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Ubri CE, Farrugia AM, Cohen AS. Mild Traumatic Brain Injury Impairs Fear Extinction and Network Excitability in the Infralimbic Cortex. J Neurotrauma 2025. [PMID: 40401451 DOI: 10.1089/neu.2025.0046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2025] Open
Abstract
Traumatic brain injury (TBI) is a leading cause of morbidity and disability, with mild TBI (concussions) representing over 80% of cases. Although often considered benign, mild TBI is associated with persistent neuropsychiatric conditions, including post-traumatic stress disorder, anxiety, and depression. A hallmark of these conditions is impaired fear extinction (FE), the process by which learned fear responses are inhibited in safe contexts. This dysfunction contributes to maladaptive fear expression and is linked to altered neurocircuitry, particularly in the infralimbic cortex (IL), a key region in FE. Despite extensive evidence of impaired FE in patients with mild TBI and animal models, the specific mechanisms underlying this deficit remain poorly understood. This study aimed to address this gap by combining cued-FE behavior, local field potential recordings, and whole-cell patch-clamp techniques to investigate how mild TBI affects IL network activity and excitability in a mouse model of TBI. Our results demonstrate that mild lateral fluid percussion injury significantly impairs FE memory, as evidenced by an elevated cued-fear response during extinction testing 10 days post-injury. Field potential recordings revealed decreased activation of the IL network in both layers II/III and V, which was consistent with the observed behavioral deficits. Further analysis of synaptic physiology revealed an imbalance in excitatory and inhibitory neurotransmission (E/I imbalance) in the IL, characterized by reduced excitatory input and enhanced inhibitory input to neurons in both layers. Moreover, intrinsic excitability was altered in IL neurons after mild TBI. This study provides novel insights into how mild TBI disrupts the neurocircuitry underlying FE, specifically by suppressing IL excitability. These results highlight the importance of understanding the mechanistic disruptions in IL activity for developing therapeutic strategies to address fear-based disorders in patients with mild TBI.
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Affiliation(s)
- Catherine E Ubri
- Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department and Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Anthony M Farrugia
- Department and Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Akiva S Cohen
- Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department and Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
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2
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Xie T, van Rooij SJH, Inman CS, Wang S, Brunner P, Willie JT. The case for hemispheric lateralization of the human amygdala in fear processing. Mol Psychiatry 2025; 30:2252-2259. [PMID: 40016388 PMCID: PMC12014508 DOI: 10.1038/s41380-025-02940-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 02/04/2025] [Accepted: 02/19/2025] [Indexed: 03/01/2025]
Affiliation(s)
- Tao Xie
- Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA
- National Center for Adaptive Neurotechnologies, St. Louis, MO, USA
| | - Sanne J H van Rooij
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
| | - Cory S Inman
- Department of Psychology, University of Utah, Salt Lake City, UT, USA
| | - Shuo Wang
- Department of Radiology, Washington University in St. Louis, St. Louis, MO, USA
| | - Peter Brunner
- Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA.
- National Center for Adaptive Neurotechnologies, St. Louis, MO, USA.
| | - Jon T Willie
- Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA.
- National Center for Adaptive Neurotechnologies, St. Louis, MO, USA.
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3
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Keding TJ, Russell JD, Zhu X, He Q, Li JJ, Herringa RJ. Diverging Effects of Violence Exposure and Psychiatric Symptoms on Amygdala-Prefrontal Maturation During Childhood and Adolescence. BIOLOGICAL PSYCHIATRY. COGNITIVE NEUROSCIENCE AND NEUROIMAGING 2025; 10:450-462. [PMID: 39182725 PMCID: PMC11885587 DOI: 10.1016/j.bpsc.2024.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 08/09/2024] [Accepted: 08/12/2024] [Indexed: 08/27/2024]
Abstract
BACKGROUND Violence exposure during childhood and adolescence is associated with increased prevalence and severity of psychopathology. Neurobiological correlates suggest that abnormal maturation of emotion-related brain circuitry, such as the amygdala-prefrontal cortex (PFC) circuit, may underlie the development of psychiatric symptoms after exposure. However, it remains unclear how amygdala-PFC circuit maturation is related to psychiatric risk in the context of violence. METHODS In this study, we analyzed individual differences in amygdala-PFC circuit maturity using data collected from the PNC (Philadelphia Neurodevelopmental Cohort) (n = 1133 youths). Neurodevelopment models of amygdala-PFC resting-state functional connectivity were built using deep learning and trained to predict chronological age in typically developing youths (not violence exposed and without a psychiatric diagnosis). Using the brain age gap estimate, an index of relative circuit maturation, patterns of atypical neurodevelopment were investigated. RESULTS Violence exposure was associated with delayed maturation of basolateral amygdala (BLA)-PFC circuits, driven by increased BLA-medial orbitofrontal cortex functional connectivity. In contrast, increased psychiatric symptoms were associated with advanced maturation of BLA-PFC functional connectivity, driven by decreased BLA-dorsolateral PFC functional connectivity. CONCLUSIONS Delayed frontoamygdala maturation after exposure to violence suggests atypical, but adaptive, development of threat appraisal processes, potentially reflecting a greater threat generalization characteristic of younger children. Advanced circuit maturation with increasing symptoms suggests divergent neurodevelopmental mechanisms underlying illness after emotion circuits have adapted to adversity, exacerbated by preexisting vulnerabilities to early maturation. Disentangling the effects of adversity and psychopathology on neurodevelopment is crucial for helping youths recover from violence and preventing illness from continuing into adulthood.
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Affiliation(s)
- Taylor J Keding
- Neuroscience Training Program, University of Wisconsin-Madison, Madison, Wisconsin; Department of Psychiatry, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; Department of Psychology, Yale University, New Haven, Connecticut.
| | - Justin D Russell
- Department of Psychiatry, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Xiaojin Zhu
- Department of Computer Science, University of Wisconsin-Madison, Madison, Wisconsin
| | - Quanfa He
- Department of Psychology, University of Wisconsin-Madison, Madison, Wisconsin
| | - James J Li
- Department of Psychology, University of Wisconsin-Madison, Madison, Wisconsin; Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin
| | - Ryan J Herringa
- Neuroscience Training Program, University of Wisconsin-Madison, Madison, Wisconsin; Department of Psychiatry, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
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4
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Zhang Y, Lin J, Dou H, Zhang H, Cao Y, Lei Y. Modulation of Fear Extinction by Non-Invasive Brain Stimulation: Systematic Review and Meta-Analysis. Psychophysiology 2025; 62:e14763. [PMID: 39905577 DOI: 10.1111/psyp.14763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 11/27/2024] [Accepted: 12/29/2024] [Indexed: 02/06/2025]
Abstract
Non-invasive brain stimulation (NIBS) is an emerging treatment for mental disorders that is painlessness and easy to administer. However, its effectiveness for modulating fear extinction requires further elucidation. We searched eight bibliographical databases and identified randomized controlled trials of NIBS and fear extinction in healthy populations. Outcomes were evaluated based on skin conductance responses (SCRs) under three experimental stimuli: threat condition stimulation (CS+), safe condition stimulation (CS-), and their discrimination (CS+ minus CS-). We applied a random-effects model to determine effect sizes (Hedge's g) post-stimulation and assessed article quality using Physiotherapy evidence database (PEDro) scale. Twenty-one studies meeting systematic review criteria were included in this analysis, incorporating 40 independent effect sizes and data from 11 studies (n = 632) in the meta-analysis. Compared with the control group, SCRs in CS+ and discrimination were significantly reducted in the intervention group. Fear extinction was more effective in the 24-h test than immediately after NIBS. In conclusion, NIBS enhanced fear extinction, and the time interval between stimulation and testing may serve as a moderating variable.
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Affiliation(s)
- Ye Zhang
- Institute of Brain and Psychological Sciences, Sichuan Normal University, Chengdu, China
| | - Jingyuan Lin
- Institute of Brain and Psychological Sciences, Sichuan Normal University, Chengdu, China
| | - Haoran Dou
- Institute of Brain and Psychological Sciences, Sichuan Normal University, Chengdu, China
| | - Huoyin Zhang
- Institute of Brain and Psychological Sciences, Sichuan Normal University, Chengdu, China
- School of Psychology, Shenzhen University, Shenzhen, China
| | - Ying Cao
- Institute of Brain and Psychological Sciences, Sichuan Normal University, Chengdu, China
| | - Yi Lei
- Institute of Brain and Psychological Sciences, Sichuan Normal University, Chengdu, China
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5
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Yu Q, Ruan M, Chen Y, Wang C. Advances in neuroscience research and big data's analysis on anxiety disorder. WILEY INTERDISCIPLINARY REVIEWS. COGNITIVE SCIENCE 2025; 16:e1692. [PMID: 39390772 DOI: 10.1002/wcs.1692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 02/16/2024] [Accepted: 07/01/2024] [Indexed: 10/12/2024]
Abstract
Anxiety disorder is a complex disease with the influence of environmental and genetic factors and multimolecular participation, and it is also one of the most common mental disorders. The causes of disorders are not clear but may include a variety of social, psychological, and biological factors. Therefore, neither genetics, neurobiology, nor neuroimaging can independently explain the pathological mechanism. By searching the Web of Science databases, Derwent Innovation Patent database, ClinicalTrials.gov database, and Cortellis database, we analyze the current situation of papers, patents, clinical trials, and drugs of anxiety disorder. Second, the existing literature was reviewed to summarize the neurophysiological mechanism, brain imaging, gene, anti-anxiety drugs, and other aspects of anxiety disorders. This article reviews the research status of anxiety disorders. The heterogeneity of the disease, lack of treatment effectiveness, and gaps in translational medicine still present barriers to further advancement. Thus, in-depth explorations of the underlying biological mechanisms of anxiety disorders, the detection and intervention of biological targets, and further developments based on existing intervention strategies will drive future research on anxiety disorders. This article is categorized under: Neuroscience > Clinical.
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Affiliation(s)
- Qianmei Yu
- Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Meihua Ruan
- Shanghai Institute of Nutrition and Health, Shanghai Information Center for Life Sciences, Chinese Academy of Science, Shanghai, China
| | - Yongjun Chen
- Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Chun Wang
- Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China
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6
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Del Vecchio M, Avanzini P, Gerbella M, Costa S, Zauli FM, d’Orio P, Focacci E, Sartori I, Caruana F. Anatomo-functional basis of emotional and motor resonance elicited by facial expressions. Brain 2024; 147:3018-3031. [PMID: 38365267 PMCID: PMC12007602 DOI: 10.1093/brain/awae050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 12/21/2023] [Accepted: 01/28/2024] [Indexed: 02/18/2024] Open
Abstract
Simulation theories predict that the observation of other's expressions modulates neural activity in the same centres controlling their production. This hypothesis has been developed by two models, postulating that the visual input is directly projected either to the motor system for action recognition (motor resonance) or to emotional/interoceptive regions for emotional contagion and social synchronization (emotional resonance). Here we investigated the role of frontal/insular regions in the processing of observed emotional expressions by combining intracranial recording, electrical stimulation and effective connectivity. First, we intracranially recorded from prefrontal, premotor or anterior insular regions of 44 patients during the passive observation of emotional expressions, finding widespread modulations in prefrontal/insular regions (anterior cingulate cortex, anterior insula, orbitofrontal cortex and inferior frontal gyrus) and motor territories (Rolandic operculum and inferior frontal junction). Subsequently, we electrically stimulated the activated sites, finding that (i) in the anterior cingulate cortex and anterior insula, the stimulation elicited emotional/interoceptive responses, as predicted by the 'emotional resonance model'; (ii) in the Rolandic operculum it evoked face/mouth sensorimotor responses, in line with the 'motor resonance' model; and (iii) all other regions were unresponsive or revealed functions unrelated to the processing of facial expressions. Finally, we traced the effective connectivity to sketch a network-level description of these regions, finding that the anterior cingulate cortex and the anterior insula are reciprocally interconnected while the Rolandic operculum is part of the parieto-frontal circuits and poorly connected with the former. These results support the hypothesis that the pathways hypothesized by the 'emotional resonance' and the 'motor resonance' models work in parallel, differing in terms of spatio-temporal fingerprints, reactivity to electrical stimulation and connectivity patterns.
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Affiliation(s)
- Maria Del Vecchio
- Institute of Neuroscience, National Research Council of Italy (CNR), 43125 Parma, Italy
| | - Pietro Avanzini
- Institute of Neuroscience, National Research Council of Italy (CNR), 43125 Parma, Italy
| | - Marzio Gerbella
- Department of Medicine and Surgery, University of Parma, 43125 Parma, Italy
| | - Sara Costa
- Department of Medicine and Surgery, University of Parma, 43125 Parma, Italy
| | - Flavia Maria Zauli
- ‘Claudio Munari’ Epilepsy Surgery Center, ASST GOM Niguarda, 20142 Milan, Italy
| | - Piergiorgio d’Orio
- ‘Claudio Munari’ Epilepsy Surgery Center, ASST GOM Niguarda, 20142 Milan, Italy
| | - Elena Focacci
- Department of Medicine and Surgery, University of Parma, 43125 Parma, Italy
| | - Ivana Sartori
- ‘Claudio Munari’ Epilepsy Surgery Center, ASST GOM Niguarda, 20142 Milan, Italy
| | - Fausto Caruana
- Institute of Neuroscience, National Research Council of Italy (CNR), 43125 Parma, Italy
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Park S, Huh Y, Kim JJ, Cho J. Bidirectional fear modulation by discrete anterior insular circuits in male mice. eLife 2024; 13:RP95821. [PMID: 39088250 PMCID: PMC11293866 DOI: 10.7554/elife.95821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/02/2024] Open
Abstract
The brain's ability to appraise threats and execute appropriate defensive responses is essential for survival in a dynamic environment. Humans studies have implicated the anterior insular cortex (aIC) in subjective fear regulation and its abnormal activity in fear/anxiety disorders. However, the complex aIC connectivity patterns involved in regulating fear remain under investigated. To address this, we recorded single units in the aIC of freely moving male mice that had previously undergone auditory fear conditioning, assessed the effect of optogenetically activating specific aIC output structures in fear, and examined the organization of aIC neurons projecting to the specific structures with retrograde tracing. Single-unit recordings revealed that a balanced number of aIC pyramidal neurons' activity either positively or negatively correlated with a conditioned tone-induced freezing (fear) response. Optogenetic manipulations of aIC pyramidal neuronal activity during conditioned tone presentation altered the expression of conditioned freezing. Neural tracing showed that non-overlapping populations of aIC neurons project to the amygdala or the medial thalamus, and the pathway bidirectionally modulated conditioned fear. Specifically, optogenetic stimulation of the aIC-amygdala pathway increased conditioned freezing, while optogenetic stimulation of the aIC-medial thalamus pathway decreased it. Our findings suggest that the balance of freezing-excited and freezing-inhibited neuronal activity in the aIC and the distinct efferent circuits interact collectively to modulate fear behavior.
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Affiliation(s)
- Sanggeon Park
- Department of Brain and Cognitive Sciences, Scranton College, Ewha Womans UniversitySeoulRepublic of Korea
- Brain Disease Research Institute, Ewha Brain Institute, Ewha Womans UniversitySeoulRepublic of Korea
| | - Yeowool Huh
- Department of Basic Medical Science, College of Medicine, Catholic Kwandong UniversityGangneungRepublic of Korea
- Institute for Bio-Medical Convergence, International St. Mary’s Hospital, Catholic Kwandong UniversityIncheonRepublic of Korea
| | - Jeansok J Kim
- Department of Psychology, University of WashingtonSeattleUnited States
| | - Jeiwon Cho
- Department of Brain and Cognitive Sciences, Scranton College, Ewha Womans UniversitySeoulRepublic of Korea
- Brain Disease Research Institute, Ewha Brain Institute, Ewha Womans UniversitySeoulRepublic of Korea
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8
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Stussi Y, Coppin G. Letter to the Editor: Stimulus intensities and sensory modalities constitute two major challenges for online threat conditioning research. Biol Psychol 2024; 190:108805. [PMID: 38679403 DOI: 10.1016/j.biopsycho.2024.108805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 04/24/2024] [Accepted: 04/24/2024] [Indexed: 05/01/2024]
Affiliation(s)
- Yoann Stussi
- Swiss Center for Affective Sciences, Campus Biotech, University of Geneva, Geneva, Switzerland; Department of Psychology, FPSE, University of Geneva, Geneva, Switzerland.
| | - Géraldine Coppin
- Swiss Center for Affective Sciences, Campus Biotech, University of Geneva, Geneva, Switzerland; UniDistance Suisse, Brig, Switzerland
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9
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Lee J, Kim YE, Lim J, Jo Y, Lee HJ, Jo YS, Choi JS. Transcranial focused ultrasound stimulation in the infralimbic cortex facilitates extinction of conditioned fear in rats. Brain Stimul 2024; 17:405-412. [PMID: 38537689 DOI: 10.1016/j.brs.2024.03.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 03/04/2024] [Accepted: 03/15/2024] [Indexed: 05/01/2024] Open
Abstract
Transcranial focused ultrasound (tFUS) neuromodulation emerges as a promising non-invasive approach for improving neurological conditions. Extinction of conditioned fear has served as a prime model for exposure-based therapies for anxiety disorders. We investigated whether tFUS stimulation to a critical brain area, the infralimbic subdivision of the prefrontal cortex (IL), could facilitate fear extinction using rats. In a series of experiments, tFUS was delivered to the IL of a freely-moving rat and compared to sham stimulation (tFUS vs. SHAM). Initially, Fos expression in the IL was measured shortly after the stimulation. The results show that Fos expression was significantly increased in the IL but not in the neighboring regions compared to SHAM. Subsequently, two groups of rats were subjected to fear conditioning, extinction, and retention while receiving stimulation during the extinction. Rats in the tFUS group froze significantly less than SHAM during both extinction and retention tests. Importantly, the reduced freezing in the tFUS group was not attributable to non-specific effect such as auditory noise, as both groups demonstrated a similar level of locomotive activity in an open field regardless of the stimulation condition. Finally, we replicated the procedure with a shortened conditioning-to-extinction interval (15 min) to induce immediate extinction deficit. The tFUS group showed a facilitated reduction in freezing during the extinction, which persisted in the subsequent retention session compared to SHAM. In summary, the current findings suggest that tFUS stimulation in the IL facilitates fear extinction, offering a potential therapeutic regimen for fear-related psychiatric disorders.
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Affiliation(s)
- Jaeyong Lee
- School of Psychology, Korea University, Seoul, 02841, Republic of Korea
| | - Ye Eun Kim
- School of Psychology, Korea University, Seoul, 02841, Republic of Korea
| | - Jihong Lim
- School of Electrical Engineering, KAIST, Daejeon, 34141, Republic of Korea
| | - Yehhyun Jo
- School of Electrical Engineering, KAIST, Daejeon, 34141, Republic of Korea
| | - Hyunjoo Jenny Lee
- School of Electrical Engineering, KAIST, Daejeon, 34141, Republic of Korea
| | - Yong Sang Jo
- School of Psychology, Korea University, Seoul, 02841, Republic of Korea
| | - June-Seek Choi
- School of Psychology, Korea University, Seoul, 02841, Republic of Korea.
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10
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Hornstein E, Leschak CJ, Parrish MH, Byrne-Haltom KE, Fanselow MS, Craske MG, Eisenberger NI. Social support and fear-inhibition: an examination of underlying neural mechanisms. Soc Cogn Affect Neurosci 2024; 19:nsae002. [PMID: 38217103 PMCID: PMC10868130 DOI: 10.1093/scan/nsae002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 12/06/2023] [Accepted: 01/08/2024] [Indexed: 01/15/2024] Open
Abstract
Recent work has demonstrated that reminders of those we are closest to have a unique combination of effects on fear learning and represent a new category of fear inhibitors, termed prepared fear suppressors. Notably, social-support-figure images have been shown to resist becoming associated with fear, suppress conditional-fear-responding and lead to long-term fear reduction. Due to the novelty of this category, understanding the underlying neural mechanisms that support these unique abilities of social-support-reminders has yet to be investigated. Here, we examined the neural correlates that enable social-support-reminders to resist becoming associated with fear during a retardation-of-acquisition test. We found that social-support-figure-images (vs stranger-images) were less readily associated with fear, replicating prior work, and that this effect was associated with decreased amygdala activity and increased ventromedial prefrontal cortex (VMPFC) activity for social-support-figure-images (vs stranger-images), suggesting that social-support-engagement of the VMPFC and consequent inhibition of the amygdala may contribute to unique their inhibitory effects. Connectivity analyses supported this interpretation, showing greater connectivity between the VMPFC and left amygdala for social-support-figure-images (vs stranger-images).
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Affiliation(s)
- E.A Hornstein
- Department of Psychology, University of California, Los Angeles, CA 90095, USA
| | - C J Leschak
- Department of Psychology, University of California, Los Angeles, CA 90095, USA
| | - M H Parrish
- Department of Psychology, University of California, Los Angeles, CA 90095, USA
| | - K E Byrne-Haltom
- Department of Psychology, University of California, Los Angeles, CA 90095, USA
| | - M S Fanselow
- Department of Psychology, University of California, Los Angeles, CA 90095, USA
- Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095, USA
| | - M G Craske
- Department of Psychology, University of California, Los Angeles, CA 90095, USA
- Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095, USA
| | - N I Eisenberger
- Department of Psychology, University of California, Los Angeles, CA 90095, USA
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11
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Motzkin JC, Hiser J, Carroll I, Wolf R, Baskaya MK, Koenigs M, Atlas LY. Human ventromedial prefrontal cortex lesions enhance the effect of expectations on pain perception. Cortex 2023; 166:188-206. [PMID: 37390595 PMCID: PMC10528632 DOI: 10.1016/j.cortex.2023.04.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 03/23/2023] [Accepted: 04/21/2023] [Indexed: 07/02/2023]
Abstract
Pain is strongly modulated by expectations and beliefs. Across species, subregions of ventromedial prefrontal cortex (VMPFC) are implicated in a variety of functions germane to pain, predictions, and learning. Human fMRI studies show that VMPFC activity tracks expectations about pain and mediates expectancy effects on pain-related activity in other brain regions. Prior lesion studies suggest that VMPFC may instead play a more general role in generating affective responses to painful stimuli. To test whether VMPFC is required to generate affective responses to pain or is more specifically involved in expectancy-based pain modulation, we studied responses to heat stimuli in five adults with bilateral surgical lesions of VMPFC and twenty healthy adults without brain damage. All participants underwent a quantitative sensory testing procedure followed by a pain expectancy task in which cues predicting either low or high pain were followed by intermittent medium intensity heat stimuli. Compared to adults without brain damage, individuals with VMPFC lesions reported larger differences in expected pain based on predictive cues and failed to update expectations following the covert introduction of unexpected medium temperature stimuli. Consistent with observed expectancy differences, subjective pain unpleasantness ratings in the VMPFC lesion group were more strongly modulated by cue during thermal stimulation. We found no group differences in overall pain sensitivity, nor in relationships between pain and autonomic arousal, suggesting that VMPFC damage specifically enhances the effect of expectations on pain processing, likely driven by impaired integration of new sensory feedback to update expectations about pain. These results provide essential new data regarding the specific functional contribution of VMPFC to pain modulation.
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Affiliation(s)
- Julian C Motzkin
- Department of Neurology, University of California, San Francisco, CA, USA; Department of Anesthesia and Perioperative Care, University of California, San Francisco CA, USA
| | - Jaryd Hiser
- Department of Psychiatry, University of Wisconsin-Madison, WI, USA
| | - Ian Carroll
- Department of Psychology, University of Wisconsin-Madison, WI, USA
| | - Richard Wolf
- Department of Psychiatry, University of Wisconsin-Madison, WI, USA
| | - Mustafa K Baskaya
- Department of Neurological Surgery, University of Wisconsin-Madison, WI, USA
| | - Michael Koenigs
- Department of Psychiatry, University of Wisconsin-Madison, WI, USA
| | - Lauren Y Atlas
- National Center for Complementary and Integrative Health, National Institutes of Health, Bethesda, MD, USA; National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA; National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
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12
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Abstract
Treatment outcomes are strongly influenced by expectations, as evidenced by the placebo effect. Meta-analyses of clinical trials reveal that placebo effects are strongest in pain, indicating that psychosocial factors directly influence pain. In this review, I focus on the neural and psychological mechanisms by which instructions, learning, and expectations shape subjective pain. I address new experimental designs that help researchers tease apart the impact of these distinct processes and evaluate the evidence regarding the neural mechanisms by which these cognitive factors shape subjective pain. Studies reveal that expectations modulate pain through parallel circuits that include both pain-specific and domain-general circuits such as those involved in affect and learning. I then review how expectations, learning, and verbal instructions impact clinical outcomes, including placebo analgesia and responses to pharmacological treatments, and discuss implications for future work.
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Affiliation(s)
- Lauren Y Atlas
- National Center for Complementary and Integrative Health and National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA;
- National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA
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13
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Avnioglu S, Sahin C, Cankaya S, Ozen O, Dikici R, Yilmaz H, Velioglu HA, Yulug B. Decreased frontal and orbital volumes and increased cerebellar volumes in patients with anosmia Of Unknown origin: A subtle connection? J Psychiatr Res 2023; 160:86-92. [PMID: 36791532 DOI: 10.1016/j.jpsychires.2023.01.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 01/03/2023] [Accepted: 01/09/2023] [Indexed: 01/13/2023]
Abstract
PURPOSE Neuroimaging studies have shown that anosmia is accompanied by a decreased olfactory bulb volume, yet little is known about alterations in cerebral and cerebellar lobule volumes. The purpose of this study was to investigate structural brain alterations in anosmic patients. METHODS Sixteen anosmic patients (mean age 42.62 ± 16.57 years; 6 women and 10 men) and 16 healthy controls (mean age 43.37 ± 18.98 years; 9 women and 7 men) were included in this retrospective study. All subjects who underwent magnetic resonance imaging scans were analyzed using VolBrain and voxel-based morphometry after olfactory testing. RESULTS Despite being statistically insignificant, analysis using VBM revealed greater gray matter (GM) and white matter in the anosmia group compared to the healthy subjects. However, decreased GM (p < 0.001) and increased cerebellar (p = 0.046) volumes were observed in the anosmic patients. CONCLUSIONS The study revealed structural brain alterations in specific areas beyond the olfactory bulb. Our results indicate that the cerebellum may play an exceptional role in the olfactory process and that this will be worth evaluating with further dynamic neuroimaging studies.
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Affiliation(s)
- Seda Avnioglu
- Alanya Alaaddin Keykubat University Faculty of Medicine, Department of Anatomy, Antalya, Turkey.
| | - Caner Sahin
- Alanya Alaaddin Keykubat University Faculty of Medicine, Department of Ear, Nose and Throat, Antalya, Turkey.
| | - Seyda Cankaya
- Alanya Alaaddin Keykubat University, Faculty of Medicine, Department of Neurology, Antalya, Turkey.
| | - Ozkan Ozen
- Alanya Alaaddin Keykubat University, Faculty of Medicine, Department of Radiology, Antalya, Turkey.
| | - Rumeysa Dikici
- Alanya Alaaddin Keykubat University Faculty of Medicine, Department of Anatomy, Antalya, Turkey.
| | - Halil Yilmaz
- Nevsehir Haci Bektas Veli University, Kozakli Vocational School, Department of Therapy and Rehabilitation, Nevsehir, Turkey.
| | - Halil Aziz Velioglu
- Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden.
| | - Burak Yulug
- Alanya Alaaddin Keykubat University, Faculty of Medicine, Department of Neurology, Antalya, Turkey.
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14
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Jenni NL, Symonds N, Floresco SB. Medial orbitofrontal cortical regulation of different aspects of Pavlovian and instrumental reward seeking. Psychopharmacology (Berl) 2023; 240:441-459. [PMID: 36322185 DOI: 10.1007/s00213-022-06265-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 10/17/2022] [Indexed: 11/07/2022]
Abstract
RATIONALE The medial subregion of the orbitofrontal cortex (mOFC) is thought to play an important role representing the expected outcome of a given course of action, as lesioning or inactivating this cortical region results in the adoption of choice strategies based more on observable (rather than previously learned) information. Despite this, its role in mediating basic associative learning remains to be fully clarified. OBJECTIVE The present series of experiments examined the role of the mOFC in (1) Pavlovian conditioned approach, (2) conditioned reinforcement, (3) extinction, and (4) cue-induced reinstatement of food-seeking behavior. METHODS Separate cohorts of rats went through Pavlovian or instrumental training. Intra-mOFC infusions of either saline or GABA agonists (to temporarily inactivate neural activity) were given prior to Pavlovian approach, conditioned reinforcement, first or second day of instrumental extinction training, or cue-induced reinstatement test days. RESULTS mOFC inactivation increased lever-CS contacts in Pavlovian conditioned approach and (2) had no effect on conditioned reinforcement. These manipulations (3) accelerated within-session instrumental extinction during the initial extinction session, but impaired subsequent extinction learning on drug-free days. (4) mOFC inactivation induced differential effects on reinstatement that depended on baseline performance. mOFC inactivation abolished reinstatement in "Reinstater" rats (who displayed robust responding under control conditions) and robustly increased reinstatement in "Non-Reinstater" rats (who showed little reinstatement under control conditions) suggesting that individual differences in reinstatement may be supported by differences in mOFC mediated representations of expected outcomes. CONCLUSIONS These findings have important implications for understanding how the mOFC uses stimulus-outcome and action-outcome expectancies to guide behavior, and how dysfunction within this region may contribute to pathological patterns of reward seeking.
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Affiliation(s)
- Nicole L Jenni
- Department of Psychology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2136 West Mall, Vancouver, B.C, V6T 1Z4, Canada
| | - Nicola Symonds
- Department of Psychology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2136 West Mall, Vancouver, B.C, V6T 1Z4, Canada
| | - Stan B Floresco
- Department of Psychology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2136 West Mall, Vancouver, B.C, V6T 1Z4, Canada.
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15
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Hua SS, Ding JJ, Sun TC, Guo C, Zhang Y, Yu ZH, Cao YQ, Zhong LH, Wu Y, Guo LY, Luo JH, Cui YH, Qiu S. NMDAR-dependent synaptic potentiation via APPL1 signaling is required for the accessibility of a prefrontal neuronal assembly in retrieving fear extinction. Biol Psychiatry 2023:S0006-3223(23)00087-2. [PMID: 36842495 DOI: 10.1016/j.biopsych.2023.02.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 02/02/2023] [Accepted: 02/14/2023] [Indexed: 02/26/2023]
Abstract
BACKGROUND The ventromedial prefrontal cortex (vmPFC) has been viewed as a locus to store and recall extinction memory. However, the synaptic and cellular mechanisms underlying this process remain elusive. METHODS We combined transgenic mice, electrophysiological recording, activity-dependent cell labeling, and chemogenetic manipulation to analyze the role of adaptor protein APPL1 in the vmPFC for fear extinction retrieval. RESULTS We found that both constitutive and conditional APPL1 knockout decreases NMDA receptor (NMDAR) function in the vmPFC and impairs fear extinction retrieval. Moreover, APPL1 undergoes nuclear translocation during extinction retrieval. Blocking APPL1 nucleocytoplasmic translocation reduces NMDAR currents and disrupts extinction retrieval. We further identified a prefrontal neuronal ensemble that is both necessary and sufficient for the storage of extinction memory. Inducible APPL1 knockout in this ensemble abolishes NMDAR-dependent synaptic potentiation and disrupts extinction retrieval, while simultaneously chemogenetic activation of this ensemble rescues the impaired behaviors. CONCLUSIONS Therefore, our results indicate that a prefrontal neuronal ensemble stores extinction memory, and APPL1 signaling supports these neurons to retrieve extinction memory via controlling NMDAR-dependent potentiation.
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Affiliation(s)
- Shu-Shan Hua
- Department of Neurobiology and Department of Anesthesiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Jin-Jun Ding
- Department of Neurobiology and Department of Anesthesiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Tian-Cheng Sun
- Department of Neurobiology and Department of Anesthesiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Chen Guo
- Department of Neurobiology and Department of Neurology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Ying Zhang
- Department of Neurobiology and Department of Anesthesiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Zi-Hui Yu
- Department of Neurobiology and Department of Anesthesiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Yi-Qing Cao
- Department of Neurobiology and Department of Anesthesiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Lin-Hong Zhong
- Department of Neurobiology and Department of Anesthesiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Yu Wu
- Department of Neurobiology and Department of Anesthesiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Lu-Ying Guo
- Kidney Disease Center of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Jian-Hong Luo
- Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, Hangzhou, 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology,ZhejiangUniversity ,Hangzhou ,310058 ,China
| | - Yi-Hui Cui
- Department of Neurobiology and Department of Neurology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
| | - Shuang Qiu
- Department of Neurobiology and Department of Anesthesiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, Hangzhou, 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology,ZhejiangUniversity ,Hangzhou ,310058 ,China.
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16
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Comparison of behavioral and brain indices of fear renewal during a standard vs. novel immersive reality Pavlovian fear extinction paradigm in healthy adults. Behav Brain Res 2023; 437:114154. [PMID: 36244544 DOI: 10.1016/j.bbr.2022.114154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 10/06/2022] [Accepted: 10/07/2022] [Indexed: 11/13/2022]
Abstract
Pavlovian conditioning paradigms model the learned fear associations inherent in posttraumatic stress disorder, including the renewal of inappropriate fear responses following extinction learning. However, very few studies in humans investigate the underlying neural mechanisms involved in fear renewal despite its clinical importance. To address this issue, our lab designed a novel, immersive-reality Pavlovian fear acquisition, extinction, recall, and renewal paradigm. We utilized an ecological threat - a snake striking towards the participant - as the unconditioned stimulus (US). Context and background were dynamic and included both visual and auditory cues that are relevant to everyday life. Using functional magnetic resonance imaging and behavioral measures (US expectancy ratings), we examined the validity of this Novel paradigm in healthy adults (n = 49) and compared it to a Standard, well-validated 2D paradigm (n = 28). The Novel paradigm, compared to the Standard, was associated with greater hippocampal activation throughout the task. Participants who underwent the Standard paradigm, compared to the Novel, also displayed insula activation; however, this was not specific to stimulus or time. During fear renewal, the Novel paradigm was associated with dorsal anterior cingulate cortex activation to CS+ (> CS-). Overall, we found that our Novel, immersive-reality paradigm, which features an ecologically relevant US, elicited greater corticolimbic activation. These results suggest that immersive Pavlovian fear conditioning paradigms paired with innately fearful stimuli may improve translatability of preclinical paradigms to clinical interventions for fear-based disorders.
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17
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LaBar KS. Neuroimaging of Fear Extinction. Curr Top Behav Neurosci 2023; 64:79-101. [PMID: 37455302 DOI: 10.1007/7854_2023_429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/18/2023]
Abstract
Extinguishing fear and defensive responses to environmental threats when they are no longer warranted is a critical learning ability that can promote healthy self-regulation and, ultimately, reduce susceptibility to or maintenance of affective-, trauma-, stressor-,and anxiety-related disorders. Neuroimaging tools provide an important means to uncover the neural mechanisms of effective extinction learning that, in turn, can abate the return of fear. Here I review the promises and pitfalls of functional neuroimaging as a method to investigate fear extinction circuitry in the healthy human brain. I discuss the extent to which neuroimaging has validated the core circuits implicated in rodent models and has expanded the scope of the brain regions implicated in extinction processes. Finally, I present new advances made possible by multivariate data analysis tools that yield more refined insights into the brain-behavior relationships involved.
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Affiliation(s)
- Kevin S LaBar
- Center for Cognitive Neuroscience, Duke University, Durham, NC, USA.
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18
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Namkung H, Thomas KL, Hall J, Sawa A. Parsing neural circuits of fear learning and extinction across basic and clinical neuroscience: Towards better translation. Neurosci Biobehav Rev 2022; 134:104502. [PMID: 34921863 DOI: 10.1016/j.neubiorev.2021.12.025] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 12/13/2021] [Accepted: 12/14/2021] [Indexed: 12/22/2022]
Abstract
Over the past decades, studies of fear learning and extinction have advanced our understanding of the neurobiology of threat and safety learning. Animal studies can provide mechanistic/causal insights into human brain regions and their functional connectivity involved in fear learning and extinction. Findings in humans, conversely, may further enrich our understanding of neural circuits in animals by providing macroscopic insights at the level of brain-wide networks. Nevertheless, there is still much room for improvement in translation between basic and clinical research on fear learning and extinction. Through the lens of neural circuits, in this article, we aim to review the current knowledge of fear learning and extinction in both animals and humans, and to propose strategies to fill in the current knowledge gap for the purpose of enhancing clinical benefits.
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Affiliation(s)
- Ho Namkung
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Kerrie L Thomas
- Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK; School of Biosciences, Cardiff University, Cardiff, UK
| | - Jeremy Hall
- Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK; School of Medicine, Cardiff University, Cardiff, UK
| | - Akira Sawa
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Department of Mental Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, 21287, USA.
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19
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Wright, N, Patel, R, Chaulk, SJ, Alcolado, G, Podnar, D, Mota, N, Monson, CM, Girard, TA, Ko, JH. Novel Analysis Identifying Functional Connectivity Patterns Associated with Posttraumatic Stress Disorder. CHRONIC STRESS (THOUSAND OAKS, CALIF.) 2022; 6:24705470221092428. [PMID: 35465401 PMCID: PMC9019376 DOI: 10.1177/24705470221092428] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 03/17/2022] [Accepted: 03/21/2022] [Indexed: 06/14/2023]
Abstract
Posttraumatic stress disorder (PTSD) is a prevalent psychiatric disorder that can result from experiencing traumatic events. Accurate diagnosis and optimal treatment strategies can be difficult to achieve, due to the heterogeneous etiology and symptomology of PTSD, and overlap with other psychiatric disorders. Advancing our understanding of PTSD pathophysiology is therefore critical. While functional connectivity alterations have shown promise for elucidating the neurobiological mechanisms of PTSD, previous findings have been inconsistent. Eleven patients with PTSD in our first cohort (PTSD-A) and 11 trauma-exposed controls (TEC) underwent functional magnetic resonance imaging. First, we investigated the intrinsic connectivity within known resting state networks (eg, default mode, salience, and central executive networks) previously implicated in functional abnormalities with PTSD symptoms. Second, the overall topology of network structure was compared between PTSD-A and TEC using graph theory. Finally, we used a novel combination of graph theory analysis and scaled subprofile modeling (SSM) to identify a disease-related, covarying pattern of brain network organization. No significant group differences were found in intrinsic connectivity of known resting state networks and graph theory metrics (clustering coefficients, characteristic path length, smallworldness, global and local efficiencies, and degree centrality). The graph theory/SSM analysis revealed a topographical pattern of altered degree centrality differentiating PTSD-A from TEC. This PTSD-related network pattern expression was additionally investigated in a separate cohort of 33 subjects who were scanned with a different MRI scanner (22 patients with PTSD or PTSD-B, and 11 healthy trauma-naïve controls or TNC). Across all participant groups, pattern expression scores were significantly lower in the TEC group, while PTSD-A, PTSD-B, and TNC subject profiles did not differ from each other. Expression level of the pattern was correlated with symptom severity in the PTSD-B group. This method offers potential in developing objective biomarkers associated with PTSD. Possible interpretations and clinical implications will be discussed.
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Affiliation(s)
- Natalie Wright,
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
- Neuroscience Research Program, Kleysen Institute for Advanced Medicine, Winnipeg, MB, Canada
| | - Ronak Patel,
- Department of Clinical Health Psychology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Sarah J. Chaulk,
- Department of Clinical Health Psychology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Gillian Alcolado,
- Department of Clinical Health Psychology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - David Podnar,
- Department of Clinical Health Psychology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Natalie Mota,
- Department of Clinical Health Psychology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | | | - Todd A. Girard,
- Department of Psychology, Ryerson University, Toronto, ON, Canada
| | - Ji Hyun Ko,
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
- Neuroscience Research Program, Kleysen Institute for Advanced Medicine, Winnipeg, MB, Canada
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20
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Alexandra Kredlow M, Fenster RJ, Laurent ES, Ressler KJ, Phelps EA. Prefrontal cortex, amygdala, and threat processing: implications for PTSD. Neuropsychopharmacology 2022; 47:247-259. [PMID: 34545196 PMCID: PMC8617299 DOI: 10.1038/s41386-021-01155-7] [Citation(s) in RCA: 133] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 08/03/2021] [Accepted: 08/06/2021] [Indexed: 02/08/2023]
Abstract
Posttraumatic stress disorder can be viewed as a disorder of fear dysregulation. An abundance of research suggests that the prefrontal cortex is central to fear processing-that is, how fears are acquired and strategies to regulate or diminish fear responses. The current review covers foundational research on threat or fear acquisition and extinction in nonhuman animals, healthy humans, and patients with posttraumatic stress disorder, through the lens of the involvement of the prefrontal cortex in these processes. Research harnessing advances in technology to further probe the role of the prefrontal cortex in these processes, such as the use of optogenetics in rodents and brain stimulation in humans, will be highlighted, as well other fear regulation approaches that are relevant to the treatment of posttraumatic stress disorder and involve the prefrontal cortex, namely cognitive regulation and avoidance/active coping. Despite the large body of translational research, many questions remain unanswered and posttraumatic stress disorder remains difficult to treat. We conclude by outlining future research directions related to the role of the prefrontal cortex in fear processing and implications for the treatment of posttraumatic stress disorder.
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Affiliation(s)
- M. Alexandra Kredlow
- grid.38142.3c000000041936754XDepartment of Psychology, Harvard University, Cambridge, MA USA
| | - Robert J. Fenster
- grid.38142.3c000000041936754XDivision of Depression and Anxiety, McLean Hospital; Department of Psychiatry, Harvard Medical School, Cambridge, MA USA
| | - Emma S. Laurent
- grid.38142.3c000000041936754XDepartment of Psychology, Harvard University, Cambridge, MA USA
| | - Kerry J. Ressler
- grid.38142.3c000000041936754XDivision of Depression and Anxiety, McLean Hospital; Department of Psychiatry, Harvard Medical School, Cambridge, MA USA
| | - Elizabeth A. Phelps
- grid.38142.3c000000041936754XDepartment of Psychology, Harvard University, Cambridge, MA USA
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21
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Wen Z, Hammoud MZ, Scott JC, Jimmy J, Brown L, Marin MF, Asnaani A, Gur RC, Foa EB, Milad MR. Impact of exogenous estradiol on task-based and resting-state neural signature during and after fear extinction in healthy women. Neuropsychopharmacology 2021; 46:2278-2287. [PMID: 34493827 PMCID: PMC8581031 DOI: 10.1038/s41386-021-01158-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 08/03/2021] [Accepted: 08/05/2021] [Indexed: 02/06/2023]
Abstract
Fluctuations of endogenous estrogen modulates fear extinction, but the influence of exogenous estradiol is less studied. Moreover, little focus has been placed on the impact of estradiol on broad network connectivity beyond the fear extinction circuit. Here, we examined the effect of acute exogenous estradiol administration on fear extinction-induced brain activation, whole-brain functional connectivity (FC) during the fear extinction task and post-extinction resting-state. Ninety healthy women (57 using oral contraceptives [OC], 33 naturally cycling [NC]) were fear conditioned on day 1. They ingested an estradiol or placebo pill prior to extinction learning on day 2 (double-blind design). Extinction memory was assessed on day 3. Task-based functional MRI data were ascertained on days 2 and 3 and resting-state data were collected post-extinction on day 2 and pre-recall on day 3. Estradiol administration significantly modulated the neural signature associated with fear extinction learning and memory, consistent with prior studies. Importantly, estradiol administration induced significant changes in FC within multiple networks, including the default mode and somatomotor networks during extinction learning, post-extinction, and during extinction memory recall. Exploratory analyses revealed that estradiol impacted ventromedial prefrontal cortex (vmPFC) activation and FC differently in the NC and OC women. The data implicate a more diffused and significant effect of acute estradiol administration on multiple networks. Such an effect might be beneficial to modulating attention and conscious processes in addition to engaging neural processes associated with emotional learning and memory consolidation.
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Affiliation(s)
- Zhenfu Wen
- Department of Psychiatry, New York University School of Medicine, New York, NY, USA
| | - Mira Z Hammoud
- Department of Psychiatry, New York University School of Medicine, New York, NY, USA
| | - J Cobb Scott
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- VISN4 Mental Illness Research, Education, and Clinical Center at the Philadelphia VA Medical Center, Philadelphia, PA, USA
| | - Jagan Jimmy
- Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA
| | - Lily Brown
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Marie-France Marin
- Departement of Psychology, Université du Québec à Montréal, Montreal, QC, Canada
- Research Center of the Institut universitaire en santé mentale de Montréal, Montreal, QC, Canada
| | - Anu Asnaani
- Department of Psychology, University of Utah, Salt Lake City, UT, USA
| | - Ruben C Gur
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Edna B Foa
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Mohammed R Milad
- Department of Psychiatry, New York University School of Medicine, New York, NY, USA.
- The Neuroscience Institute, New York University School of Medicine, New York, NY, USA.
- Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
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22
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Roeckner AR, Oliver KI, Lebois LAM, van Rooij SJH, Stevens JS. Neural contributors to trauma resilience: a review of longitudinal neuroimaging studies. Transl Psychiatry 2021; 11:508. [PMID: 34611129 PMCID: PMC8492865 DOI: 10.1038/s41398-021-01633-y] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 09/02/2021] [Accepted: 09/14/2021] [Indexed: 12/15/2022] Open
Abstract
Resilience in the face of major life stressors is changeable over time and with experience. Accordingly, differing sets of neurobiological factors may contribute to an adaptive stress response before, during, and after the stressor. Longitudinal studies are therefore particularly effective in answering questions about the determinants of resilience. Here we provide an overview of the rapidly-growing body of longitudinal neuroimaging research on stress resilience. Despite lingering gaps and limitations, these studies are beginning to reveal individual differences in neural circuit structure and function that appear protective against the emergence of future psychopathology following a major life stressor. Here we outline a neural circuit model of resilience to trauma. Specifically, pre-trauma biomarkers of resilience show that an ability to modulate activity within threat and salience networks predicts fewer stress-related symptoms. In contrast, early post-trauma biomarkers of subsequent resilience or recovery show a more complex pattern, spanning a number of major circuits including attention and cognitive control networks as well as primary sensory cortices. This novel synthesis suggests stress resilience may be scaffolded by stable individual differences in the processing of threat cues, and further buttressed by post-trauma adaptations to the stressor that encompass multiple mechanisms and circuits. More attention and resources supporting this work will inform the targets and timing of mechanistic resilience-boosting interventions.
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Affiliation(s)
- Alyssa R. Roeckner
- grid.189967.80000 0001 0941 6502Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA USA
| | - Katelyn I. Oliver
- grid.189967.80000 0001 0941 6502Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA USA
| | - Lauren A. M. Lebois
- grid.240206.20000 0000 8795 072XDivision of Depression and Anxiety Disorders, McLean Hospital, Belmont, MA USA ,grid.38142.3c000000041936754XDepartment of Psychiatry, Harvard Medical School, Boston, MA USA
| | - Sanne J. H. van Rooij
- grid.189967.80000 0001 0941 6502Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA USA
| | - Jennifer S. Stevens
- grid.189967.80000 0001 0941 6502Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA USA
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23
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Baldi E, Costa A, Rani B, Passani MB, Blandina P, Romano A, Provensi G. Oxytocin and Fear Memory Extinction: Possible Implications for the Therapy of Fear Disorders? Int J Mol Sci 2021; 22:10000. [PMID: 34576161 PMCID: PMC8467761 DOI: 10.3390/ijms221810000] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 09/07/2021] [Accepted: 09/10/2021] [Indexed: 02/07/2023] Open
Abstract
Several psychiatric conditions such as phobias, generalized anxiety, and post-traumatic stress disorder (PTSD) are characterized by pathological fear and anxiety. The main therapeutic approach used in the management of these disorders is exposure-based therapy, which is conceptually based upon fear extinction with the formation of a new safe memory association, allowing the reduction in behavioral conditioned fear responses. Nevertheless, this approach is only partially resolutive, since many patients have difficulty following the demanding and long process, and relapses are frequently observed over time. One strategy to improve the efficacy of the cognitive therapy is the combination with pharmacological agents. Therefore, the identification of compounds able to strengthen the formation and persistence of the inhibitory associations is a key goal. Recently, growing interest has been aroused by the neuropeptide oxytocin (OXT), which has been shown to have anxiolytic effects. Furthermore, OXT receptors and binding sites have been found in the critical brain structures involved in fear extinction. In this review, the recent literature addressing the complex effects of OXT on fear extinction at preclinical and clinical levels is discussed. These studies suggest that the OXT roles in fear behavior are due to its local effects in several brain regions, most notably, distinct amygdaloid regions.
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Affiliation(s)
- Elisabetta Baldi
- Section of Physiological Sciences, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy;
| | - Alessia Costa
- Section of Clinical Pharmacology and Oncology, Department of Health Sciences (DSS), University of Florence, 50139 Florence, Italy; (A.C.); (B.R.); (M.B.P.)
| | - Barbara Rani
- Section of Clinical Pharmacology and Oncology, Department of Health Sciences (DSS), University of Florence, 50139 Florence, Italy; (A.C.); (B.R.); (M.B.P.)
| | - Maria Beatrice Passani
- Section of Clinical Pharmacology and Oncology, Department of Health Sciences (DSS), University of Florence, 50139 Florence, Italy; (A.C.); (B.R.); (M.B.P.)
| | - Patrizio Blandina
- Section of Pharmacology of Toxicology, Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, 50139 Florence, Italy;
| | - Adele Romano
- Department of Physiology and Pharmacology ‘V. Erspamer’, Sapienza University of Rome, 00185 Rome, Italy;
| | - Gustavo Provensi
- Section of Pharmacology of Toxicology, Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, 50139 Florence, Italy;
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24
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Feng P, Chen Z, Becker B, Liu X, Zhou F, He Q, Qiu J, Lei X, Chen H, Feng T. Predisposing Variations in Fear-Related Brain Networks Prospectively Predict Fearful Feelings during the 2019 Coronavirus (COVID-19) Pandemic. Cereb Cortex 2021; 32:540-553. [PMID: 34297795 DOI: 10.1093/cercor/bhab232] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 06/20/2021] [Accepted: 06/21/2021] [Indexed: 01/21/2023] Open
Abstract
The novel coronavirus (COVID-19) pandemic has led to a surge in mental distress and fear-related disorders, including posttraumatic stress disorder (PTSD). Fear-related disorders are characterized by dysregulations in fear and the associated neural pathways. In the present study, we examined whether individual variations in the fear neural connectome can predict fear-related symptoms during the COVID-19 pandemic. Using machine learning algorithms and back-propagation artificial neural network (BP-ANN) deep learning algorithms, we demonstrated that the intrinsic neural connectome before the COVID-19 pandemic could predict who would develop high fear-related symptoms at the peak of the COVID-19 pandemic in China (Accuracy rate = 75.00%, Sensitivity rate = 65.83%, Specificity rate = 84.17%). More importantly, prediction models could accurately predict the level of fear-related symptoms during the COVID-19 pandemic by using the prepandemic connectome state, in which the functional connectivity of lvmPFC (left ventromedial prefrontal cortex)-rdlPFC (right dorsolateral), rdACC (right dorsal anterior cingulate cortex)-left insula, lAMY (left amygdala)-lHip (left hippocampus) and lAMY-lsgACC (left subgenual cingulate cortex) was contributed to the robust prediction. The current study capitalized on prepandemic data of the neural connectome of fear to predict participants who would develop high fear-related symptoms in COVID-19 pandemic, suggesting that individual variations in the intrinsic organization of the fear circuits represent a neurofunctional marker that renders subjects vulnerable to experience high levels of fear during the COVID-19 pandemic.
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Affiliation(s)
- Pan Feng
- Faculty of Psychology, Southwest University, Chongqing 400715, China.,Key Laboratory of Cognition and Personality, Ministry of Education, Chongqing 400715, China
| | - Zhiyi Chen
- Faculty of Psychology, Southwest University, Chongqing 400715, China.,Key Laboratory of Cognition and Personality, Ministry of Education, Chongqing 400715, China
| | - Benjamin Becker
- Center for Information in Medicine, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 611731, China.,The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Laboratory for Neuroinformation, Chengdu 611731, China
| | - Xiqin Liu
- Center for Information in Medicine, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 611731, China.,The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Laboratory for Neuroinformation, Chengdu 611731, China
| | - Feng Zhou
- Center for Information in Medicine, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 611731, China.,The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Laboratory for Neuroinformation, Chengdu 611731, China
| | - Qinghua He
- Faculty of Psychology, Southwest University, Chongqing 400715, China.,Key Laboratory of Cognition and Personality, Ministry of Education, Chongqing 400715, China
| | - Jiang Qiu
- Faculty of Psychology, Southwest University, Chongqing 400715, China.,Key Laboratory of Cognition and Personality, Ministry of Education, Chongqing 400715, China
| | - Xu Lei
- Faculty of Psychology, Southwest University, Chongqing 400715, China.,Key Laboratory of Cognition and Personality, Ministry of Education, Chongqing 400715, China
| | - Hong Chen
- Faculty of Psychology, Southwest University, Chongqing 400715, China.,Key Laboratory of Cognition and Personality, Ministry of Education, Chongqing 400715, China
| | - Tingyong Feng
- Faculty of Psychology, Southwest University, Chongqing 400715, China.,Key Laboratory of Cognition and Personality, Ministry of Education, Chongqing 400715, China
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25
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Michaels TI, Stone E, Singal S, Novakovic V, Barkin RL, Barkin S. Brain reward circuitry: The overlapping neurobiology of trauma and substance use disorders. World J Psychiatry 2021; 11:222-231. [PMID: 34168969 PMCID: PMC8209534 DOI: 10.5498/wjp.v11.i6.222] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 04/14/2021] [Accepted: 05/20/2021] [Indexed: 02/06/2023] Open
Abstract
Mental health symptoms secondary to trauma exposure and substance use disorders (SUDs) co-occur frequently in both clinical and community samples. The possibility of a shared aetiology remains an important question in translational neuroscience. Advancements in genetics, basic science, and neuroimaging have led to an improved understanding of the neural basis of these disorders, their frequent comorbidity and high rates of relapse remain a clinical challenge. This project aimed to conduct a review of the field's current understanding regarding the neural circuitry underlying posttraumatic stress disorder and SUD. A comprehensive review was conducted of available published literature regarding the shared neurobiology of these disorders, and is summarized in detail, including evidence from both animal and clinical studies. Upon summarizing the relevant literature, this review puts forth a hypothesis related to their shared neurobiology within the context of fear processing and reward cues. It provides an overview of brain reward circuitry and its relation to the neurobiology, symptomology, and phenomenology of trauma and substance use. This review provides clinical insights and implications of the proposed theory, including the potential development of novel pharmacological and therapeutic treatments to address this shared neurobiology. Limitations and extensions of this theory are discussed to provide future directions and insights for this shared phenomena.
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Affiliation(s)
- Timothy I Michaels
- Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY 11004, United States
- Department of Psychiatry, The Donald and Barbara Zucker School of Medicine, Hofstra/Northwell, Glen Oaks, NY 11004, United States
| | - Emily Stone
- Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY 11004, United States
| | - Sonali Singal
- Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY 11004, United States
| | - Vladan Novakovic
- Department of Psychiatry, The Donald and Barbara Zucker School of Medicine, Hofstra/Northwell, Glen Oaks, NY 11004, United States
| | - Robert L Barkin
- Department of Anesthesiology, Rush University Medical College, Chicago, IL 60612, United States
| | - Stacy Barkin
- Private Practice, Scottsdale, AZ 85250, United States
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26
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Donoso JR, Packheiser J, Pusch R, Lederer Z, Walther T, Uengoer M, Lachnit H, Güntürkün O, Cheng S. Emergence of complex dynamics of choice due to repeated exposures to extinction learning. Anim Cogn 2021; 24:1279-1297. [PMID: 33978856 PMCID: PMC8492564 DOI: 10.1007/s10071-021-01521-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 03/27/2021] [Accepted: 04/27/2021] [Indexed: 01/12/2023]
Abstract
Extinction learning, the process of ceasing an acquired behavior in response to altered reinforcement contingencies, is not only essential for survival in a changing environment, but also plays a fundamental role in the treatment of pathological behaviors. During therapy and other forms of training involving extinction, subjects are typically exposed to several sessions with a similar structure. The effects of this repeated exposure are not well understood. Here, we studied the behavior of pigeons across several sessions of a discrimination-learning task in context A, extinction in context B, and a return to context A to test the context-dependent return of the learned responses (ABA renewal). By focusing on individual learning curves across animals, we uncovered a session-dependent variability of behavior: (1) during extinction, pigeons preferred the unrewarded alternative choice in one-third of the sessions, predominantly during the first one. (2) In later sessions, abrupt transitions of behavior at the onset of context B emerged, and (3) the renewal effect decayed as sessions progressed. We show that the observed results can be parsimoniously accounted for by a computational model based only on associative learning between stimuli and actions. Our work thus demonstrates the critical importance of studying the trial-by-trial dynamics of learning in individual sessions, and the power of “simple” associative learning processes.
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Affiliation(s)
- José R Donoso
- Institute for Neural Computation, Ruhr-Universität Bochum, Universitätstr. 150, 44801, Bochum, Germany
| | - Julian Packheiser
- Department of Biopsychology, Ruhr-Universität Bochum, Universitätstr. 150, 44801, Bochum, Germany
| | - Roland Pusch
- Department of Biopsychology, Ruhr-Universität Bochum, Universitätstr. 150, 44801, Bochum, Germany
| | - Zhiyin Lederer
- Institute for Neural Computation, Ruhr-Universität Bochum, Universitätstr. 150, 44801, Bochum, Germany
| | - Thomas Walther
- Institute for Neural Computation, Ruhr-Universität Bochum, Universitätstr. 150, 44801, Bochum, Germany
| | - Metin Uengoer
- Department of Psychology, Philipps-Universität Marburg, Gutenbergstraße 18, 35032, Marburg, Germany
| | - Harald Lachnit
- Department of Psychology, Philipps-Universität Marburg, Gutenbergstraße 18, 35032, Marburg, Germany
| | - Onur Güntürkün
- Department of Biopsychology, Ruhr-Universität Bochum, Universitätstr. 150, 44801, Bochum, Germany
| | - Sen Cheng
- Institute for Neural Computation, Ruhr-Universität Bochum, Universitätstr. 150, 44801, Bochum, Germany.
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27
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Peng Y, Knotts JD, Taylor CT, Craske MG, Stein MB, Bookheimer S, Young KS, Simmons AN, Yeh HW, Ruiz J, Paulus MP. Failure to Identify Robust Latent Variables of Positive or Negative Valence Processing Across Units of Analysis. BIOLOGICAL PSYCHIATRY. COGNITIVE NEUROSCIENCE AND NEUROIMAGING 2021; 6:518-526. [PMID: 33676919 PMCID: PMC8113074 DOI: 10.1016/j.bpsc.2020.12.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 11/10/2020] [Accepted: 12/10/2020] [Indexed: 11/26/2022]
Abstract
BACKGROUND The heterogeneous nature of mood and anxiety disorders highlights a need for dimensionally based descriptions of psychopathology that inform better classification and treatment approaches. Following the Research Domain Criteria approach, this investigation sought to derive constructs assessing positive and negative valence domains across multiple units of analysis. METHODS Adults with clinically impairing mood and anxiety symptoms (N = 225) completed comprehensive assessments across several units of analysis. Self-report assessments included nine questionnaires that assess mood and anxiety symptoms and traits reflecting the negative and positive valence systems. Behavioral assessments included emotional reactivity and distress tolerance tasks, during which skin conductance and heart rate were measured. Neuroimaging assessments included fear conditioning and a reward processing task. The latent variable structure underlying these measures was explored using sparse Bayesian group factor analysis. RESULTS Group factor analysis identified 11 latent variables explaining 31.2% of the variance across tasks, none of which loaded across units of analysis or tasks. Instead, variance was best explained by individual latent variables for each unit of analysis within each task. Post hoc analyses 1) showed associations with small effect sizes between latent variables that were derived separately from functional magnetic resonance imaging and self-report data and 2) showed that some latent variables are not directly related to individual valence system constructs. CONCLUSIONS The lack of latent structure across units of analysis highlights challenges of the Research Domain Criteria approach and suggests that while dimensional analyses work well to reveal within-task features, more targeted approaches are needed to reveal latent cross-modal relationships that could illuminate psychopathology.
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Affiliation(s)
- Yujia Peng
- Department of Psychology and Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California
| | - Jeffrey D Knotts
- Department of Psychology and Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California.
| | - Charles T Taylor
- Department of Psychiatry, University of California San Diego, La Jolla, California
| | - Michelle G Craske
- Department of Psychology and Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California
| | - Murray B Stein
- Department of Psychiatry, University of California San Diego, La Jolla, California; VA San Diego Healthcare System, San Diego, California
| | - Susan Bookheimer
- Department of Psychology and Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California
| | - Katherine S Young
- Social, Genetic and Developmental Psychiatry Centre, King's College, London, United Kingdom
| | - Alan N Simmons
- Department of Psychiatry, University of California San Diego, La Jolla, California; VA San Diego Healthcare System, San Diego, California
| | - Hung-Wen Yeh
- Health Services & Outcomes Research, Children's Mercy Hospital, Kansas City, Missouri
| | - Julian Ruiz
- Department of Psychology and Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California
| | - Martin P Paulus
- Department of Psychiatry, University of California San Diego, La Jolla, California; Laureate Institute for Brain Research, Tulsa, Oklahoma
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28
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Jiang X, Burleigh L, Greening SG. Complete the triangulation: Quantifying differential fear conditioning with a noninterfering and sensitive behavioral measure along with self-report and physiological measures. Psychophysiology 2021; 58:e13831. [PMID: 33932035 DOI: 10.1111/psyp.13831] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 01/20/2021] [Accepted: 04/08/2021] [Indexed: 11/27/2022]
Abstract
According to the multicomponent view, emotion is expressed through subjective feelings and thoughts, physiological activation, and behavioral responses. In human fear conditioning research, the former two are much more popular than the third category. One concern is that concurrent behavioral probes may interfere with the conditioning process. To allow triangulation of emotion research through simultaneous employment of subjective, physiological, and behavioral measurement, it is necessary to find behavioral measures that meet the criteria of causing no interference while being sensitive to conditioning. In this study, a basic visual attention task was examined in terms of its impact on differential fear conditioning as measured by both subjective (i.e., self-reported fear and shock estimation) and physiological (i.e., skin conductance response/SCR) expression; and its ability to detect fear conditioning indicated by a reaction time (RT) or accuracy difference between the two conditioned stimuli (CS+ vs. CS-). While participants in the probe group (n = 86) completed differential fear conditioning with the behavioral task, those in the no-probe group (n = 76) underwent conditioning by itself. Based on self-reported fear, shock estimation, and SCR, both groups successfully acquired differential fear with no apparent between-group difference in the degree of conditioning. In the probe group, RT but not accuracy exhibited a difference between CS+ and CS-. These findings suggest that the selected visual attention task does not interfere with differential fear conditioning measured via SCR and self-report and is a sensitive measure of differential conditioning. Exploratory individual analyses also revealed significant relationships between the above measures.
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Affiliation(s)
- Xinrui Jiang
- Department of Psychology, Louisiana State University, Baton Rouge, LA, USA
| | - Lauryn Burleigh
- Department of Psychology, Louisiana State University, Baton Rouge, LA, USA
| | - Steven G Greening
- Department of Psychology, Louisiana State University, Baton Rouge, LA, USA.,Pennington Biomedical Research Center, Baton Rouge, LA, USA.,Department of Psychology, University of Manitoba, Winnipeg, MB, Canada
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29
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Besteher B, Gaser C, Nenadić I. Brain Structure and Subclinical Symptoms: A Dimensional Perspective of Psychopathology in the Depression and Anxiety Spectrum. Neuropsychobiology 2021; 79:270-283. [PMID: 31340207 DOI: 10.1159/000501024] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Accepted: 05/18/2019] [Indexed: 11/19/2022]
Abstract
Human psychopathology is the result of complex and subtle neurobiological alterations. Categorial DSM or ICD diagnoses do not allow a biologically founded and differentiated description of these diverse processes across a spectrum or continuum, emphasising the need for a scientific and clinical paradigm shift towards a dimensional psychiatric nosology. The subclinical part of the spectrum is, however, of special interest for early detection of mental disorders. We review the current evidence of brain structural correlates (grey matter volume, cortical thickness, and gyrification) in non-clinical (psychiatrically healthy) subjects with minor depressive and anxiety symptoms. We identified 16 studies in the depressive spectrum and 20 studies in the anxiety spectrum. These studies show effects associated with subclinical symptoms in the hippocampus, anterior cingulate cortex, and anterior insula similar to major depression and changes in amygdala similar to anxiety disorders. Precuneus and temporal areas as parts of the default mode network were affected specifically in the subclinical studies. We derive several methodical considerations crucial to investigations of brain structural correlates of minor psycho(patho)logical symptoms in healthy participants. And we discuss neurobiological overlaps with findings in patients as well as distinct findings, e.g. in areas involved in the default mode network. These results might lead to more insight into the early pathogenesis of clinical significant depression or anxiety and need to be enhanced by multi-centre and longitudinal studies.
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Affiliation(s)
- Bianca Besteher
- Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany,
| | - Christian Gaser
- Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.,Department of Neurology, Jena University Hospital, Jena, Germany
| | - Igor Nenadić
- Department of Psychiatry and Psychotherapy, Philipps University Marburg/Marburg University Hospital - UKGM, Marburg, Germany
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30
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Syrjänen E, Fischer H. A Review of the Effects of Valenced Odors on Face Perception and Evaluation. Iperception 2021; 12:20416695211009552. [PMID: 33996021 PMCID: PMC8111279 DOI: 10.1177/20416695211009552] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 03/23/2021] [Indexed: 12/12/2022] Open
Abstract
How do valenced odors affect the perception and evaluation of facial expressions? We reviewed 25 studies published from 1989 to 2020 on cross-modal behavioral effects of odors on the perception of faces. The results indicate that odors may influence facial evaluations and classifications in several ways. Faces are rated as more arousing during simultaneous odor exposure, and the rated valence of faces is affected in the direction of the odor valence. For facial classification tasks, in general, valenced odors, whether pleasant or unpleasant, decrease facial emotion classification speed. The evidence for valence congruency effects was inconsistent. Some studies found that exposure to a valenced odor facilitates the processing of a similarly valenced facial expression. The results for facial evaluation were mirrored in classical conditioning studies, as faces conditioned with valenced odors were rated in the direction of the odor valence. However, the evidence of odor effects was inconsistent when the task was to classify faces. Furthermore, using a z-curve analysis, we found clear evidence for publication bias. Our recommendations for future research include greater consideration of individual differences in sensation and cognition, individual differences (e.g., differences in odor sensitivity related to age, gender, or culture), establishing standardized experimental assessments and stimuli, larger study samples, and embracing open research practices.
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Affiliation(s)
- Elmeri Syrjänen
- Elmeri Syrjänen, Psykologiska Institutionen, Stockholms Universitet, Stockholm 106 91, Sweden.
| | - Håkan Fischer
- Department of Psychology, Stockholm University, Stockholm, Sweden
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31
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Neria Y. Functional Neuroimaging in PTSD: From Discovery of Underlying Mechanisms to Addressing Diagnostic Heterogeneity. Am J Psychiatry 2021; 178:128-135. [PMID: 33517750 DOI: 10.1176/appi.ajp.2020.20121727] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Yuval Neria
- Departments of Psychiatry and Epidemiology and New York State Psychiatric Institute, Columbia University Irving Medical Center, New York
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32
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Chien JH, Colloca L, Korzeniewska A, Meeker TJ, Bienvenu OJ, Saffer MI, Lenz FA. Behavioral, Physiological and EEG Activities Associated with Conditioned Fear as Sensors for Fear and Anxiety. SENSORS (BASEL, SWITZERLAND) 2020; 20:E6751. [PMID: 33255916 PMCID: PMC7728331 DOI: 10.3390/s20236751] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 11/03/2020] [Accepted: 11/10/2020] [Indexed: 11/16/2022]
Abstract
Anxiety disorders impose substantial costs upon public health and productivity in the USA and worldwide. At present, these conditions are quantified by self-report questionnaires that only apply to behaviors that are accessible to consciousness, or by the timing of responses to fear- and anxiety-related words that are indirect since they do not produce fear, e.g., Dot Probe Test and emotional Stroop. We now review the conditioned responses (CRs) to fear produced by a neutral stimulus (conditioned stimulus CS+) when it cues a painful laser unconditioned stimulus (US). These CRs include autonomic (Skin Conductance Response) and ratings of the CS+ unpleasantness, ability to command attention, and the recognition of the association of CS+ with US (expectancy). These CRs are directly related to fear, and some measure behaviors that are minimally accessible to consciousness e.g., economic scales. Fear-related CRs include non-phase-locked phase changes in oscillatory EEG power defined by frequency and time post-stimulus over baseline, and changes in phase-locked visual and laser evoked responses both of which include late potentials reflecting attention or expectancy, like the P300, or contingent negative variation. Increases (ERS) and decreases (ERD) in oscillatory power post-stimulus may be generalizable given their consistency across healthy subjects. ERS and ERD are related to the ratings above as well as to anxious personalities and clinical anxiety and can resolve activity over short time intervals like those for some moods and emotions. These results could be incorporated into an objective instrumented test that measures EEG and CRs of autonomic activity and psychological ratings related to conditioned fear, some of which are subliminal. As in the case of instrumented tests of vigilance, these results could be useful for the direct, objective measurement of multiple aspects of the risk, diagnosis, and monitoring of therapies for anxiety disorders and anxious personalities.
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Affiliation(s)
- Jui-Hong Chien
- Department of Neurosurgery, Johns Hopkins University, Baltimore, MD 21287-7713, USA; (J.-H.C.); (T.J.M.); (M.I.S.)
| | - Luana Colloca
- Department of Pain Translational Symptom Science, School of Nursing, University of Maryland, Baltimore, MD 21201-1595, USA;
- Department of Anesthesiology, School of Medicine, University of Maryland, Baltimore, MD 21201-1595, USA
| | - Anna Korzeniewska
- Department of Neurology, Johns Hopkins University, Baltimore, MD 21287-7713, USA;
| | - Timothy J. Meeker
- Department of Neurosurgery, Johns Hopkins University, Baltimore, MD 21287-7713, USA; (J.-H.C.); (T.J.M.); (M.I.S.)
| | - O. Joe Bienvenu
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD 21287-7713, USA;
| | - Mark I. Saffer
- Department of Neurosurgery, Johns Hopkins University, Baltimore, MD 21287-7713, USA; (J.-H.C.); (T.J.M.); (M.I.S.)
| | - Fred A. Lenz
- Department of Neurosurgery, Johns Hopkins University, Baltimore, MD 21287-7713, USA; (J.-H.C.); (T.J.M.); (M.I.S.)
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33
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Kim JH, Ganella DE. A Review of Preclinical Studies to Understand Fear During Adolescence. AUSTRALIAN PSYCHOLOGIST 2020. [DOI: 10.1111/ap.12066] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
| | - Despina E Ganella
- Behavioural Neuroscience Division, The Florey Institute of Neuroscience and Mental Health and Florey Department of Neuroscience and Mental Health, University of Melbourne
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34
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Childhood violence exposure and social deprivation predict adolescent amygdala-orbitofrontal cortex white matter connectivity. Dev Cogn Neurosci 2020; 45:100849. [PMID: 32890959 PMCID: PMC7481532 DOI: 10.1016/j.dcn.2020.100849] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Childhood adversity is heterogeneous with potentially distinct dimensions of violence exposure and social deprivation. These dimensions may differentially shape emotion-based neural circuitry, such as amygdala-PFC white matter connectivity. Amygdala-orbitofrontal cortex (OFC) white matter connectivity has been linked to regulation of the amygdala's response to emotional stimuli. Using a preregistered analysis plan, we prospectively examined the effects of childhood exposure to two dimensions of adversity, violence exposure and social deprivation, on the adolescent amygdala-PFC white matter connectivity. We also reproduced the negative correlation between amygdala-PFC white matter connectivity and amygdala activation to threat faces. 183 15-17-year-olds were recruited from the Fragile Families and Child Wellbeing Study - a longitudinal, birth cohort, sample of predominantly low-income youth. Probabilistic tractography revealed that childhood violence exposure and social deprivation interacted to predict the probability of adolescent right hemisphere amygdala-OFC white matter connectivity. High violence exposure with high social deprivation related to less amygdala-OFC white matter connectivity. Violence exposure was not associated with white matter connectivity when social deprivation was at mean or low levels (i.e., relatively socially supportive contexts). Therefore, social deprivation may exacerbate the effects of childhood violence exposure on the development of white matter connections involved in emotion processing and regulation. Conversely, social support may buffer against them.
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35
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Tabibnia G. An affective neuroscience model of boosting resilience in adults. Neurosci Biobehav Rev 2020; 115:321-350. [DOI: 10.1016/j.neubiorev.2020.05.005] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 05/09/2020] [Accepted: 05/10/2020] [Indexed: 12/11/2022]
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36
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Goetschius LG, Hein TC, Mitchell C, Lopez-Duran NL, McLoyd VC, Jeanne, McLanahan SS, Hyde LW, Monk CS. WITHDRAWN:Childhood violence exposure and social deprivation predict adolescent amygdala-orbitofrontal cortex white matter connectivity. Dev Cogn Neurosci 2020; 45:100822. [PMID: 32868265 PMCID: PMC7365931 DOI: 10.1016/j.dcn.2020.100822] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 07/01/2020] [Accepted: 07/04/2020] [Indexed: 02/07/2023] Open
Abstract
This article has been withdrawn: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been withdrawn at the request of the editor and publisher. The publisher regrets that an error occurred which led to the premature publication of this paper. This error bears no reflection on the article or its authors. The publisher apologizes to the authors and the readers for this unfortunate error.
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Affiliation(s)
- Leigh G Goetschius
- Department of Psychology, University of Michigan, Ann Arbor, MI, 48109, United States
| | - Tyler C Hein
- Department of Psychology, University of Michigan, Ann Arbor, MI, 48109, United States; Serious Mental Illness Treatment Resource and Evaluation Center (SMITREC), Office of Mental Health and Suicide Prevention, Department of Veterans Affairs, United States
| | - Colter Mitchell
- Survey Research Center of the Institute for Social Research, University of Michigan, Ann Arbor, MI, 48109, United States; Population Studies Center of the Institute for Social Research, University of Michigan, Ann Arbor, MI, 48109, United States
| | - Nestor L Lopez-Duran
- Department of Psychology, University of Michigan, Ann Arbor, MI, 48109, United States
| | - Vonnie C McLoyd
- Department of Psychology, University of Michigan, Ann Arbor, MI, 48109, United States
| | - Jeanne
- Teachers College and The College of Physicians and Surgeons, Columbia University, 10027, United States
| | - Sara S McLanahan
- Department of Sociology, Princeton University, 08544, United States
| | - Luke W Hyde
- Department of Psychology, University of Michigan, Ann Arbor, MI, 48109, United States; Survey Research Center of the Institute for Social Research, University of Michigan, Ann Arbor, MI, 48109, United States
| | - Christopher S Monk
- Department of Psychology, University of Michigan, Ann Arbor, MI, 48109, United States; Survey Research Center of the Institute for Social Research, University of Michigan, Ann Arbor, MI, 48109, United States; Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, 48109, United States; Department of Psychiatry, University of Michigan, Ann Arbor, MI, 48109, United States.
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37
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Suarez-Jimenez B, Albajes-Eizagirre A, Lazarov A, Zhu X, Harrison BJ, Radua J, Neria Y, Fullana MA. Neural signatures of conditioning, extinction learning, and extinction recall in posttraumatic stress disorder: a meta-analysis of functional magnetic resonance imaging studies. Psychol Med 2020; 50:1442-1451. [PMID: 31258096 PMCID: PMC9624122 DOI: 10.1017/s0033291719001387] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Establishing neurobiological markers of posttraumatic stress disorder (PTSD) is essential to aid in diagnosis and treatment development. Fear processing deficits are central to PTSD, and their neural signatures may be used as such markers. METHODS Here, we conducted a meta-analysis of seven Pavlovian fear conditioning fMRI studies comparing 156 patients with PTSD and 148 trauma-exposed healthy controls (TEHC) using seed-based d-mapping, to contrast neural correlates of experimental phases, namely conditioning, extinction learning, and extinction recall. RESULTS Patients with PTSD, as compared to TEHCs, exhibited increased activation in the anterior hippocampus (extending to the amygdala) and medial prefrontal cortex during conditioning; in the anterior hippocampus-amygdala regions during extinction learning; and in the anterior hippocampus-amygdala and medial prefrontal areas during extinction recall. Yet, patients with PTSD have shown an overall decreased activation in the thalamus during all phases in this meta-analysis. CONCLUSION Findings from this metanalysis suggest that PTSD is characterized by increased activation in areas related to salience and threat, and lower activation in the thalamus, a key relay hub between subcortical areas. If replicated, these fear network alterations may serve as objective diagnostic markers for PTSD, and potential targets for novel treatment development, including pharmacological and brain stimulation interventions. Future longitudinal studies are needed to examine whether these observed network alteration in PTSD are the cause or the consequence of PTSD.
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Affiliation(s)
- Benjamin Suarez-Jimenez
- Department of Psychiatry, Columbia University Medical Center, New York, USA
- New York State Psychiatric Institute, New York, USA
| | | | - Amit Lazarov
- Department of Psychiatry, Columbia University Medical Center, New York, USA
- New York State Psychiatric Institute, New York, USA
- School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Xi Zhu
- Department of Psychiatry, Columbia University Medical Center, New York, USA
- New York State Psychiatric Institute, New York, USA
| | - Ben J. Harrison
- Department of Psychiatry, Melbourne Neuropsychiatry Centre, The University of Melbourne and Melbourne Health, Victoria, Australia
| | - Joaquim Radua
- FIDMAG Germanes Hospitalàries, CIBERSAM, Sant Boi de Llobregat, Barcelona, Spain
- Institute of Psychiatry, King’s College London, De Crespigny Park, London, UK
- Department of Clinical Neuroscience, Centre for Psychiatric Research and Education, Karolinska Institutet, Stockholm, Sweden
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERSAM, Barcelona, Spain
| | - Yuval Neria
- Department of Psychiatry, Columbia University Medical Center, New York, USA
- New York State Psychiatric Institute, New York, USA
| | - Miquel A. Fullana
- FIDMAG Germanes Hospitalàries, CIBERSAM, Sant Boi de Llobregat, Barcelona, Spain
- Department of Psychiatry, Universitat Autònoma de Barcelona, Barcelona, Spain
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38
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Zhou F, Geng Y, Xin F, Li J, Feng P, Liu C, Zhao W, Feng T, Guastella AJ, Ebstein RP, Kendrick KM, Becker B. Human Extinction Learning Is Accelerated by an Angiotensin Antagonist via Ventromedial Prefrontal Cortex and Its Connections With Basolateral Amygdala. Biol Psychiatry 2019; 86:910-920. [PMID: 31471037 DOI: 10.1016/j.biopsych.2019.07.007] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 06/27/2019] [Accepted: 07/10/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND Deficient extinction learning and threat adaptation in the ventromedial prefrontal cortex (vmPFC)-amygdala circuitry strongly impede the efficacy of exposure-based interventions in anxiety disorders. Recent animal models suggest a regulatory role of the renin-angiotensin system in both these processes. Against this background, the present randomized placebo-controlled pharmacologic functional magnetic resonance imaging experiment aimed at determining the extinction enhancing potential of the angiotensin II type 1 receptor antagonist losartan (LT) in humans. METHODS Seventy healthy male subjects underwent Pavlovian threat conditioning and received single-dose LT (50 mg) or placebo administration before extinction. Psychophysiological threat reactivity (skin conductance response) and neural activity during extinction served as primary outcomes. Psychophysiological interaction, voxelwise mediation, and novel multivariate pattern classification analyses were used to determine the underlying neural mechanisms. RESULTS LT significantly accelerated the decline of the psychophysiological threat response during within-session extinction learning. On the neural level, the acceleration was accompanied and critically mediated by threat-specific enhancement of vmPFC activation. Furthermore, LT enhanced vmPFC-basolateral amygdala coupling and attenuated the neural threat expression, particularly in the vmPFC, during early extinction. CONCLUSIONS Overall the results indicate that LT facilitates within-session threat memory extinction by augmenting threat-specific encoding in the vmPFC and its regulatory control over the amygdala. The findings document a pivotal role of angiotensin regulation of extinction learning in humans and suggest that adjunct LT administration has the potential to facilitate the efficacy of exposure-based interventions in anxiety disorders.
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Affiliation(s)
- Feng Zhou
- Clinical Hospital of Chengdu Brain Science Institute and Ministry of Education (MOE) Key Laboratory for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China
| | - Yayuan Geng
- Clinical Hospital of Chengdu Brain Science Institute and Ministry of Education (MOE) Key Laboratory for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China
| | - Fei Xin
- Clinical Hospital of Chengdu Brain Science Institute and Ministry of Education (MOE) Key Laboratory for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China
| | - Jialin Li
- Clinical Hospital of Chengdu Brain Science Institute and Ministry of Education (MOE) Key Laboratory for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China
| | - Pan Feng
- Faculty of Psychology, Southwest University, Chongqing, China; Key Laboratory of Cognition and Personality, Ministry of Education, Southwest University, Chongqing, China
| | - Congcong Liu
- Clinical Hospital of Chengdu Brain Science Institute and Ministry of Education (MOE) Key Laboratory for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China
| | - Weihua Zhao
- Clinical Hospital of Chengdu Brain Science Institute and Ministry of Education (MOE) Key Laboratory for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China
| | - Tingyong Feng
- Faculty of Psychology, Southwest University, Chongqing, China; Key Laboratory of Cognition and Personality, Ministry of Education, Southwest University, Chongqing, China
| | - Adam J Guastella
- Autism Clinic for Translational Research, Brain and Mind Centre, Central Clinical School, Faculty of Medicine, University of Sydney, Camperdown, Australia; Youth Mental Health Unit, Brain and Mind Centre, Central Clinical School, Faculty of Medicine, University of Sydney, Camperdown, Australia
| | - Richard P Ebstein
- China Center for Behavior Economics and Finance, Southwestern University of Finance and Economics, Chengdu, China
| | - Keith M Kendrick
- Clinical Hospital of Chengdu Brain Science Institute and Ministry of Education (MOE) Key Laboratory for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China
| | - Benjamin Becker
- Clinical Hospital of Chengdu Brain Science Institute and Ministry of Education (MOE) Key Laboratory for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China.
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39
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Bellucci G, Molter F, Park SQ. Neural representations of honesty predict future trust behavior. Nat Commun 2019; 10:5184. [PMID: 31729396 PMCID: PMC6858375 DOI: 10.1038/s41467-019-13261-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Accepted: 10/28/2019] [Indexed: 01/08/2023] Open
Abstract
Theoretical accounts propose honesty as a central determinant of trustworthiness impressions and trusting behavior. However, behavioral and neural evidence on the relationships between honesty and trust is missing. Here, combining a novel paradigm that successfully induces trustworthiness impressions with functional MRI and multivariate analyses, we demonstrate that honesty-based trustworthiness is represented in the posterior cingulate cortex, dorsolateral prefrontal cortex and intraparietal sulcus. Crucially, brain signals in these regions predict individual trust in a subsequent social interaction with the same partner. Honesty recruited the ventromedial prefrontal cortex (VMPFC), and stronger functional connectivity between the VMPFC and temporoparietal junction during honesty encoding was associated with higher trust in the subsequent interaction. These results suggest that honesty signals in the VMPFC are integrated into trustworthiness beliefs to inform present and future social behaviors. These findings improve our understanding of the neural representations of an individual’s social character that guide behaviors during interpersonal interactions. We tend to be more trusting of people who we know to be honest. Here, the authors show using fMRI that honesty-based trustworthiness is represented in the posterior cingulate cortex, dorsolateral prefrontal cortex and intraparietal sulcus, and predicts subsequent trust decisions.
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Affiliation(s)
- Gabriele Bellucci
- Department of Psychology I, University of Lübeck, Lübeck, Germany. .,Department of Education and Psychology, Freie Universität Berlin, Berlin, Germany. .,Department of Decision Neuroscience and Nutrition, German Institute of Human Nutrition (DIfE), Nuthetal, Germany.
| | - Felix Molter
- WZB Berlin Social Science Center, Berlin, Germany
| | - Soyoung Q Park
- Department of Psychology I, University of Lübeck, Lübeck, Germany.,Department of Decision Neuroscience and Nutrition, German Institute of Human Nutrition (DIfE), Nuthetal, Germany.,Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Neuroscience Research Center, Berlin, Germany.,Deutsches Zentrum für Diabetes, Neuherberg, Germany
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40
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Gaby JM, Dalton P. Discrimination Between Individual Body Odors Is Unaffected by Perfume. Perception 2019; 48:1104-1123. [PMID: 31474186 DOI: 10.1177/0301006619872055] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Jessica M Gaby
- Monell Chemical Senses Center, Philadelphia, PA, USA; Department of Psychology, Cornell University, Ithaca, NY, USA; Department of Food Science, Penn State University, State College, PA, USA
| | - Pamela Dalton
- Monell Chemical Senses Center, Philadelphia, PA, USA
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41
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Velasco ER, Florido A, Milad MR, Andero R. Sex differences in fear extinction. Neurosci Biobehav Rev 2019; 103:81-108. [PMID: 31129235 PMCID: PMC6692252 DOI: 10.1016/j.neubiorev.2019.05.020] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 03/08/2019] [Accepted: 05/19/2019] [Indexed: 12/18/2022]
Abstract
Despite the exponential increase in fear research during the last years, few studies have included female subjects in their design. The need to include females arises from the knowledge gap of mechanistic processes underlying the behavioral and neural differences observed in fear extinction. Moreover, the exact contribution of sex and hormones in relation to learning and behavior is still largely unknown. Insights from this field could be beneficial as fear-related disorders are twice as prevalent in women compared to men. Here, we review an up-to-date summary of animal and human studies in adulthood that report sex differences in fear extinction from a structural and functional approach. Furthermore, we describe how these factors could contribute to the observed sex differences in fear extinction during normal and pathological conditions.
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Affiliation(s)
- E R Velasco
- Institut de Neurociències, Universitat Autònoma de Barcelona, Spain
| | - A Florido
- Institut de Neurociències, Universitat Autònoma de Barcelona, Spain
| | - M R Milad
- Department of Psychiatry, University of Illinois at Chicago, USA
| | - R Andero
- Institut de Neurociències, Universitat Autònoma de Barcelona, Spain; CIBERSAM, Corporació Sanitaria Parc Taulí, Sabadell, Spain; Department of Psychobiology and Methodology of Health Sciences, Universitat Autònoma de Barcelona, Spain.
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42
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Iannilli E, Leopold D, Hornung D, Hummel T. Advances in Understanding Parosmia: An fMRI Study. ORL J Otorhinolaryngol Relat Spec 2019; 81:185-192. [DOI: 10.1159/000500558] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 04/23/2019] [Indexed: 11/19/2022]
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43
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Seo J, Moore KN, Gazecki S, Bottary RM, Milad MR, Song H, Pace-Schott EF. Delayed fear extinction in individuals with insomnia disorder. Sleep 2019; 41:5026048. [PMID: 29860407 DOI: 10.1093/sleep/zsy095] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Indexed: 11/13/2022] Open
Abstract
Study Objectives Insomnia increases the risk for anxiety disorders that are also associated with fear-extinction deficits. We compared activation of fear and extinction networks between insomnia disorder (ID) without comorbidity and good sleepers (GS). Methods Twenty-three ID participants age- and sex-matched to 23 GS participants completed 14 days of actigraphy and diaries, three nights of ambulatory polysomnography and a 2-day fear conditioning and extinction paradigm. Fear conditioning and extinction learning occurred on the first day, followed 24 hours later by extinction recall. Blood-oxygen-level-dependent functional magnetic resonance imaging (fMRI) signal and skin conductance responses (SCR) were recorded. Nineteen participants per group produced usable fMRI data. Beta weights from areas where activation differed between groups were regressed against sleep and psychophysiological measures. SCR was compared between groups at various stages of the paradigm. Results During fear conditioning, both ID (N = 19) and GS (N = 19) activated fear-related structures. Across extinction learning, ID (N = 19) demonstrated little change, whereas GS (N = 16) activated both fear and extinction-related areas, including the hippocampus, insula, dorsal anterior cingulate (dACC), and ventromedial prefrontal (vmPFC) cortices. During extinction recall, while GS (N = 17) demonstrated limited activation, ID (N = 16) activated regions similar to those previously activated in GS (vmPFC, dACC, insula). Sleep quality was predictive of activations seen at various stages of the paradigm. SCR data suggested ID were more physiologically reactive than GS. Conclusions Across extinction learning, GS but not ID activated both fear and extinction-related networks. At extinction recall, ID engaged similar regions whereas GS no longer did so. Individuals with ID may show a delayed acquisition of fear extinction memories.
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Affiliation(s)
- Jeehye Seo
- Department of Psychiatry, Massachusetts General Hospital, Charlestown MA.,Department of Psychiatry, Harvard Medical School, Charlestown, MA.,Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA
| | - Kylie N Moore
- Department of Psychiatry, Massachusetts General Hospital, Charlestown MA.,Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA
| | - Samuel Gazecki
- Department of Psychiatry, Massachusetts General Hospital, Charlestown MA.,Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA
| | - Ryan M Bottary
- Department of Psychiatry, Massachusetts General Hospital, Charlestown MA.,Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA
| | - Mohammed R Milad
- Department of Psychiatry, University of Illinois at Chicago, Chicago, IL
| | - Huijin Song
- Institute of Biomedical Engineering Research, Kyungpook National University, Daegu, Korea
| | - Edward F Pace-Schott
- Department of Psychiatry, Massachusetts General Hospital, Charlestown MA.,Department of Psychiatry, Harvard Medical School, Charlestown, MA.,Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA
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44
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Packheiser J, Güntürkün O, Pusch R. Renewal of extinguished behavior in pigeons (Columba livia) does not require memory consolidation of acquisition or extinction in a free-operant appetitive conditioning paradigm. Behav Brain Res 2019; 370:111947. [PMID: 31102600 DOI: 10.1016/j.bbr.2019.111947] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 04/18/2019] [Accepted: 05/14/2019] [Indexed: 11/25/2022]
Abstract
Extinction learning is a fundamental capacity for adaptive and flexible behavior. As extinguished conditioned responding is prone to relapse under certain conditions, the necessity of memory consolidation for recovery phenomena to occur has been highlighted recently. Several studies have demonstrated that both acquisition and extinction training need to be properly consolidated for a relapse of the original acquired memory trace to occur. Does this imply that extinguished responses cannot relapse before memory consolidation? To answer this question, we investigated the renewal effect subsequent to an immediate or a delayed (24 h) extinction in a discriminative operant conditioning paradigm. In three different experiments, we could show (1) that acquisition learning does not need to be long-term consolidated for the occurrence of renewal, (2) that the offset of extinction training is a reliable marker for extinction recall in a free-operant extinction learning paradigm where organisms undergo consecutive acquisition training, extinction training as well as testing of conditioned responding and (3), that immediate and long-term consolidated renewal do not demonstrate any qualitative difference in terms of the behavioral output. Our results indicate on the behavioral level that the inhibitory nature of extinction is already present in free-operant learning paradigms and that it does not seem to be affected by the absence of long-term memory consolidation.
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Affiliation(s)
- Julian Packheiser
- Institute of Cognitive Neuroscience, Biopsychology, Department of Psychology, Ruhr University Bochum, Germany.
| | - Onur Güntürkün
- Institute of Cognitive Neuroscience, Biopsychology, Department of Psychology, Ruhr University Bochum, Germany
| | - Roland Pusch
- Institute of Cognitive Neuroscience, Biopsychology, Department of Psychology, Ruhr University Bochum, Germany
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45
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Nuñez M, Zinbarg RE, Mittal VA. Efficacy and mechanisms of non-invasive brain stimulation to enhance exposure therapy: A review. Clin Psychol Rev 2019; 70:64-78. [PMID: 30986744 DOI: 10.1016/j.cpr.2019.04.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 02/15/2019] [Accepted: 04/03/2019] [Indexed: 12/19/2022]
Abstract
Though cognitive behavioral techniques are generally effective in the treatment of anxiety disorders, some people fail to benefit from exposure therapy or experience a return of fear after terminating exposure therapy. The burgeoning field of non-invasive brain stimulation provides a potential method of augmenting exposure therapy so that it is more effective. Successful exposure therapy is hypothesized to occur due to inhibition, and research suggests that brain stimulation can alter inhibitory learning and related processes. As such, one can reasonably posit that brain stimulation could be used to test the inhibitory learning theory of exposure therapy and to increase the efficacy of exposure therapy by inducing stronger inhibitory learning during exposures. Four known studies that pair brain stimulation with exposure therapy have yielded promising preliminary evidence in support of the therapeutic use of brain stimulation. In this review we describe research illustrating the mechanisms and efficacy of non-invasive brain stimulation to enhance the understanding of and outcomes produced by exposure therapy.
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Affiliation(s)
- Mia Nuñez
- Northwestern University, United States; Rogers Behavioral Health, United States.
| | - Richard E Zinbarg
- Northwestern University, United States; The Family Institute, Northwestern University, United States
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46
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Congenital olfactory impairment is linked to cortical changes in prefrontal and limbic brain regions. Brain Imaging Behav 2019; 12:1569-1582. [PMID: 29442274 DOI: 10.1007/s11682-017-9817-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The human sense of smell is closely associated with morphological differences of the fronto-limbic system, specifically the piriform cortex and medial orbitofrontal cortex (mOFC). Still it is unclear whether cortical volume in the core olfactory areas and connected brain regions are shaped differently in individuals who suffer from lifelong olfactory deprivation relative to healthy normosmic individuals. To address this question, we examined if regional variations in gray matter volume were associated with smell ability in seventeen individuals with isolated congenital olfactory impairment (COI) matched with sixteen normosmic controls. All subjects underwent whole-brain magnetic resonance imaging, and voxel-based morphometry was used to estimate regional variations in grey matter volume. The analyses showed that relative to controls, COI subjects had significantly larger grey matter volumes in left middle frontal gyrus and right superior frontal sulcus (SFS). COI subjects with severe olfactory impairment (anosmia) had reduced grey matter volume in the left mOFC and increased volume in right piriform cortex and SFS. Within the COI group olfactory ability, measured with the "Sniffin' Sticks" test, was positively associated with larger grey matter volume in right posterior cingulate and parahippocampal cortices whereas the opposite relationship was observed in controls. Across COI subjects and controls, better olfactory detection threshold was associated with smaller volume in right piriform cortex, while olfactory identification was negatively associated with right SFS volume. Our findings suggest that lifelong olfactory deprivation trigger changes in the cortical volume of prefrontal and limbic brain regions previously linked to olfactory memory.
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47
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Gärtner A, Dörfel D, Diers K, Witt SH, Strobel A, Brocke B. Impact of FAAH genetic variation on fronto-amygdala function during emotional processing. Eur Arch Psychiatry Clin Neurosci 2019; 269:209-221. [PMID: 30291441 DOI: 10.1007/s00406-018-0944-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2018] [Accepted: 09/28/2018] [Indexed: 12/30/2022]
Abstract
Recent translational studies identified a common endocannabinoid polymorphism, FAAH C385A, in the gene for the fatty acid amide hydrolase (FAAH). This polymorphism alters endocannabinoid anandamide levels, which are known to be involved in the fronto-amygdala circuitry implicated in mood regulation and anxiety-like behaviors. While it has been shown that the variant that selectively enhances fronto-amygdala connectivity at rest is associated with decreased anxiety-like behaviors, no study so far has investigated whether this finding of FAAH-related differential plasticity extends to task-related differential functional expression and regulation during negative emotional processing. Using an imaging genetics approach, this study aimed to replicate and extend prior findings by examining functional activity and task-related connectivity in fronto-amygdala regions during emotion reactivity and emotional down-regulation of negative affect. Therefore, 48 healthy young adults underwent a functional MRI resting state measurement, completed an emotion regulation paradigm and provided self-reports on anxiety and use of emotion regulation strategies. In line with previous studies, preliminary evidence suggests that A-allele carriers demonstrate stronger fronto-amygdala connectivity during rest. In addition, exploratory whole-brain analyses indicate differential functional activity of A-allele carriers during emotion reactivity and emotion regulation. There were no associations with anxiety-related self-reports and use of emotional regulation strategies. Further research using larger samples and polygenic approaches is indicated to clarify the precise role and its underlying mechanisms in emotion processing.
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Affiliation(s)
- Anne Gärtner
- Faculty of Psychology, Technische Universität Dresden, Dresden, Germany.
| | - Denise Dörfel
- Faculty of Psychology, Technische Universität Dresden, Dresden, Germany
| | - Kersten Diers
- Faculty of Psychology, Technische Universität Dresden, Dresden, Germany
| | - Stephanie H Witt
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Alexander Strobel
- Faculty of Psychology, Technische Universität Dresden, Dresden, Germany
| | - Burkhard Brocke
- Faculty of Psychology, Technische Universität Dresden, Dresden, Germany
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48
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Tan SZK, Sheng V, Chan YS, Lim LW. Eternal sunshine of the neuromodulated mind: Altering fear memories through neuromodulation. Exp Neurol 2019; 314:9-19. [PMID: 30639183 DOI: 10.1016/j.expneurol.2019.01.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 12/27/2018] [Accepted: 01/09/2019] [Indexed: 11/17/2022]
Abstract
Anxiety disorders pose one of the greatest threats to mental health. Modern treatment methods exist but are hindered by relapse, toxicity, and low efficacy. The use of neuromodulation to treat anxiety disorders has shown promising results, yet its underpinning mechanisms remain poorly understood. In this review, we make the case for further development of neuromodulation techniques to alter fear memories, with particular regard to future clinical applications in treating anxiety disorders. We start by briefly summarizing the neural circuitry of fear while identifying the pros and cons of possible neuromodulation targets. We then highlight recent advances in neuromodulation techniques that have been used to alter fear memories. Next, we apply a novel network-based approach to elucidate possible mechanisms of neuromodulation which may disrupt the consolidation of fear memory. Finally, we emphasize the need for more systematic neuromodulation studies on animal models and the developing brain. Overall, we aim to provide an integrated framework for future action, identifying key research priorities that must be addressed before effective neuromodulation-based treatments can be developed for practical use.
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Affiliation(s)
- Shawn Zheng Kai Tan
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region
| | - Victoria Sheng
- School of Biological Sciences, The University of Hong Kong, Hong Kong Special Administrative Region
| | - Ying-Shing Chan
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region
| | - Lee Wei Lim
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region.
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49
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Morriss J, Gell M, van Reekum CM. The uncertain brain: A co-ordinate based meta-analysis of the neural signatures supporting uncertainty during different contexts. Neurosci Biobehav Rev 2018; 96:241-249. [PMID: 30550858 DOI: 10.1016/j.neubiorev.2018.12.013] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 12/09/2018] [Accepted: 12/10/2018] [Indexed: 12/23/2022]
Abstract
Uncertainty is often inevitable in everyday life and can be both stressful and exciting. Given its relevance to psychopathology and wellbeing, recent research has begun to address the brain basis of uncertainty. In the current review we examined whether there are discrete and shared neural signatures for different uncertain contexts. From the literature we identified three broad categories of uncertainty currently empirically studied using functional MRI (fMRI): basic threat and reward uncertainty, decision-making under uncertainty, and associative learning under uncertainty. We examined the neural basis of each category by using a coordinate based meta-analysis, where brain activation foci from previously published fMRI experiments were drawn together (1998-2017; 87 studies). The analyses revealed shared and discrete patterns of neural activation for uncertainty, such as the insula and amygdala, depending on the category. Such findings will have relevance for researchers attempting to conceptualise uncertainty, as well as clinical researchers examining the neural basis of uncertainty in relation to psychopathology.
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Affiliation(s)
- Jayne Morriss
- Centre for Integrative Neuroscience and Neurodynamics, School of Psychology and Clinical Language Sciences, University of Reading, Reading, UK.
| | - Martin Gell
- Centre for Integrative Neuroscience and Neurodynamics, School of Psychology and Clinical Language Sciences, University of Reading, Reading, UK
| | - Carien M van Reekum
- Centre for Integrative Neuroscience and Neurodynamics, School of Psychology and Clinical Language Sciences, University of Reading, Reading, UK
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50
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Murray SB, Strober M, Craske MG, Griffiths S, Levinson CA, Strigo IA. Fear as a translational mechanism in the psychopathology of anorexia nervosa. Neurosci Biobehav Rev 2018; 95:383-395. [DOI: 10.1016/j.neubiorev.2018.10.013] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 10/11/2018] [Accepted: 10/22/2018] [Indexed: 12/30/2022]
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