B., Porter, K. E., Liberzon, I., & Rauch, S. A. M. (2020) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2020.111062 · Cited by 18 · see citing works
“The dlPFC has previously been implicated in emotion regulation models and has demonstrated greater activation in participants with PTSD undergoing cognitive reappraisal tasks (Sheynin and Liberzon, 2017).”
BackgroundSelf-citation
Induced pluripotent stem cell-derived neural progenitor cell transplantation promotes regeneration and functional recovery after post-traumatic stress disorder in rats
Liu, Q., Zhang, L., & Zhang, J. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110981 · Cited by 15 · see citing works
Should Posttraumatic Stress Be a Disorder or a Specifier? Towards Improved Nosology Within the DSM Categorical Classification System
Guina, J., Baker, M., Stinson, K., Maust, J., Coles, J., & Broderick, P. J. (2017) · Current Psychiatry Reports · doi:10.1007/s11920-017-0821-7 · Cited by 17 · see citing works
Cannabis use and posttraumatic stress disorder comorbidity: Epidemiology, biology and the potential for novel treatment approaches
Kondev, V., Winters, N. D., & Patel, S. (2021) · International review of neurobiology · doi:10.1016/bs.irn.2020.09.007 · Cited by 17 · see citing works
The role of BDNF in mediating the prophylactic effects of (R,S)-ketamine on fear generalization and extinction
Ryan, J. D., Tse, N., Huang, C., Yang, R., & Lee, F. S. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02116-4 · Cited by 17 · see citing works
Enhancing Agency in Posttraumatic Stress Disorder Therapies Through Sensorimotor Technologies
Adrien, V., Bosc, N., Peccia-Galletto, C., Diot, T., Claverie, D., Reggente, N., Trousselard, M., Bui, É., Baubet, T., & Schoeller, F. (2024) · Journal of Medical Internet Research · doi:10.2196/58390 · Cited by 15 · see citing works
“Over time, the failure to integrate the traumatic memory leads to a default in contextual processing [84,85,109,110], resulting in trauma-related cognitions, such as guilt and shame, which in turn induce a wide array of comorbid complications, such as depression [111], anxiety [112], and…”
Fabp7 Is Required for Normal Sleep Suppression and Anxiety-Associated Phenotype following Single-Prolonged Stress in Mice
Vanderheyden, W. M., Lefton, M., Flores, C. C., Owada, Y., & Gerstner, J. (2022) · Neuroglia · doi:10.3390/neuroglia3020005 · Cited by 13 · see citing works
“The neural circuits that have been implicated in PTSD include fear learning, emotional processing, arousal, and context processing circuitry [33,34].”
Parsing neural circuits of fear learning and extinction across basic and clinical neuroscience: towards better translation.
Namkung, H., Thomas, K. L., Hall, J., & Sawa, A. (2021) · Neuroscience and Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.12.025 · Cited by 12 · see citing works
Transcranial magnetic stimulation for obsessive-compulsive disorder and post-traumatic stress disorder: A comprehensive systematic review and analysis of therapeutic benefits, cortical targets, and psychopathophysiological mechanisms
Vicheva, P., Osborne, C., Krieg, S. M., Ahmadi, R., & Shotbolt, P. (2024) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2024.111147 · Cited by 14 · see citing works
“…impairments in fear conditioning, extinction learning and retention, inhibitory control, attention to trauma-related stimuli, and contextual fear memory (Rauch et al., 1998; Rauch et al., 2006; Shin and Handwerger, 2009; Ross et al., 2017; Sheynin and Liberzon, 2017; VanElzakker et al., 2018).”
Background
An insight into crosstalk among multiple signalling pathways contributing to the pathophysiology of PTSD and depressive disorders
‬‬‬‬‬‬‬Bommaraju, S., Dhokne, M. D., Arun, E. V., Srinivasan, K., Sharma, S. S., & Datusalia, A. K. (2024) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2024.110943 · Cited by 12 · see citing works
A Systematic Review of Neurocognitive Effects of Subanesthetic Doses of Intravenous Ketamine in Major Depressive Disorder, Post-Traumatic Stress Disorder, and Healthy Population
Shiroma, P., Velit-Salazar, M. R., & Vorobyov, Y. L. (2022) · Clinical drug investigation · doi:10.1007/s40261-022-01169-z · Cited by 10 · see citing works
Resting-state connectivity subtype of comorbid PTSD and alcohol use disorder moderates improvement from integrated prolonged exposure therapy in Veterans
Stout, D. M., Harlé, K. M., Norman, S. B., Simmons, A. N., & Spadoni, A. D. (2021) · Psychological Medicine · doi:10.1017/s0033291721001513 · Cited by 9 · see citing works
Hypothesis testing of the adoption of pseudoscientific methods
McKay, D., & Coreil, A. (2023) · Medical Hypotheses · doi:10.1016/j.mehy.2023.111229 · Cited by 8 · see citing works
Neurophysiological Response to Olfactory Stimuli in Combat Veterans With Posttraumatic Stress Disorder
Bedwell, J., Bohil, C. J., Neider, M., Gramlich, M. A., Neer, S., O’Donnell, J. P., & Beidel, D. (2018) · Journal of Nervous and Mental Disease · doi:10.1097/nmd.0000000000000818 · Cited by 7 · see citing works
Interaction of Temporal Lobe Epilepsy and Posttraumatic Stress Disorder: Network Analysis of a Single Case
Biran, I., Admon, R., Gazit, T., & Fahoum, F. (2020) · Frontiers in Psychology · doi:10.3389/fpsyg.2020.01010 · Cited by 6 · see citing works
Modeling of Post-Traumatic Stress Disorder in Mice: Nonlinear Relationship with the Strength of the Traumatic Event
Toropova, K., & Anokhin, K. (2019) · Neuroscience and Behavioral Physiology · doi:10.1007/s11055-019-00814-z · Cited by 6
“For several decades, the main view of the causes of PTSD consisted of the concept of impairment to the operation of the body’s stress response system due to the trauma experienced [Cohen and Zohar, 2004; Liberzon et al., 2005; Sheynin and Liberzon, 2017].”
Background
Functional deficit in hippocampal activity during fear extinction recall in the single prolonged-stress model of PTSD in male rats
Winters, J. J., Hardy, L. W., Sullivan, J. M., Powell, N. A., Qutaish, M. Q., Nair, S., Heimann, J., Ghayoor, A., Polyak, I., Chaby, L. E., et al. (2020) · Behavioural Brain Research · doi:10.1016/j.bbr.2020.112902 · Cited by 10 · see citing works
Self-citation
Innovating transcranial magnetic stimulation treatment for post-traumatic stress disorder: Zapping away the bad memory
Yuan, T., Wang, T., Li, S., Wei, P., Wang, L., Pan, B., Hu, J., Wu, S., Shen, Y., Yuan, Z., et al. (2025) · Fundamental Research · doi:10.1016/j.fmre.2025.08.013 · Cited by 3 · see citing works
“Brain regions and neurocircuits implicated in PTSD [ 49 , 51 , 58 ].”
Electrophysiological signatures of resting state networks under new environmental conditions
Bocharov, A. V., Savostyanov, A. N., Tamozhnikov, S. S., Karpova, A. G., Milakhina, N. S., Zavarzin, E. A., Сапрыгин, А. Е., & Knyazev, G. G. (2022) · Neuroscience Letters · doi:10.1016/j.neulet.2022.137012 · Cited by 4 · see citing works
The Role of Glucocorticoid Hormones in the Stress-Protective Effects of Hypoxic Postconditioning in Models of Depression and Post-Traumatic Stress Disorder in Rats
Zenko, M. Y., & Rybnikova, E. A. (2021) · Neuroscience and Behavioral Physiology · doi:10.1007/s11055-021-01132-z · Cited by 1 · see citing works
“The hippocampus was selected because this brain structure plays a key role in regulating HHAS function [Jacobson and Sapolsky, 1991; Harvey, 2006; Gulyaeva, 2015], which is impaired in these pathologies [Morris, 2012; Sheynin and Liberzon, 2017].”
Method
Reduced Energy Per Cycle, a Marker of Glutamatergic Synaptic Strength, in Individuals Diagnosed with PTSD and DepressionPreprint
Averill, L., Jiang, L.-H., Purohit, P., Coppoli, A., Averill, C. L., Roscoe, J., Kelmendi, B., de Feyter, H., de Graaf, R. D., Gueorguieva, R., et al. (2021) · medRxiv · doi:10.1101/2021.04.09.21255211 · Cited by 1 · see citing works
“While the neurobiology of trauma and stress is not fully known [2], converging evidence suggest a critical role for glutamatergic synaptic connectivity alterations that produce the dysfunction of brain networks regulating memory and emotion associated with the emergence of symptoms [3-5].”
Background
Salience Network Disruption in US Army Soldiers with PTSDPreprint
Abdallah, C. G., Averill, C. L., Ramage, A. E., Averill, L. A., Goktas, S., Krystal, J. H., Roache, J. D., Resick, P. A., Young‐McCaughan, S., Peterson, A. L., et al. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/496505 · Cited by 1 · see citing works
Evidence‐Based Practice for Posttraumatic Stress Disorder
Frueh, B. C., Grubaugh, A. L., Madan, A., Neer, S. M., Elhai, J. D., & Beidel, D. C. (2017) · Wiley eBooks · doi:10.1002/9781119462996.ch7 · Cited by 14 · see citing works
Neuroinflammation does not exacerbate post-traumatic stress-disorder (PTSD)-like brain measures or behaviour after a traumatic event in male rats
Xavier, S., Al-Saabary, H., Foran, D., Kovatchev, M., Almadani, M., Almuqati, N., Younesi, S., Verghese, E., & Spencer, S. J. (2025) · Neuroscience · doi:10.1016/j.neuroscience.2025.12.014
A memory-based neuronal substrate model of psychogenic non-epileptic seizure and posttraumatic stress disorder
Dawood, S. (2019) · The European Journal of Psychiatry · doi:10.1016/j.ejpsy.2019.02.001
Neurobiological Models of Psychotherapy: How Psychotherapy Changes the Brain
Alberini, C. (2019) · Frontiers Research Topics · doi:10.3389/978-2-88963-036-3
“…deficits may be a transdiagnostic factor contributing to the development and maintenance of various types of psychopathology (Bradley et al., 2011; Sheynin and Liberzon, 2017), therefore, increased connectivity in that region may reflect an alleviation in symptoms due to an effective treatment in…”
BackgroundInfluential

Authors: Sheynin, J., & Liberzon, I.
Affiliations: University of Michigan (US)
Corresponding author: Liberzon, Israel
ORCID: Sheynin, Jony
Liberzon, Israel
Venue: Neuroscience Letters
Publisher: Elsevier BV
Published: 2017-05
Volume: 649
Pages: 133-138
ISSN: 0304-3940 (ISSN-L)
DOI: 10.1016/j.neulet.2016.11.014
PMC: PMC5422122
OpenAlex: W2550103662
Cited by: 68
References: 86
Citations by year: 2025: 4 · 2024: 5 · 2023: 3 · 2022: 6 · 2021: 9 · 2020: 10 · 2019: 9 · 2018: 12 · 2017: 10
FWCI: 1.53
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (am, 368 d)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Neuroscience Letters (acceptedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: Department of Defense (W81XWH-13-1-0377)
National Institute of Mental Health (MH075999)
Topics: Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Social Sciences › Psychology › Clinical Psychology › Psychoanalysis and Psychopathology Research
Keywords: post-traumatic stress disorder, neural circuits, amygdala, dorsal anterior cingulate cortex, insula, medial prefrontal cortex, hippocampus, fear learning, threat detection, context processing, emotion regulation, exposure therapy, pharmacotherapy, brain stimulation, cognitive therapy
MeSH terms: Amygdala, Animals, Brain, Conditioning, Classical, Emotions, Fear, Hippocampus, Humans, Neural Pathways, Stress Disorders, Post-Traumatic, Prefrontal Cortex

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Circuit dysregulation and circuit-based treatments in posttraumatic stress disorder

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