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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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2
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Hinostroza F, Mahr MM. The Implementation of the Biopsychosocial Model: Individuals With Alcohol Use Disorder and Post-Traumatic Stress Disorder. Brain Behav 2025; 15:e70230. [PMID: 39740784 DOI: 10.1002/brb3.70230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 12/06/2024] [Accepted: 12/08/2024] [Indexed: 01/02/2025] Open
Abstract
INTRODUCTION This extensive literature review investigates the relationship between post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD), focusing on the neurobiological changes associated with their co-occurrence. Given that these disorders frequently coexist, we analyze mechanisms through which alcohol serves as a coping strategy for PTSD symptoms, particularly highlighting the drinking-to-cope self-medication model, which suggests that alcohol use exacerbates PTSD symptoms and complicates recovery. METHODS A systematic literature search was conducted across multiple databases, including PubMed and Google Scholar, to identify studies examining the intersection of the biopsychosocial model with PTSD, AUD, and associated neural alterations. RESULTS Findings demonstrate that chronic PTSD is associated with progressive dysfunction in the amygdala, hippocampus, prefrontal cortex, hypothalamic-pituitary-adrenal axis, and white matter pathways. Also, our findings underscore alterations within the reward system, prefrontal cortex, hippocampus, amygdala, basal ganglia, and hypothalamic-pituitary-adrenal axis that contribute to the pathophysiology of AUD. Our results support the notion that a biopsychosocial framework is essential for contemporary addiction treatment, particularly in the context of alcohol addiction and PTSD. CONCLUSION PTSD frequently leads individuals to use alcohol as a maladaptive coping strategy, ultimately resulting in neuroadaptive alterations across critical brain regions. These neurobiological changes contribute to the development and maintenance of AUD. The findings reiterate the necessity of employing a biopsychosocial model in treating individuals grappling with both PTSD and AUD. This model allows for a comprehensive understanding of the unique challenges faced by this population, integrating biological, psychological, and social factors that influence recovery.
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Affiliation(s)
- Fernando Hinostroza
- Centro de Investigación de Estudios Avanzados del Maule, Vicerrectoría de Investigación y Postgrado, Universidad Católica del Maule, Talca, Chile
- Centro de Investigación en Neuropsicología y Neurociencias Cognitivas, Facultad de Ciencias de la Salud, Universidad Católica del Maule, Talca, Chile
- Escuela de Química y Farmacia, Departamento de Medicina Traslacional, Facultad de Medicina, Universidad Católica del Maule, Talca, Chile
- Centro para la Investigación Traslacional en Neurofarmacología, Universidad de Valparaíso, Valparaíso, Chile
| | - Michele M Mahr
- Rehabilitation Psychology, Health Science Center, Texas Tech University, Lubbock, Texas, USA
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Grégoire L, Robinson TD, Choi JM, Greening SG. Conscious expectancy rather than associative strength elicits brain activity during single-cue fear conditioning. Soc Cogn Affect Neurosci 2023; 18:nsad054. [PMID: 37756616 PMCID: PMC10597625 DOI: 10.1093/scan/nsad054] [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: 04/19/2021] [Revised: 07/14/2023] [Accepted: 09/21/2023] [Indexed: 09/29/2023] Open
Abstract
The neurocognitive processes underlying Pavlovian conditioning in humans are still largely debated. The conventional view is that conditioned responses (CRs) emerge automatically as a function of the contingencies between a conditioned stimulus (CS) and an unconditioned stimulus (US). As such, the associative strength model asserts that the frequency or amplitude of CRs reflects the strength of the CS-US associations. Alternatively, the expectation model asserts that the presentation of the CS triggers conscious expectancy of the US, which is responsible for the production of CRs. The present study tested the hypothesis that there are dissociable brain networks related to the expectancy and associative strength theories using a single-cue fear conditioning paradigm with a pseudo-random intermittent reinforcement schedule during functional magnetic resonance imaging. Participants' (n = 21) trial-by-trial expectations of receiving shock displayed a significant linear effect consistent with the expectation model. We also found a positive linear relationship between the expectancy model and activity in frontoparietal brain areas including the dorsolateral prefrontal cortex (PFC) and dorsomedial PFC. While an exploratory analysis found a linear relationship consistent with the associated strength model in the insula and early visual cortex, our primary results are consistent with the view that conscious expectancy contributes to CRs.
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Affiliation(s)
- Laurent Grégoire
- Department of Psychology, Louisiana State University, Baton Rouge, LA 70803, USA
- Department of Psychology and Brain Sciences, Texas A&M, College Station, TX 77843-4235, USA
| | - Tyler D Robinson
- Department of Psychology, Louisiana State University, Baton Rouge, LA 70803, USA
| | - Jong Moon Choi
- Department of Psychology, Louisiana State University, Baton Rouge, LA 70803, USA
- Statistical Methodology Division, Statistics Research Institute, Daejeon 35208, South Korea
| | - Steven G Greening
- Department of Psychology, Louisiana State University, Baton Rouge, LA 70803, USA
- Department of Psychology, University of Manitoba, Winnipeg R3T 2N2, Canada
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4
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Kirstein CF, Güntürkün O, Ocklenburg S. Ultra-high field imaging of the amygdala - A narrative review. Neurosci Biobehav Rev 2023; 152:105245. [PMID: 37230235 DOI: 10.1016/j.neubiorev.2023.105245] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 05/11/2023] [Accepted: 05/21/2023] [Indexed: 05/27/2023]
Abstract
The amygdala is an evolutionarily conserved core structure in emotion processing and one of the key regions of interest in affective neuroscience. Results of neuroimaging studies focusing on the amygdala are, however, often heterogeneous since it is composed of functionally and neuroanatomically distinct subnuclei. Fortunately, ultra-high-field imaging offers several advances for amygdala research, most importantly more accurate representation of functional and structural properties of subnuclei and their connectivity. Most clinical studies using ultra-high-field imaging focused on major depression, suggesting either overall rightward amygdala atrophy or distinct bilateral patterns of subnuclear atrophy and hypertrophy. Other pathologies are only sparsely covered. Connectivity analyses identified widespread networks for learning and memory, stimulus processing, cognition, and social processes. They provide evidence for distinct roles of the central, basal, and basolateral nucleus, and the extended amygdala in fear and emotion processing. Amid largely sparse and ambiguous evidence, we propose theoretical and methodological considerations that will guide ultra-high-field imaging in comprehensive investigations to help disentangle the ambiguity of the amygdala's function, structure, connectivity, and clinical relevance.
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Affiliation(s)
- Cedric Fabian Kirstein
- Department of Biopsychology, Institute of Cognitive Neuroscience, Faculty of Psychology, Ruhr University Bochum, Germany.
| | - Onur Güntürkün
- Department of Biopsychology, Institute of Cognitive Neuroscience, Faculty of Psychology, Ruhr University Bochum, Germany; Research Center One Health Ruhr, Research Alliance Ruhr, Ruhr-University Bochum, Bochum, Germany
| | - Sebastian Ocklenburg
- Department of Biopsychology, Institute of Cognitive Neuroscience, Faculty of Psychology, Ruhr University Bochum, Germany; Department of Psychology, MSH Medical School Hamburg, Germany; Institute for Cognitive and Affective Neuroscience, MSH Medical School Hamburg, Germany
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5
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Dark HE, Harnett NG, Goodman AM, Wheelock MD, Mrug S, Schuster MA, Elliott MN, Tortolero Emery S, Knight DC. Stress-induced Changes in Autonomic Reactivity Vary with Adolescent Violence Exposure and Resting-state Functional Connectivity. Neuroscience 2023; 522:81-97. [PMID: 37172687 PMCID: PMC10330471 DOI: 10.1016/j.neuroscience.2023.05.005] [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: 10/28/2022] [Revised: 04/13/2023] [Accepted: 05/04/2023] [Indexed: 05/15/2023]
Abstract
Exposure to violence during childhood can lead to functional changes in brain regions that are important for emotion expression and regulation, which may increase susceptibility to internalizing disorders in adulthood. Specifically, childhood violence exposure can disrupt the functional connectivity among brain regions that include the prefrontal cortex (PFC), hippocampus, and amygdala. Together, these regions are important for modulating autonomic responses to stress. However, it is unclear to what extent changes in brain connectivity relate to autonomic stress reactivity and how the relationship between brain connectivity and autonomic responses to stress varies with childhood violence exposure. Thus, the present study examined whether stress-induced changes in autonomic responses (e.g., heart rate, skin conductance level (SCL)) varied with amygdala-, hippocampus-, and ventromedial prefrontal cortex (vmPFC)-whole brain resting-state functional connectivity (rsFC) as a function of violence exposure. Two hundred and ninety-seven participants completed two resting-state functional magnetic resonance imaging scans prior to (pre-stress) and after (post-stress) a psychosocial stress task. Heart rate and SCL were recorded during each scan. Post-stress heart rate varied negatively with post-stress amygdala-inferior parietal lobule rsFC and positively with post-stress hippocampus-anterior cingulate cortex rsFC among those exposed to high, but not low, levels of violence. Results from the present study suggest that post-stress fronto-limbic and parieto-limbic rsFC modulates heart rate and may underlie differences in the stress response among those exposed to high levels of violence.
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Affiliation(s)
- Heather E Dark
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Nathaniel G Harnett
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Adam M Goodman
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Muriah D Wheelock
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Sylvie Mrug
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Mark A Schuster
- Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA, USA
| | | | - Susan Tortolero Emery
- School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - David C Knight
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA.
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6
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McDonald RJ, Hong NS, Germaine C, Kolb B. Peripherally-administered amphetamine induces plasticity in medial prefrontal cortex and nucleus accumbens in rats with amygdala lesions: implications for neural models of memory modulation. Front Behav Neurosci 2023; 17:1187976. [PMID: 37358968 PMCID: PMC10285066 DOI: 10.3389/fnbeh.2023.1187976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 05/12/2023] [Indexed: 06/28/2023] Open
Abstract
The amygdala has been implicated in a variety of functions linked to emotions. One popular view is that the amygdala modulates consolidation in other brain systems thought to be mainly involved in learning and memory processes. This series of experiments represents a further exploration into the role of the amygdala in memory modulation and consolidation. One interesting line of research has shown that drugs of abuse, like amphetamine, produce dendritic changes in select brain regions and these changes are thought to be equivalent to a usurping of normal plasticity processes. We were interested in the possibility that this modulation of plasticity processes would be dependent on interactions with the amygdala. According to the modulation view of amygdala function, amphetamine would activate modulation mechanisms in the amygdala that would alter plasticity processes in other brain regions. If the amygdala was rendered dysfunctional, these effects should not occur. Accordingly, this series of experiments evaluated the effects of extensive neurotoxic amygdala damage on amphetamine-induced dendritic changes in the nucleus accumbens and prefrontal cortex. The results showed that rats with large lesions of the amygdala showed the normal pattern of dendritic changes in these brain regions. This pattern of results suggests that the action of not all memory modulators, activated during emotional events, require the amygdala to impact memory.
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7
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Ewers SP, Dreier TM, Al-Bas S, Schwenkreis P, Pleger B. Classical conditioning of faciliatory paired-pulse TMS. Sci Rep 2023; 13:6192. [PMID: 37062779 PMCID: PMC10106457 DOI: 10.1038/s41598-023-32894-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 04/04/2023] [Indexed: 04/18/2023] Open
Abstract
In this proof-of-concept study, we questioned whether the influence of TMS on cortical excitability can be applied to classical conditioning. More specifically, we investigated whether the faciliatory influence of paired-pulse TMS on the excitability of the human motor cortex can be transferred to a simultaneously presented auditory stimulus through conditioning. During the conditioning phase, 75 healthy young participants received 170 faciliatory paired TMS pulses (1st pulse at 95% resting motor threshold, 2nd at 130%, interstimulus interval 12 ms), always presented simultaneously with one out of two acoustic stimuli. In the test phase, 20 min later, we pseudorandomly applied 100 single TMS pulses (at 130% MT), 50 paired with the conditioned tone-50 paired with a control tone. Using the Wilcoxon-Signed Rank test, we found significantly enhanced median amplitudes of motor evoked potentials (MEPs) paired with the conditioned tone as compared to the control tone, suggesting successful conditioning (p = 0.031, responder rate 55%, small effect size of r = - 0.248). The same comparison in only those participants with a paired-pulse amplitude < 2 mV in the conditioning phase, increased the responder rate to 61% (n = 38) and effect size to moderate (r = - 0.389). If we considered only those participants with a median paired-pulse amplitude < 1 mV, responder rate increased further to 79% (n = 14) and effect size to r = - 0.727 (i.e., large effect). These findings suggest increasingly stronger conditioning effects for smaller MEP amplitudes during paired-pulse TMS conditioning. These proof-of-concept findings extend the scope of classical conditioning to faciliatory paired-pulse TMS.
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Affiliation(s)
- Stefan P Ewers
- Department of Neurology, BG University Clinic Bergmannsheil, Ruhr-University Bochum, Bürkle-de-la-Camp Platz 1, 44789, Bochum, Germany
| | - Timo M Dreier
- Department of Neurology, BG University Clinic Bergmannsheil, Ruhr-University Bochum, Bürkle-de-la-Camp Platz 1, 44789, Bochum, Germany
| | - Siham Al-Bas
- Department of Neurology, BG University Clinic Bergmannsheil, Ruhr-University Bochum, Bürkle-de-la-Camp Platz 1, 44789, Bochum, Germany
| | - Peter Schwenkreis
- Department of Neurology, BG University Clinic Bergmannsheil, Ruhr-University Bochum, Bürkle-de-la-Camp Platz 1, 44789, Bochum, Germany
| | - Burkhard Pleger
- Department of Neurology, BG University Clinic Bergmannsheil, Ruhr-University Bochum, Bürkle-de-la-Camp Platz 1, 44789, Bochum, Germany.
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8
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Silva F, Masella G, Madeira MF, Duarte CB, Santos M. TrkC Intracellular Signalling in the Brain Fear Network During the Formation of a Contextual Fear Memory. Mol Neurobiol 2023; 60:3507-3521. [PMID: 36882590 PMCID: PMC10122637 DOI: 10.1007/s12035-023-03292-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 02/21/2023] [Indexed: 03/09/2023]
Abstract
Learned fear is orchestrated by a brain fear network that comprises the amygdala, hippocampus and the medial prefrontal cortex. Synaptic plasticity within this network is critical for the formation of proper fear memories. Known for their role in the promotion of synaptic plasticity, neurotrophins position as obvious candidates in the regulation of fear processes. Indeed, recent evidence from our laboratory and others associates dysregulated signalling through neurotrophin-3 and its receptor TrkC with the pathophysiology of anxiety and fear-related disorders. Here, we put wild-type C57Bl/6J mice through a contextual fear conditioning paradigm in order to characterize TrkC activation and expression in the main brain regions involved in (learned) fear - amygdala, hippocampus, and prefrontal cortex - during the formation of a fear memory. We report an overall decreased activation of TrkC in the fear network during fear consolidation and reconsolidation. During reconsolidation, hippocampal TrkC downregulation was accompanied by a decrease in the expression and activation of Erk, a critical signalling pathway in fear conditioning. Moreover, we did not find evidence that the observed decrease of TrkC activation was caused by altered expression of dominant negative form of TrkC, neurotrophin-3, or the PTP1B phosphatase. Our results indicate hippocampal TrkC inactivation through Erk signalling as a potential mechanism in the regulation of contextual fear memory formation.
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Affiliation(s)
- Francisca Silva
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- Institute of Interdisciplinary Research, University of Coimbra (iiiUC), Coimbra, Portugal
| | - Gianluca Masella
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- Institute of Interdisciplinary Research, University of Coimbra (iiiUC), Coimbra, Portugal
| | | | - Carlos B Duarte
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- Department of Life Sciences, University of Coimbra, Coimbra, Portugal
| | - Mónica Santos
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
- Institute of Interdisciplinary Research, University of Coimbra (iiiUC), Coimbra, Portugal.
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9
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Goodman AM, Wheelock MD, Harnett NG, Davis ES, Mrug S, Deshpande G, Knight DC. Stress-Induced Changes in Effective Connectivity During Regulation of the Emotional Response to Threat. Brain Connect 2022; 12:629-638. [PMID: 34541896 PMCID: PMC9634990 DOI: 10.1089/brain.2021.0062] [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: 11/12/2022] Open
Abstract
Background: Stress-related disruption of emotion regulation appears to involve the prefrontal cortex (PFC) and amygdala. However, the interactions between brain regions that mediate stress-induced changes in emotion regulation remain unclear. The present study builds upon prior work that assessed stress-induced changes in the neurobehavioral response to threat by investigating effective connectivity between these brain regions. Methods: Participants completed the Montreal Imaging Stress Task followed by a Pavlovian fear conditioning procedure during functional magnetic resonance imaging. Stress ratings and psychophysiological responses were used to assess stress reactivity. Effective connectivity during fear conditioning was identified using multivariate autoregressive modeling. Effective connectivity values were calculated during threat presentations that were either predictable (preceded by a warning cue) or unpredictable (no warning cue). Results: A neural hub within the dorsomedial PFC (dmPFC) showed greater effective connectivity to other PFC regions, inferior parietal lobule, insula, and amygdala during predictable than unpredictable threat. The dmPFC also showed greater connectivity to different dorsolateral PFC and amygdala regions during unpredictable than predictable threat. Stress ratings varied with connectivity differences from the dmPFC to the amygdala. Connectivity from dmPFC to amygdala was greater in general during unpredictable than predictable threat, however, this connectivity increased during predictable compared with unpredictable threat as stress reactivity increased. Conclusions: Our findings suggest that acute stress disrupts connectivity underlying top-down emotion regulation of the threat response. Furthermore, increased connectivity between the dmPFC and amygdala may play a critical role in stress-induced changes in the emotional response to threat. Impact statement The present study builds upon prior work that assessed stress-induced changes in the human neurobehavioral response to threat by demonstrating that increased top-down connectivity from the dorsomedial prefrontal cortex to the amygdala varies with individual differences in stress reactivity. These findings provide novel evidence in humans of stress-induced disruption of a specific top-down corticolimbic circuit during active emotion regulation processes, which may play a causal role in the long-term effects of chronic or excessive stress exposure.
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Affiliation(s)
- Adam M. Goodman
- Department of Psychology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Muriah D. Wheelock
- Department of Psychology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Nathaniel G. Harnett
- Department of Psychology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Elizabeth S. Davis
- Department of Psychology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Sylvie Mrug
- Department of Psychology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Gopikrishna Deshpande
- Auburn University MRI Research Center, Department of Electrical and Computer Engineering, Auburn University, Auburn, Alabama, USA
- Department of Psychological Sciences, Auburn University, Auburn, Alabama, USA
- Alabama Advanced Imaging Consortium, University of Alabama Birmingham, Alabama, USA
- Center for Neuroscience, Auburn University, Auburn, Alabama, USA
- School of Psychology, Capital Normal University, Beijing, China
- Key Laboratory for Learning and Cognition, Capital Normal University, Beijing, China
- Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - David C. Knight
- Department of Psychology, University of Alabama at Birmingham, Birmingham, Alabama, USA
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Picco S, Bavassi L, Fernández RS, Pedreira ME. Highly Demand Working Memory Intervention Weakens a Reactivated Threat Memory and the Associated Cognitive Biases. Neuroscience 2022; 497:257-270. [PMID: 35803491 DOI: 10.1016/j.neuroscience.2022.07.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 06/28/2022] [Accepted: 07/01/2022] [Indexed: 11/24/2022]
Abstract
Anxiety disorders are the most frequent type of mental disorder. Threat-conditioning memory plays a central role in anxiety disorders, impacting complex cognitive systems by modifying behavioral responses to fearful stimuli and inducing an overestimation of potential threats. Here, we analyzed the reminder-dependent amnesia on physiological responses, unconditioned stimulus (US) expectancy ratings, and measures of cognitive bias towards the threat of a threat-conditioning memory. Subjects received differential threat-conditioning. Twenty-four hours later, after reactivation of the memory of threat-conditioning, one group performed a high demand working memory task (HWM) and a second group a low demand working memory task (LWM). A third group only performed the HWM task. Retention of conditioned threat memory was tested on Day 3 in an extinction session followed by a reinstatement test. Tasks targeting stimulus representation, valuation, and attentional bias towards threat were performed. We show that the reminder-dependent intervention with an HWM weakened memory retention as expressed in skin conductance response (SCR) and faded the representation and valuation towards the threat, but it did not affect US expectancy or attentional bias. Our findings provide evidence for the experimental psychopathology approach opening the possibility to weaken both Threat conditioning memory and the systems associated with the maintenance of anxiety features.
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Affiliation(s)
- Soledad Picco
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIByNE)-CONICET, Argentina; Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina
| | - Luz Bavassi
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIByNE)-CONICET, Argentina; Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina; Departamento de Física, Universidad de Buenos Aires, Argentina
| | - Rodrigo S Fernández
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIByNE)-CONICET, Argentina; Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina
| | - María E Pedreira
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIByNE)-CONICET, Argentina; Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina.
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11
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Ramot M, Martin A. Closed-loop neuromodulation for studying spontaneous activity and causality. Trends Cogn Sci 2022; 26:290-299. [PMID: 35210175 PMCID: PMC9396631 DOI: 10.1016/j.tics.2022.01.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 01/30/2022] [Accepted: 01/31/2022] [Indexed: 01/01/2023]
Abstract
Having established that spontaneous brain activity follows meaningful coactivation patterns and correlates with behavior, researchers have turned their attention to understanding its function and behavioral significance. We suggest closed-loop neuromodulation as a neural perturbation tool uniquely well suited for this task. Closed-loop neuromodulation has primarily been viewed as an interventionist tool to teach subjects to directly control their own brain activity. We examine an alternative operant conditioning model of closed-loop neuromodulation which, through implicit feedback, can manipulate spontaneous activity at the network level, without violating the spontaneous or endogenous nature of the signal, thereby providing a direct test of network causality.
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12
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DiFazio LE, Fanselow M, Sharpe MJ. The effect of stress and reward on encoding future fear memories. Behav Brain Res 2022; 417:113587. [PMID: 34543677 PMCID: PMC11164563 DOI: 10.1016/j.bbr.2021.113587] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 09/09/2021] [Accepted: 09/09/2021] [Indexed: 01/19/2023]
Abstract
Prior experience changes the way we learn about our environment. Stress predisposes individuals to developing psychological disorders, just as positive experiences protect from this eventuality (Kirkpatrick & Heller, 2014; Koenigs & Grafman, 2009; Pechtel & Pizzagalli, 2011). Yet current models of how the brain processes information often do not consider a role for prior experience. The considerable literature that examines how stress impacts the brain is an exception to this. This research demonstrates that stress can bias the interpretation of ambiguous events towards being aversive in nature, owed to changes in amygdala physiology (Holmes et al., 2013; Perusini et al., 2016; Rau et al., 2005; Shors et al., 1992). This is thought to be an important model for how people develop anxiety disorders, like post-traumatic stress disorder (PTSD; Rau et al., 2005). However, more recent evidence suggests that experience with reward learning can also change the neural circuits that are involved in learning about fear (Sharpe et al., 2021). Specifically, the lateral hypothalamus, a region typically restricted to modulating feeding and reward behavior, can be recruited to encode fear memories after experience with reward learning. This review discusses the literature on how stress and reward change the way we acquire and encode memories for aversive events, offering a testable model of how these regions may interact to promote either adaptive or maladaptive fear memories.
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Affiliation(s)
- Lauren E DiFazio
- Department of Psychology, University of California, Los Angeles, CA, USA.
| | - Michael Fanselow
- Department of Psychology, University of California, Los Angeles, CA, USA; Staglin Center for Brain and Behavioral Health, University of California, Los Angeles, CA, USA
| | - Melissa J Sharpe
- Department of Psychology, University of California, Los Angeles, CA, USA.
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13
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Vinberg K, Rosén J, Kastrati G, Ahs F. Whole brain correlates of individual differences in skin conductance responses during discriminative fear conditioning to social cues. eLife 2022; 11:69686. [PMID: 36413209 PMCID: PMC9721615 DOI: 10.7554/elife.69686] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 11/21/2022] [Indexed: 11/23/2022] Open
Abstract
Understanding the neural basis for individual differences in the skin conductance response (SCR) during discriminative fear conditioning may inform on our understanding of autonomic regulation in fear-related psychopathology. Previous region-of-interest (ROI) analyses have implicated the amygdala in regulating conditioned SCR, but whole brain analyses are lacking. This study examined correlations between individual differences in SCR during discriminative fear conditioning to social stimuli and neural activity throughout the brain, by using data from a large functional magnetic resonance imaging study of twins (N = 285 individuals). Results show that conditioned SCR correlates with activity in the dorsal anterior cingulate cortex/anterior midcingulate cortex, anterior insula, bilateral temporoparietal junction, right frontal operculum, bilateral dorsal premotor cortex, right superior parietal lobe, and midbrain. A ROI analysis additionally showed a positive correlation between amygdala activity and conditioned SCR in line with previous reports. We suggest that the observed whole brain correlates of SCR belong to a large-scale midcingulo-insular network related to salience detection and autonomic-interoceptive processing. Altered activity within this network may underlie individual differences in conditioned SCR and autonomic aspects of psychopathology.
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Affiliation(s)
- Kevin Vinberg
- Department of Psychology and Social Work, Mid Sweden UniversityÖstersundSweden
| | - Jörgen Rosén
- Department of Psychology and Social Work, Mid Sweden UniversityÖstersundSweden,Department of Psychology, Uppsala UniversityUppsalaSweden
| | - Granit Kastrati
- Department of Psychology and Social Work, Mid Sweden UniversityÖstersundSweden,Department of Clinical Neuroscience, Karolinska InstitutetStockholmSweden
| | - Fredrik Ahs
- Department of Psychology and Social Work, Mid Sweden UniversityÖstersundSweden
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14
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Alexander C, Vasefi M. Cannabidiol and the corticoraphe circuit in post-traumatic stress disorder. IBRO Neurosci Rep 2021; 11:88-102. [PMID: 34485973 PMCID: PMC8408530 DOI: 10.1016/j.ibneur.2021.08.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 08/04/2021] [Accepted: 08/18/2021] [Indexed: 01/06/2023] Open
Abstract
Post-Traumatic Stress Disorder (PTSD), characterized by re-experiencing, avoidance, negative affect, and impaired memory processing, may develop after traumatic events. PTSD is complicated by impaired plasticity and medial prefrontal cortex (mPFC) activity, hyperactivity of the amygdala, and impaired fear extinction. Cannabidiol (CBD) is a promising candidate for treatment due to its multimodal action that enhances plasticity and calms hyperexcitability. CBD’s mechanism in the mPFC of PTSD patients has been explored extensively, but literature on the mechanism in the dorsal raphe nucleus (DRN) is lacking. Following the PRISMA guidelines, we examined current literature regarding CBD in PTSD and overlapping symptomologies to propose a mechanism by which CBD treats PTSD via corticoraphe circuit. Acute CBD inhibits excess 5-HT release from DRN to amygdala and releases anandamide (AEA) onto amygdala inputs. By first reducing amygdala and DRN hyperactivity, CBD begins to ameliorate activity disparity between mPFC and amygdala. Chronic CBD recruits the mPFC, creating harmonious corticoraphe signaling. DRN releases enough 5-HT to ameliorate mPFC hypoactivity, while the mPFC continuously excites DRN 5-HT neurons via glutamate. Meanwhile, AEA regulates corticoraphe activity to stabilize signaling. AEA prevents DRN GABAergic interneurons from inhibiting 5-HT release so the DRN can assist the mPFC in overcoming its hypoactivity. DRN-mediated restoration of mPFC activity underlies CBD’s mechanism on fear extinction and learning of stress coping.
CBD reduces PTSD symptoms via the DRN and corticoraphe circuit. Acute effects of CBD reduce DRN-amygdala excitatory signaling to lessen the activity disparity between amygdala and mPFC. Chronic CBD officially resolves mPFC hypoactivity by facilitating 5-HT release from DRN to mPFC. CBD-facilitated endocannabinoid signaling stabilizes DRN activity and restores mPFC inhibitory control. Chronically administered CBD acts via the corticoraphe circuit to favor fear extinction over fear memory reconsolidation.
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Key Words
- 2-AG, 2-arachidonoylglycerol
- 5-HT, Serotonin
- 5-HT1AR, 5-HT Receptor Type 1A
- 5-HT2AR, 5-HT Receptor Type 2 A
- AEA, Anandamide
- CB1R, Cannabinoid Receptor Type 1
- CB2R, Cannabinoid Receptor Type 2
- CBD, Cannabidiol
- COVID-19, SARS-CoV-2
- Cannabidiol
- DRN, Dorsal Raphe Nucleus
- ERK1/2, Extracellular Signal-Related Kinases Type 1 or Type 2
- FAAH, Fatty Acid Amide Hydrolase
- GABA, Gamma-Aminobutyric Acid
- GPCRs, G-Protein Coupled Receptors
- NMDAR, N-Methyl-D-aspartate Receptors
- PET, Positron Emission Tomography
- PFC, DRN and Raphe
- PFC, Prefrontal Cortex
- PTSD
- PTSD, Post-Traumatic Stress Disorder
- SSNRI, Selective Norepinephrine Reuptake Inhibitor
- SSRI, Selective Serotonin Reuptake Inhibitor
- Serotonin
- TRPV1, Transient Receptor Potential Vanilloid 1 Channels
- Traumatic Stress
- fMRI, Functional Magnetic Resonance Imaging
- mPFC, Medial Prefrontal Cortex
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Affiliation(s)
- Claire Alexander
- Department of Biology, Lamar University, Beaumont, TX 77710, USA
| | - Maryam Vasefi
- Department of Biology, Lamar University, Beaumont, TX 77710, USA
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15
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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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16
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Harnett NG, van Rooij SJH, Ely TD, Lebois LAM, Murty VP, Jovanovic T, Hill SB, Dumornay NM, Merker JB, Bruce SE, House SL, Beaudoin FL, An X, Zeng D, Neylan TC, Clifford GD, Linnstaedt SD, Germine LT, Bollen KA, Rauch SL, Lewandowski C, Hendry PL, Sheikh S, Storrow AB, Musey PI, Haran JP, Jones CW, Punches BE, Swor RA, McGrath ME, Pascual JL, Seamon MJ, Mohiuddin K, Chang AM, Pearson C, Peak DA, Domeier RM, Rathlev NK, Sanchez LD, Pietrzak RH, Joormann J, Barch DM, Pizzagalli DA, Sheridan JF, Harte SE, Elliott JM, Kessler RC, Koenen KC, Mclean S, Ressler KJ, Stevens JS. Prognostic neuroimaging biomarkers of trauma-related psychopathology: resting-state fMRI shortly after trauma predicts future PTSD and depression symptoms in the AURORA study. Neuropsychopharmacology 2021; 46:1263-1271. [PMID: 33479509 PMCID: PMC8134491 DOI: 10.1038/s41386-020-00946-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 12/12/2020] [Accepted: 12/16/2020] [Indexed: 01/30/2023]
Abstract
Neurobiological markers of future susceptibility to posttraumatic stress disorder (PTSD) may facilitate identification of vulnerable individuals in the early aftermath of trauma. Variability in resting-state networks (RSNs), patterns of intrinsic functional connectivity across the brain, has previously been linked to PTSD, and may thus be informative of PTSD susceptibility. The present data are part of an initial analysis from the AURORA study, a longitudinal, multisite study of adverse neuropsychiatric sequalae. Magnetic resonance imaging (MRI) data from 109 recently (i.e., ~2 weeks) traumatized individuals were collected and PTSD and depression symptoms were assessed at 3 months post trauma. We assessed commonly reported RSNs including the default mode network (DMN), central executive network (CEN), and salience network (SN). We also identified a proposed arousal network (AN) composed of a priori brain regions important for PTSD: the amygdala, hippocampus, mamillary bodies, midbrain, and pons. Primary analyses assessed whether variability in functional connectivity at the 2-week imaging timepoint predicted 3-month PTSD symptom severity. Left dorsolateral prefrontal cortex (DLPFC) to AN connectivity at 2 weeks post trauma was negatively related to 3-month PTSD symptoms. Further, right inferior temporal gyrus (ITG) to DMN connectivity was positively related to 3-month PTSD symptoms. Both DLPFC-AN and ITG-DMN connectivity also predicted depression symptoms at 3 months. Our results suggest that, following trauma exposure, acutely assessed variability in RSN connectivity was associated with PTSD symptom severity approximately two and a half months later. However, these patterns may reflect general susceptibility to posttraumatic dysfunction as the imaging patterns were not linked to specific disorder symptoms, at least in the subacute/early chronic phase. The present data suggest that assessment of RSNs in the early aftermath of trauma may be informative of susceptibility to posttraumatic dysfunction, with future work needed to understand neural markers of long-term (e.g., 12 months post trauma) dysfunction. Furthermore, these findings are consistent with neural models suggesting that decreased top-down cortico-limbic regulation and increased network-mediated fear generalization may contribute to ongoing dysfunction in the aftermath of trauma.
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Affiliation(s)
- Nathaniel G Harnett
- Division of Depression and Anxiety, McLean Hospital, Belmont, MA, USA.
- Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
| | - Sanne J H van Rooij
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA
| | - Timothy D Ely
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA
| | - Lauren A M Lebois
- Division of Depression and Anxiety, McLean Hospital, Belmont, MA, USA
- Department of Psychiatry, Harvard Medical School, Boston, MA, USA
| | - Vishnu P Murty
- Department of Psychology, Temple University, Philadelphia, PA, USA
| | - Tanja Jovanovic
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, MI, USA
| | - Sarah B Hill
- Division of Depression and Anxiety, McLean Hospital, Belmont, MA, USA
| | | | - Julia B Merker
- Division of Depression and Anxiety, McLean Hospital, Belmont, MA, USA
| | - Steve E Bruce
- Department of Psychological Sciences, University of Missouri - St. Louis, Springfield, MO, USA
| | - Stacey L House
- Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Francesca L Beaudoin
- Department of Emergency Medicine & Health Services, Policy, and Practice, Rhode Island Hospital and The Miriam Hospital, The Alpert Medical School of Brown University, Providence, RI, USA
| | - Xinming An
- Institute of Trauma Recovery, Department of Anesthesiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Donglin Zeng
- Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Thomas C Neylan
- Departments of Psychiatry and Neurology, University of California at San Francisco, San Francisco, CA, USA
| | - Gari D Clifford
- Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA, USA
- Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Sarah D Linnstaedt
- Institute of Trauma Recovery, Department of Anesthesiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Laura T Germine
- Institute for Technology in Psychiatry, McLean Hospital, Belmont, MA, USA
| | - Kenneth A Bollen
- Department of Psychology and Neuroscience, Department of Sociology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Scott L Rauch
- Department of Psychiatry, McLean Hospital, Belmont, MA, USA
| | | | - Phyllis L Hendry
- Department of Emergency Medicine, University of Florida College of Medicine, Jacksonville, FL, USA
| | - Sophia Sheikh
- Department of Emergency Medicine, University of Florida College of Medicine, Jacksonville, FL, USA
| | - Alan B Storrow
- Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Paul I Musey
- Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - John P Haran
- Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Christopher W Jones
- Department of Emergency Medicine, Cooper Medical School of Rowan University, Camden, NJ, USA
| | - Brittany E Punches
- Department of Emergency Medicine, College of Medicine & College of Nursing, University of Cincinnati, Cincinnati, OH, USA
| | - Robert A Swor
- Department of Emergency Medicine, Oakland University William Beaumont School of Medicine, Rochester, MI, USA
| | - Meghan E McGrath
- Department of Emergency Medicine, Boston Medical Center, Boston, MA, USA
| | - Jose L Pascual
- Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Mark J Seamon
- Division of Traumatology, Surgical Critical Care and Emergency Surgery, University of Pennsylvania, Philadelphia, PA, USA
| | - Kamran Mohiuddin
- Department of Emergency Medicine, Einstein Medical Center, Philadelphia, PA, USA
| | - Anna M Chang
- Department of Emergency Medicine, Jefferson University Hospitals, Philadelphia, PA, USA
| | - Claire Pearson
- Department of Emergency Medicine, Wayne State University, Detroit, MI, USA
| | - David A Peak
- Department of Emergency Medicine, Massachusetts General Hospital, Massachusetts, MA, USA
| | - Robert M Domeier
- Department of Emergency Medicine, Saint Joseph Mercy Hospital, Ann Arbor, MI, USA
| | - Niels K Rathlev
- Department of Emergency Medicine, University of Massachusetts Medical School-Baystate, Springfield, MO, USA
| | - Leon D Sanchez
- Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Department of Emergency Medicine, Harvard Medical School, Boston, MA, USA
| | - Robert H Pietrzak
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
- U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, VA Connecticut Healthcare System, West Haven, CT, USA
| | - Jutta Joormann
- Department of Psychology, Yale University, New Haven, CT, USA
| | - Deanna M Barch
- Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, USA
| | - Diego A Pizzagalli
- Division of Depression and Anxiety, McLean Hospital, Belmont, MA, USA
- Department of Psychiatry, Harvard Medical School, Boston, MA, USA
| | - John F Sheridan
- Department of Biosciences and Neuroscience, OSU Wexner Medical Center, Columbus, OH, USA
- Institute for Behavioral Medicine Research, OSU Wexner Medical Center, Columbus, OH, USA
| | - Steven E Harte
- Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Internal Medicine-Rheumatology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - James M Elliott
- The Kolling Institute of Medical Research, Northern Clinical School, University of Sydney, Camperdown, NSW, Australia
- Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia
- Physical Therapy & Human Movement Sciences, Feinberg School of Medicine at Northwestern University, Chicago, IL, USA
| | - Ronald C Kessler
- Department of Health Care Policy, Harvard Medical School, Boston, MA, USA
| | - Karestan C Koenen
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Samuel Mclean
- Institute of Trauma Recovery, Department of Anesthesiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Emergency Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Kerry J Ressler
- Division of Depression and Anxiety, McLean Hospital, Belmont, MA, USA
- Department of Psychiatry, Harvard Medical School, Boston, MA, USA
| | - Jennifer S Stevens
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
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17
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Neurocircuitry of Contingency Awareness in Pavlovian Fear Conditioning. COGNITIVE AFFECTIVE & BEHAVIORAL NEUROSCIENCE 2021; 21:1039-1053. [PMID: 33990933 DOI: 10.3758/s13415-021-00909-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 04/22/2021] [Indexed: 01/12/2023]
Abstract
In Pavlovian fear conditioning, contingency awareness provides an indicator of explicit fear learning. A less studied aspect of fear-based psychopathologies and their treatment, awareness of learned fear is a common cause of distress in persons with such conditions and is a focus of their treatment. The present work is a substudy of a broader fear-conditioning fMRI study. Following fear conditioning, we identified a subset of individuals who did not exhibit explicit awareness of the CS-US contingency. This prompted an exploratory analysis of differences in "aware" versus "unaware" individuals after fear conditioning. Self-reported expectancies of the CS-US contingency obtained immediately following fear conditioning were used to differentiate the two groups. Results corrected for multiple comparisons indicated significantly greater BOLD signal in the bilateral dlPFC, right vmPFC, bilateral vlPFC, left insula, left hippocampus, and bilateral amygdala for the CS+>CS- contrast in the aware group compared with the unaware group (all p values ≤ 0.004). PPI analysis with a left hippocampal seed indicated stronger coupling with the dlPFC and vmPFC in the aware group compared with the unaware group (all p values ≤ 0.002). Our findings add to our current knowledge of the networks involved in explicit learning and awareness of conditioned fear, with important clinical implications.
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18
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Dark HE, Harnett NG, Goodman AM, Wheelock MD, Mrug S, Schuster MA, Elliott MN, Emery ST, Knight DC. Violence exposure, affective style, and stress-induced changes in resting state functional connectivity. COGNITIVE, AFFECTIVE & BEHAVIORAL NEUROSCIENCE 2020; 20:1261-1277. [PMID: 33000367 PMCID: PMC7718383 DOI: 10.3758/s13415-020-00833-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 09/13/2020] [Indexed: 01/14/2023]
Abstract
Chronic childhood stress is linked to greater susceptibility to internalizing disorders in adulthood. Specifically, chronic stress leads to changes in brain connectivity patterns, and, in turn, affects psychological functioning. Violence exposure, a chronic stressor, increases stress reactivity and disrupts emotion regulation processes. However, it is unclear to what extent violence exposure affects the neural circuitry underlying emotion regulation. Individual differences in affective style also moderate the impact of stress on psychological function and can thus alter the relationship between violence exposure and brain function. Resting-state functional connectivity (rsFC) is an index of intrinsic brain activity. Stress-induced changes in rsFC between the amygdala, hippocampus, and prefrontal cortex (PFC) are associated with emotion dysregulation and may elucidate how affective style modulates the relationship between violence exposure and brain connectivity. Therefore, the present study examined the impact of violence exposure and affective style on stress-induced changes in rsFC. Participants (n = 233) completed two 6-minute resting-state functional magnetic resonance imaging scans, one before (pre-stress) and one after (post-stress) a psychosocial stress task. The bilateral amygdala, hippocampus, and ventromedial prefrontal cortex (vmPFC) were used as seed regions for rsFC analyses. Significant stress-induced changes in the prefrontal, fronto-limbic, and parieto-limbic rsFC were observed. Further, pre-stress to post-stress differences in rsFC varied with violence exposure and affective style. These findings suggest that prefrontal, fronto-limbic, and parieto-limbic connectivity is associated with the emotional response to stress and provide new insight into the neural mechanisms through which affective style moderates the impact violence exposure has on the brain.
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Affiliation(s)
- Heather E Dark
- Department of Psychology, The University of Alabama at Birmingham, CIRC 235H, 1720 2nd Ave S., Birmingham, AL, 35294, USA
| | - Nathaniel G Harnett
- Department of Psychology, The University of Alabama at Birmingham, CIRC 235H, 1720 2nd Ave S., Birmingham, AL, 35294, USA
| | - Adam M Goodman
- Department of Psychology, The University of Alabama at Birmingham, CIRC 235H, 1720 2nd Ave S., Birmingham, AL, 35294, USA
| | - Muriah D Wheelock
- Department of Psychology, The University of Alabama at Birmingham, CIRC 235H, 1720 2nd Ave S., Birmingham, AL, 35294, USA
| | - Sylvie Mrug
- Department of Psychology, The University of Alabama at Birmingham, CIRC 235H, 1720 2nd Ave S., Birmingham, AL, 35294, USA
| | - Mark A Schuster
- Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA, USA
| | | | - Susan Tortolero Emery
- School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - David C Knight
- Department of Psychology, The University of Alabama at Birmingham, CIRC 235H, 1720 2nd Ave S., Birmingham, AL, 35294, USA.
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19
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Samide R, Ritchey M. Reframing the Past: Role of Memory Processes in Emotion Regulation. COGNITIVE THERAPY AND RESEARCH 2020. [DOI: 10.1007/s10608-020-10166-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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20
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Jones CE, Wickham PT, Lim MM. Early life sleep disruption is a risk factor for increased ethanol drinking after acute footshock stress in prairie voles. Behav Neurosci 2020; 134:424-434. [PMID: 32700922 DOI: 10.1037/bne0000410] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Early postnatal experiences are important for shaping the development of the stress response and may contribute to the later emergence of alcohol use disorders. We have previously found that early life sleep disruption impairs social development and alters GABA neurons in the brain of adult prairie voles, a socially monogamous rodent that displays natural ethanol preference in the laboratory. However, it is unclear whether these effects on social behavior are due, in part, to overall anhedonia and/or altered behavioral response to stress. To address this question, litters containing prairie vole pups were sleep disrupted by gentle cage agitation for 7 consecutive days from postnatal days (P) 14 to 21 (early life sleep disruption, or ELSD group) or allowed to sleep undisturbed (Control). Adult voles underwent a 2-bottle choice ethanol drinking procedure integrated with a single session of footshocks. Ethanol intake after footshock was measured as well as c-Fos immunoreactivity in the lateral and central amygdala. ELSD animals showed increased ethanol consumption and increased neural activity in these amygdala regions after footshock compared to control animals. There were no differences in baseline ethanol drinking prior to exposure to a stressor. These results suggest that early life sleep disruption in prairie voles does not produce anhedonia but can have long-lasting effects on stress reactivity. In addition to shaping species-typical social behavior, early life sleep may be important in the development of stress induced ethanol consumption and the activation of limbic pathways associated with stress. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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21
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Measuring learning in human classical threat conditioning: Translational, cognitive and methodological considerations. Neurosci Biobehav Rev 2020; 114:96-112. [DOI: 10.1016/j.neubiorev.2020.04.019] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 04/15/2020] [Accepted: 04/18/2020] [Indexed: 02/06/2023]
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22
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Harnett NG, Goodman AM, Knight DC. PTSD-related neuroimaging abnormalities in brain function, structure, and biochemistry. Exp Neurol 2020; 330:113331. [PMID: 32343956 DOI: 10.1016/j.expneurol.2020.113331] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 04/06/2020] [Accepted: 04/24/2020] [Indexed: 12/20/2022]
Abstract
Although approximately 90% of the U.S. population will experience a traumatic event within their lifetime, only a fraction of those traumatized individuals will develop posttraumatic stress disorder (PTSD). In fact, approximately 7 out of 100 people in the U.S. will be afflicted by this debilitating condition, which suggests there is substantial inter-individual variability in susceptibility to PTSD. This uncertainty regarding who is susceptible to PTSD necessitates a thorough understanding of the neurobiological processes that underlie PTSD development in order to build effective predictive models for the disorder. In turn, these predictive models may lead to the development of improved diagnostic markers, early intervention techniques, and targeted treatment approaches for PTSD. Prior research has characterized a fear learning and memory network, centered on the prefrontal cortex, hippocampus, and amygdala, that plays a key role in the pathology of PTSD. Importantly, changes in the function, structure, and biochemistry of this network appear to underlie the cognitive-affective dysfunction observed in PTSD. The current review discusses prior research that has demonstrated alterations in brain function, structure, and biochemistry associated with PTSD. Further, the potential for future research to address current gaps in our understanding of the neural processes that underlie the development of PTSD is discussed. Specifically, this review emphasizes the need for multimodal neuroimaging research and investigations into the acute effects of posttraumatic stress. The present review provides a framework to move the field towards a comprehensive neurobiological model of PTSD.
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Affiliation(s)
- Nathaniel G Harnett
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Adam M Goodman
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - David C Knight
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA.
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23
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Hammoud MZ, Foa EB, Milad MR. Oestradiol, threat conditioning and extinction, post-traumatic stress disorder, and prolonged exposure therapy: A common link. J Neuroendocrinol 2020; 32:e12800. [PMID: 31595559 DOI: 10.1111/jne.12800] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 09/12/2019] [Accepted: 10/02/2019] [Indexed: 12/24/2022]
Abstract
The accumulating evidence regarding the impact of estradiol on learning and memory synergized studies to examine its influence on enhancing animal's ability to quell fear and anxiety. In this review, we first provide a foundational platform regarding the impact of oestradiol on cellular mechanisms of learning and memory and we review recent advances from rodent and human data showing that oestrogen enhances extinction learning across species. We then propose clinical application to these data. We discuss the potential role of oestradiol variance on the aetiology, maintenance and treatment for post-traumatic stress disorder. Specifically, we argue that the use of oestradiol as an adjunct to prolonged exposure (PE) therapy for PTSD may provide a new treatment approach for enhancing the efficacy of PE in women with PTSD. This could advance our understanding of the mechanisms of PTSD and help tailor sex-specific treatments for this disorder.
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Affiliation(s)
- Mira Z Hammoud
- Department of Psychiatry, New York University Medical Center, New York, NY, USA
| | - Edna B Foa
- Department of Psychiatry, Center for the Treatment and Study of Anxiety, University of Pennsylvania, Philadelphia, PA, USA
| | - Mohammed R Milad
- Department of Psychiatry, New York University Medical Center, New York, NY, USA
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Harnett NG, Wheelock MD, Wood KH, Goodman AM, Mrug S, Elliott MN, Schuster MA, Tortolero S, Knight DC. Negative life experiences contribute to racial differences in the neural response to threat. Neuroimage 2019; 202:116086. [PMID: 31401241 PMCID: PMC6819267 DOI: 10.1016/j.neuroimage.2019.116086] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 07/11/2019] [Accepted: 08/07/2019] [Indexed: 12/12/2022] Open
Abstract
Threat-related emotional function is supported by a neural circuit that includes the prefrontal cortex (PFC), hippocampus, and amygdala. The function of this neural circuit is altered by negative life experiences, which can potentially affect threat-related emotional processes. Notably, Black-American individuals disproportionately endure negative life experiences compared to White-American individuals. However, the relationships among negative life experiences, race, and the neural substrates that support threat-related emotional function remains unclear. Therefore, the current study investigated whether the brain function that supports threat-related emotional processes varies with racial differences in negative life experiences. In the present study, adolescent violence exposure, family income, and neighborhood disadvantage were measured prospectively (i.e., at 11-19 years of age) for Black-American and White-American volunteers. Participants then, as young adults (i.e., 18-23 years of age), completed a Pavlovian fear conditioning task during functional magnetic resonance imaging (fMRI). Cued and non-cued threats were presented during the conditioning task and behavioral (threat expectancy) and psychophysiological responses (skin conductance response; SCR) were recorded simultaneously with fMRI. Racial differences were observed in neural (fMRI activity), behavioral (threat expectancy), and psychophysiological (SCR) responses to threat. These threat-elicited responses also varied with negative life experiences (violence exposure, family income, and neighborhood disadvantage). Notably, racial differences in brain activity to threat were smaller after accounting for negative life experiences. The present findings suggest that racial differences in the neural and behavioral response to threat are due, in part, to exposure to negative life experiences and may provide new insight into the mechanisms underlying racial disparities in mental health.
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Affiliation(s)
- Nathaniel G Harnett
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Muriah D Wheelock
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Kimberly H Wood
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Adam M Goodman
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Sylvie Mrug
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | | | - Mark A Schuster
- Harvard Medical School, Boston, MA, USA; Boston Children's Hospital, Boston, MA, USA; Kaiser Permanente School of Medicine, Pasadena, CA, USA
| | - Susan Tortolero
- Health Science Center, University of Texas, Houston, TX, USA
| | - David C Knight
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA.
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25
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Orem TR, Wheelock MD, Goodman AM, Harnett NG, Wood KH, Gossett EW, Granger DA, Mrug S, Knight DC. Amygdala and prefrontal cortex activity varies with individual differences in the emotional response to psychosocial stress. Behav Neurosci 2019; 133:203-211. [PMID: 30907618 PMCID: PMC6435298 DOI: 10.1037/bne0000305] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Stress elicits a variety of psychophysiological responses that show large interindividual variability. Determining the neural mechanisms that mediate individual differences in the emotional response to stress would provide new insight that would have important implications for understanding stress-related disorders. Therefore, the present study examined individual differences in the relationship between brain activity and the emotional response to stress. In the largest stress study to date, 239 participants completed the Montreal Imaging Stress Task (MIST) while heart rate, skin conductance response (SCR), cortisol, self-reported stress, and blood oxygen level dependent (BOLD) functional MRI (fMRI) signal responses were measured. The relationship between differential responses (heart rate, SCR, cortisol, and self-reported stress) and differential BOLD fMRI data was analyzed. Dorsolateral prefrontal cortex (PFC), dorsomedial PFC, ventromedial PFC, and amygdala activity varied with the behavioral response (i.e., SCR and self-reported stress). These results suggest the PFC and amygdala support processes that are important for the expression and regulation of the emotional response to stress, and that stress-related PFC and amygdala activity underlie interindividual variability in peripheral physiologic measures of the stress response. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
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Affiliation(s)
- Tyler R. Orem
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Muriah D. Wheelock
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Adam M. Goodman
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Nathaniel G. Harnett
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Kimberly H. Wood
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Ethan W. Gossett
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Douglas A. Granger
- Institute for Interdisciplinary Salivary Bioscience Research, University of California at Irvine, Irvine, CA, USA
- UCI Center for the Neurobiology of Learning and Memory, University of California at Irvine, Irvine, CA, USA
- Johns Hopkins University School of Medicine, School of Nursing, and Bloomberg School of Public Health, Baltimore, MD USA
| | - Sylvie Mrug
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - David C. Knight
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
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Zuj DV, Norrholm SD. The clinical applications and practical relevance of human conditioning paradigms for posttraumatic stress disorder. Prog Neuropsychopharmacol Biol Psychiatry 2019; 88:339-351. [PMID: 30134147 DOI: 10.1016/j.pnpbp.2018.08.014] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 07/31/2018] [Accepted: 08/15/2018] [Indexed: 01/17/2023]
Abstract
The classical conditioning paradigm of fear learning has spawned a number of experimental variations for the explanation of posttraumatic stress disorder (PTSD) etiology. These paradigms include extinction learning and recall, fear inhibition, fear generalization, and conditioned avoidance. As such, each of these paradigms have significant applications for understanding the development, maintenance, treatment, and relapse of the fear-related features of PTSD. In the present review, we describe each of these conditioning-based paradigms with reference to the clinical applications, and supported by case examples from patients with severe PTSD symptoms. We also review the neurobiological models of conditioning and extinction in animals, psychiatrically healthy humans, and PTSD patients, and discuss the current balance of evidence suggesting a number of biological, behavioral, and cognitive mechanisms/moderators of the conditioning and extinction process in experimental and clinical contexts.
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Affiliation(s)
- Daniel V Zuj
- Department of Psychology, Swansea University, UK
| | - Seth Davin Norrholm
- Atlanta Veterans Affairs Medical Center, Mental Health Service Line, USA; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, USA.
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27
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Harnett NG, Ference EW, Wood KH, Wheelock MD, Knight AJ, Knight DC. Trauma exposure acutely alters neural function during Pavlovian fear conditioning. Cortex 2018; 109:1-13. [PMID: 30265859 PMCID: PMC6261786 DOI: 10.1016/j.cortex.2018.08.015] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 06/29/2018] [Accepted: 08/22/2018] [Indexed: 12/30/2022]
Abstract
Posttraumatic stress disorder (PTSD) is associated with dysfunction of the neural circuitry that supports fear learning and memory processes. However, much of what is known about neural dysfunction in PTSD is based on research in chronic PTSD populations. Less is known about neural function that supports fear learning acutely following trauma exposure. Determining the acute effects of trauma exposure on brain function would provide new insight into the neural processes that mediate the cognitive-affective dysfunction associated with PTSD. Therefore, the present study investigated neural activity that supports fear learning and memory processes in recently Trauma-Exposed (TE) and Non-Trauma-Exposed (NTE) participants. Participants completed a Pavlovian fear conditioning procedure during functional magnetic resonance imaging (fMRI). During fMRI, participants' threat expectancy was continuously monitored. NTE participants showed greater threat expectancy during warning than safety cues, while no difference was observed in the TE group. This finding suggests TE participants overgeneralized the fear association to the safety cue. Further, only the TE group showed a negative relationship between fMRI signal responses within dorsomedial prefrontal cortex (PFC) and threat expectancy during safety cues. These results suggest the dorsomedial PFC mediates overgeneralization of learned fear as an acute result of trauma exposure. Finally, neural activity within the PFC and inferior parietal lobule showed a negative relationship with PTSD symptom severity assessed three months posttrauma. Thus, neural activity measured acutely following trauma exposure predicted future PTSD symptom severity. The present findings elucidate the acute effects of trauma exposure on cognitive-affective function and provide new insight into the neural mechanisms of PTSD.
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Affiliation(s)
- Nathaniel G Harnett
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Edward W Ference
- Department of Physical Medicine and Rehabilitation, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Kimberly H Wood
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Muriah D Wheelock
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Amy J Knight
- Department of Physical Medicine and Rehabilitation, University of Alabama at Birmingham, Birmingham, AL, USA
| | - David C Knight
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA.
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28
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Gorka AX, Fuchs B, Grillon C, Ernst M. Impact of induced anxiety on neural responses to monetary incentives. Soc Cogn Affect Neurosci 2018; 13:1111-1119. [PMID: 30289497 PMCID: PMC6234319 DOI: 10.1093/scan/nsy082] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 08/30/2018] [Accepted: 09/17/2018] [Indexed: 11/13/2022] Open
Abstract
Previous research demonstrates that aversive stimuli can interrupt appetitive processing and that brain regions involved with the processing of potential rewards, such as the ventral striatum (VS), also respond to threatening information. Potential losses can likewise activate the VS and, thus, the full extent to which threat can impact neural responses during incentive processing remains unclear. Here, unpredictable threat of shock was used to induce anxiety while participants performed the monetary incentive delay (MID) task during functional magnetic resonance imaging (fMRI). During anticipation, anxiety impacted neural responses within the bilateral VS and distributed regions of the occipital cortex. Anxiety enhanced activity within the VS to both gain and loss trials. Furthermore, anxiety enhanced activity to both gain and loss trials within dorsal areas of BA19. However, anxiety only enhanced activity during gain, but not loss trials, within ventral areas of BA19. These results suggest that during anticipation, induced anxiety enhanced VS activity to incentives generally, which might reflect changes in the subjective salience of gains and losses. Collectively, these results suggest that the impact of induced anxiety on responses to monetary incentives depend on the neural region, type of incentive, and stage of processing.
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Affiliation(s)
- Adam X Gorka
- Section on the Neurobiology of Fear & Anxiety, National Institute of Mental Health, Bethesda, MD, USA
| | - Bari Fuchs
- Department of Nutritional Sciences, Penn State University, State College, PA, USA
| | - Christian Grillon
- Section on the Neurobiology of Fear & Anxiety, National Institute of Mental Health, Bethesda, MD, USA
| | - Monique Ernst
- Section on the Neurobiology of Fear & Anxiety, National Institute of Mental Health, Bethesda, MD, USA
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Sevenster D, Visser RM, D'Hooge R. A translational perspective on neural circuits of fear extinction: Current promises and challenges. Neurobiol Learn Mem 2018; 155:113-126. [PMID: 29981423 PMCID: PMC6805216 DOI: 10.1016/j.nlm.2018.07.002] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Revised: 06/20/2018] [Accepted: 07/03/2018] [Indexed: 02/07/2023]
Abstract
Fear extinction is the well-known process of fear reduction through repeated re-exposure to a feared stimulus without the aversive outcome. The last two decades have witnessed a surge of interest in extinction learning. First, extinction learning is observed across species, and especially research on rodents has made great strides in characterising the physical substrate underlying extinction learning. Second, extinction learning is considered of great clinical significance since it constitutes a crucial component of exposure treatment. While effective in reducing fear responding in the short term, extinction learning can lose its grip, resulting in a return of fear (i.e., laboratory model for relapse of anxiety symptoms in patients). Optimization of extinction learning is, therefore, the subject of intense investigation. It is thought that the success of extinction learning is, at least partly, determined by the mismatch between what is expected and what actually happens (prediction error). However, while much of our knowledge about the neural circuitry of extinction learning and factors that contribute to successful extinction learning comes from animal models, translating these findings to humans has been challenging for a number of reasons. Here, we present an overview of what is known about the animal circuitry underlying extinction of fear, and the role of prediction error. In addition, we conducted a systematic literature search to evaluate the degree to which state-of-the-art neuroimaging methods have contributed to translating these findings to humans. Results show substantial overlap between networks in animals and humans at a macroscale, but current imaging techniques preclude comparisons at a smaller scale, especially in sub-cortical areas that are functionally heterogeneous. Moreover, human neuroimaging shows the involvement of numerous areas that are not typically studied in animals. Results obtained in research aimed to map the extinction circuit are largely dependent on the methods employed, not only across species, but also across human neuroimaging studies. Directions for future research are discussed.
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Affiliation(s)
- Dieuwke Sevenster
- Laboratory of Biological Psychology, Department of Psychology, KU Leuven, Tiensestraat 102, B-3000 Leuven, Belgium; Clinical Psychology, Utrecht University, Heidelberglaan 1, 3584 CS Utrecht, The Netherlands.
| | - Renée M Visser
- Medical Research Council Cognition and Brain Sciences Unit, University of Cambridge, 15 Chaucer Road, Cambridge CB2 7EF, United Kingdom
| | - Rudi D'Hooge
- Laboratory of Biological Psychology, Department of Psychology, KU Leuven, Tiensestraat 102, B-3000 Leuven, Belgium
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30
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Using optimal combined moderators to define heterogeneity in neural responses to randomized conditions: Application to the effect of sleep loss on fear learning. Neuroimage 2018; 181:718-727. [PMID: 30041060 DOI: 10.1016/j.neuroimage.2018.07.051] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 07/18/2018] [Accepted: 07/21/2018] [Indexed: 12/24/2022] Open
Abstract
Comparing the neural outcomes of two randomized experimental groups is a primary aim of many functional neuroimaging studies. However, between-group effects can be obscured by heterogeneity in neural responses. Optimal Combined Moderator (OCM) approaches have previously been used to clarify heterogeneity in clinical outcomes following treatment randomization. We show that OCMs can also be used to clarify heterogeneity in the effect of a randomized experimental condition on neural responses. In 78 healthy adults aged 18-30 from the Effects of Dose-Dependent Sleep Disruption on Fear and Reward (SFeRe) study, we used demographic, clinical, genetic, and polysomnographic characteristics to develop OCMs for the effect of a randomized sleep restriction (SR) versus normal sleep (NS) condition on blood-oxygen-level dependent responses in the right amygdala (RAmyg) and subgenual anterior cingulate cortex (sgACC) during fear conditioning (FC) and extinction (FE) paradigms. The OCM for the RAmyg during FE was strongest [r (95% CI) = 0.52 (0.42, 0.68)], withstood cross-validation, and divided the sample into two subgroups with opposing experimental effects. Among N = 48 participants ("SR < NS"), those with SR exhibited less RAmyg activation during FE than those with NS [d (95%CI) = -1.10 (-1.86, -0.77)]. Among the remaining N = 30 participants ("SR > NS"), those with SR exhibited greater RAmyg activation during FE following SR than those with NS [d (95%CI) = 0.87 (0.37,1.78)]. SR > NS participants were more likely to be female, white, l/l genotype carriers, and have a psychiatric history. They had less sleep (overall and in REM), lower REM density, and lower spindle activity (12-16 Hz). Applying OCMs to randomized studies with neural outcomes can clarify neural heterogeneity and jumpstart mechanistic research; with further validation they also offer promise for personalized brain-based treatments and interventions.
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31
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Hofmann SG, Hay AC. Rethinking avoidance: Toward a balanced approach to avoidance in treating anxiety disorders. J Anxiety Disord 2018; 55:14-21. [PMID: 29550689 PMCID: PMC5879019 DOI: 10.1016/j.janxdis.2018.03.004] [Citation(s) in RCA: 120] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Revised: 03/07/2018] [Accepted: 03/07/2018] [Indexed: 12/31/2022]
Abstract
Avoidance is typically considered a maladaptive behavioral response to excessive fear and anxiety, leading to the maintenance of anxiety disorders. Exposure is a core element of cognitive-behavioral therapy for anxiety disorders. One important aspect of this treatment is repeated and prolonged exposure to a threat while discouraging patients from using avoidance strategies, such as escape or safety behaviors. We will first revisit the role of avoidance learning in the development and maintenance of anxiety disorders, including important insights from the neuroscience literature. Next, we will consider both the negative and positive aspects of avoidance for therapeutic interventions. Finally, we will explore the application of adaptive avoidance in exposure therapy for anxiety disorders. We will argue that there are occasions when avoidance behaviors can serve as effective coping strategies to enhance the person's perception of control over the environment and the potential threat. We conclude that avoidance behaviors can be a valuable therapeutic element, depending on the function of these behaviors.
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Affiliation(s)
- Stefan G Hofmann
- Boston University, Department of Psychological and Brain Sciences, 648 Beacon St., 6(th) Floor, Boston, MA, 02215, USA.
| | - Aleena C Hay
- Boston University, Department of Psychological and Brain Sciences, 648 Beacon St., 6(th) Floor, Boston, MA, 02215, USA
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32
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Hong JS, Kim SM, Jung HY, Kang KD, Min KJ, Han DH. Cognitive avoidance and aversive cues related to tobacco in male smokers. Addict Behav 2017; 73:158-164. [PMID: 28521241 DOI: 10.1016/j.addbeh.2017.05.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Revised: 03/31/2017] [Accepted: 05/02/2017] [Indexed: 11/29/2022]
Abstract
BACKGROUND Treatment using aversive conditioning has been suggested for smoking cessation. The efficacy of this method is thought to be associated with cognitive avoidance. We compare differences in avoidance traits and patterns of associated brain activation in response to cues that induce cravings versus aversion between smokers and non-smokers. METHODS Fifteen smokers and fifteen non-smokers completed cue reactivity tasks while undergoing functional magnetic resonance imaging (fMRI) to examine brain responses to craving-inducing cues (Cr) and aversion-inducing cues (Av). Participant avoidant traits were also assessed. RESULTS Activation of the left frontal subcallosal gyrus in response to Cr was greater in smokers than in non-smokers. Smokers showed less activation in the right temporal lobe in response to Av than did non-smokers. Brain activation in response to Cr in the left frontal subcallosal gyrus was positively correlated with Fagerstrom Test for Nicotine Dependence (FTND) scores in smokers. Brain activation in response to Av in the right temporal lobe was negatively correlated with the Korean Version of the Cognitive Avoidance Questionnaire (KCAQ) scores in non-smokers. CONCLUSIONS Cognitive avoidance in smokers during aversive stimulation might result in sustaining addictive behaviors. On the other hand, non-smokers may be able to emotionally confront the adverse effects of smoking.
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Harnett NG, Wood KH, Ference EW, Reid MA, Lahti AC, Knight AJ, Knight DC. Glutamate/glutamine concentrations in the dorsal anterior cingulate vary with Post-Traumatic Stress Disorder symptoms. J Psychiatr Res 2017; 91:169-176. [PMID: 28478230 DOI: 10.1016/j.jpsychires.2017.04.010] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Revised: 04/24/2017] [Accepted: 04/27/2017] [Indexed: 02/07/2023]
Abstract
Trauma and stress-related disorders (e.g., Acute Stress Disorder; ASD and Post-Traumatic Stress Disorder; PTSD) that develop following a traumatic event are characterized by cognitive-affective dysfunction. The cognitive and affective functions disrupted by stress disorder are mediated, in part, by glutamatergic neural systems. However, it remains unclear whether neural glutamate concentrations, measured acutely following trauma, vary with ASD symptoms and/or future PTSD symptom expression. Therefore, the current study utilized proton magnetic resonance spectroscopy (1H-MRS) to investigate glutamate/glutamine (Glx) concentrations within the dorsal anterior cingulate cortex (ACC) of recently (i.e., within one month) traumatized individuals and non-traumatized controls. Although Glx concentrations within dorsal ACC did not differ between recently traumatized and non-traumatized control groups, a positive linear relationship was observed between Glx concentrations and current stress disorder symptoms in traumatized individuals. Further, Glx concentrations showed a positive linear relationship with future stress disorder symptoms (i.e., assessed 3 months post-trauma). The present results suggest glutamate concentrations may play a role in both acute and future post-traumatic stress symptoms following a traumatic experience. The current results expand our understanding of the neurobiology of stress disorder and suggest glutamate within the dorsal ACC plays an important role in cognitive-affective dysfunction following a traumatic experience.
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Affiliation(s)
- Nathaniel G Harnett
- Department of Psychology, University of Alabama at Birmingham, United States
| | - Kimberly H Wood
- Department of Psychology, University of Alabama at Birmingham, United States
| | - Edward W Ference
- Department of Physical Medicine and Rehabilitation, University of Alabama at Birmingham, United States
| | - Meredith A Reid
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, United States; Department of Electrical and Computer Engineering, Auburn University, United States
| | - Adrienne C Lahti
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, United States
| | - Amy J Knight
- Department of Physical Medicine and Rehabilitation, University of Alabama at Birmingham, United States
| | - David C Knight
- Department of Psychology, University of Alabama at Birmingham, United States.
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Balderston NL, Hale E, Hsiung A, Torrisi S, Holroyd T, Carver FW, Coppola R, Ernst M, Grillon C. Threat of shock increases excitability and connectivity of the intraparietal sulcus. eLife 2017; 6. [PMID: 28555565 PMCID: PMC5478270 DOI: 10.7554/elife.23608] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Accepted: 05/29/2017] [Indexed: 11/30/2022] Open
Abstract
Anxiety disorders affect approximately 1 in 5 (18%) Americans within a given 1 year period, placing a substantial burden on the national health care system. Therefore, there is a critical need to understand the neural mechanisms mediating anxiety symptoms. We used unbiased, multimodal, data-driven, whole-brain measures of neural activity (magnetoencephalography) and connectivity (fMRI) to identify the regions of the brain that contribute most prominently to sustained anxiety. We report that a single brain region, the intraparietal sulcus (IPS), shows both elevated neural activity and global brain connectivity during threat. The IPS plays a key role in attention orienting and may contribute to the hypervigilance that is a common symptom of pathological anxiety. Hyperactivation of this region during elevated state anxiety may account for the paradoxical facilitation of performance on tasks that require an external focus of attention, and impairment of performance on tasks that require an internal focus of attention. DOI:http://dx.doi.org/10.7554/eLife.23608.001 Anxiety disorders affect around one in five Americans, and in many cases people experience anxiety so intensely that they have difficulties performing day-to-day activities. To help these people, it is important to understand how anxiety works. Current research suggests that anxiety disorders are caused when the connections in the brain that control our response to threat are either excessively or inappropriately activated. However, it was not clear what causes the anxiety to last for long periods. To better understand this phenomenon, Balderston et al. studied the brains of over 30 volunteers using two types of measurements called magnetoencephalography and fMRI. In the each experiment, participants experienced periods of threat, where they could receive unpredictable electric shocks. In the first experiment, Balderston et al. measured the brain activity by recording the magnetic fields generated in the brain. In the second experiment, they used fMRI to record changes in the blood flow throughout the brain to measure how the different regions in the brain communicate. The recordings identified a single part of the brain that increased its activity and changed its communication pattern with the other regions in the brain, when people are anxious. This region in a part of the brain called parietal lobe, is also important for processing attention, which suggests that anxiety might make people also more aware of their surroundings. However, this extra awareness might also make it more difficult for people to concentrate. Future studies may be able to stimulate this area of the brain through the scalp to potentially reduce anxiety, as the affected area is close to the skull. DOI:http://dx.doi.org/10.7554/eLife.23608.002
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Affiliation(s)
- Nicholas L Balderston
- Section on Neurobiology of Fear and Anxiety, National Institute of Mental Health, National Institutes of Health, Bethesda, United States
| | - Elizabeth Hale
- Section on Neurobiology of Fear and Anxiety, National Institute of Mental Health, National Institutes of Health, Bethesda, United States
| | - Abigail Hsiung
- Section on Neurobiology of Fear and Anxiety, National Institute of Mental Health, National Institutes of Health, Bethesda, United States
| | - Salvatore Torrisi
- Section on Neurobiology of Fear and Anxiety, National Institute of Mental Health, National Institutes of Health, Bethesda, United States
| | - Tom Holroyd
- MEG Core Facility, National Institute of Mental Health, National Institutes of Health, Bethesda, United States
| | - Frederick W Carver
- MEG Core Facility, National Institute of Mental Health, National Institutes of Health, Bethesda, United States
| | - Richard Coppola
- MEG Core Facility, National Institute of Mental Health, National Institutes of Health, Bethesda, United States
| | - Monique Ernst
- Section on Neurobiology of Fear and Anxiety, National Institute of Mental Health, National Institutes of Health, Bethesda, United States
| | - Christian Grillon
- Section on Neurobiology of Fear and Anxiety, National Institute of Mental Health, National Institutes of Health, Bethesda, United States
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Petro NM, Gruss LF, Yin S, Huang H, Miskovic V, Ding M, Keil A. Multimodal Imaging Evidence for a Frontoparietal Modulation of Visual Cortex during the Selective Processing of Conditioned Threat. J Cogn Neurosci 2017; 29:953-967. [PMID: 28253082 DOI: 10.1162/jocn_a_01114] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Emotionally salient cues are detected more readily, remembered better, and evoke greater visual cortical responses compared with neutral stimuli. The current study used concurrent EEG-fMRI recordings to identify large-scale network interactions involved in the amplification of visual cortical activity when viewing aversively conditioned cues. To generate a continuous neural signal from pericalcarine visual cortex, we presented rhythmic (10/sec) phase-reversing gratings, the orientation of which predicted the presence (CS+) or absence (CS-) of a cutaneous electric shock (i.e., the unconditioned stimulus). The resulting single trial steady-state visual evoked potential (ssVEP) amplitude was regressed against the whole-brain BOLD signal, resulting in a measure of ssVEP-BOLD coupling. Across all trial types, ssVEP-BOLD coupling was observed in both primary and extended visual cortical regions, the rolandic operculum, as well as the thalamus and bilateral hippocampus. For CS+ relative to CS- trials during the conditioning phase, BOLD-alone analyses showed CS+ enhancement at the occipital pole, superior temporal sulci, and the anterior insula bilaterally, whereas ssVEP-BOLD coupling was greater in the pericalcarine cortex, inferior parietal cortex, and middle frontal gyrus. Dynamic causal modeling analyses supported connectivity models in which heightened activity in pericalcarine cortex for threat (CS+) arises from cortico-cortical top-down modulation, specifically from the middle frontal gyrus. No evidence was observed for selective pericalcarine modulation by deep cortical structures such as the amygdala or anterior insula, suggesting that the heightened engagement of pericalcarine cortex for threat stimuli is mediated by cortical structures that constitute key nodes of canonical attention networks.
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Harnett NG, Shumen JR, Wagle PA, Wood KH, Wheelock MD, Baños JH, Knight DC. Neural mechanisms of human temporal fear conditioning. Neurobiol Learn Mem 2016; 136:97-104. [PMID: 27693343 DOI: 10.1016/j.nlm.2016.09.019] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 09/20/2016] [Accepted: 09/26/2016] [Indexed: 01/21/2023]
Abstract
Learning the temporal relationship between a warning cue (conditioned stimulus; CS) and aversive threat (unconditioned stimulus; UCS) is an important aspect of Pavlovian conditioning. Although prior functional magnetic resonance imaging (fMRI) research has identified brain regions that support Pavlovian conditioning, it remains unclear whether these regions support time-related processes important for this type of associative learning. Elucidating the neural substrates of temporal conditioning is important for a complete understanding of the Pavlovian conditioning process. Therefore, the present study used a temporal Pavlovian conditioning procedure to investigate brain activity that mediates the formation of temporal associations. During fMRI, twenty-three healthy volunteers completed a temporal conditioning procedure and a control task that does not support conditioning. Specifically, during the temporal conditioning procedure, the UCS was presented at fixed intervals (ITI: 20s) while in the control condition the UCS was presented at random intervals (Average ITI: 20s, ITI Range: 6-34s). We observed greater skin conductance responses and expectancy of the UCS during fixed (i.e., temporal conditioning) relative to random (i.e., control procedure) interval trials. These findings demonstrate fixed trials support temporal conditioning, while random trials do not. During fixed interval trials, greater conditioned fMRI signal responses were observed within dorsolateral prefrontal cortex, inferior parietal lobule, inferior and middle temporal cortex, hippocampus, and amygdala. The current findings suggest these brain regions constitute a neural circuit that encodes the temporal information necessary for Pavlovian fear conditioning.
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Affiliation(s)
- Nathaniel G Harnett
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL 35294, United States
| | - Joshua R Shumen
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL 35294, United States
| | - Pooja A Wagle
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL 35294, United States
| | - Kimberly H Wood
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL 35294, United States
| | - Muriah D Wheelock
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL 35294, United States
| | - James H Baños
- Department of Medical Education, University of Alabama at Birmingham, Birmingham, AL 35294, United States
| | - David C Knight
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
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Zuj DV, Palmer MA, Lommen MJJ, Felmingham KL. The centrality of fear extinction in linking risk factors to PTSD: A narrative review. Neurosci Biobehav Rev 2016; 69:15-35. [PMID: 27461912 DOI: 10.1016/j.neubiorev.2016.07.014] [Citation(s) in RCA: 93] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 07/13/2016] [Accepted: 07/14/2016] [Indexed: 02/08/2023]
Abstract
Recent prospective studies in emergency services have identified impaired fear extinction learning and memory to be a significant predictor of Posttraumatic Stress Disorder (PTSD), complementing a wealth of cross-sectional evidence of extinction deficits associated with the disorder. Additional fields of research show specific risk factors and biomarkers of the disorder, including candidate genotypes, stress and sex hormones, cognitive factors, and sleep disturbances. Studies in mostly nonclinical populations also reveal that the aforementioned factors are involved in fear extinction learning and memory. Here, we provide a comprehensive narrative review of the literature linking PTSD to these risk factors, and linking these risk factors to impaired fear extinction. On balance, the evidence suggests that fear extinction may play a role in the relationship between risk factors and PTSD. Should this notion hold true, this review carries important implications for the improvement of exposure-based treatments, as well as strategies for the implementation of treatment.
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Affiliation(s)
- Daniel V Zuj
- Division of Psychology, School of Medicine, University of Tasmania, Tasmania, Australia.
| | - Matthew A Palmer
- Division of Psychology, School of Medicine, University of Tasmania, Tasmania, Australia
| | - Miriam J J Lommen
- Department of Psychology, University of Groningen, Groningen, The Netherlands
| | - Kim L Felmingham
- Division of Psychology, School of Medicine, University of Tasmania, Tasmania, Australia
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Cismaru AL, Gui L, Vasung L, Lejeune F, Barisnikov K, Truttmann A, Borradori Tolsa C, Hüppi PS. Altered Amygdala Development and Fear Processing in Prematurely Born Infants. Front Neuroanat 2016; 10:55. [PMID: 27242451 PMCID: PMC4870280 DOI: 10.3389/fnana.2016.00055] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 05/02/2016] [Indexed: 12/21/2022] Open
Abstract
Context: Prematurely born children have a high risk of developmental and behavioral disabilities. Cerebral abnormalities at term age have been clearly linked with later behavior alterations, but existing studies did not focus on the amygdala. Moreover, studies of early amygdala development after premature birth in humans are scarce. Objective: To compare amygdala volumes in very preterm infants at term equivalent age (TEA) and term born infants, and to relate premature infants’ amygdala volumes with their performance on the Laboratory Temperament Assessment Battery (Lab-TAB) fear episode at 12 months. Participants: Eighty one infants born between 2008 and 2014 at the University Hospitals of Geneva and Lausanne, taking part in longitudinal and functional imaging studies, who had undergone a magnetic resonance imaging (MRI) scan at TEA enabling manual amygdala delineation. Outcomes: Amygdala volumes assessed by manual segmentation of MRI scans; volumes of cortical and subcortical gray matter, white matter and cerebrospinal fluid (CSF) automatically segmented in 66 infants; scores for the Lab-TAB fear episode for 42 premature infants at 12 months. Results: Amygdala volumes were smaller in preterm infants at TEA than term infants (mean difference 138.03 mm3, p < 0.001), and overall right amygdala volumes were larger than left amygdala volumes (mean difference 36.88 mm3, p < 0.001). White matter volumes were significantly smaller (p < 0.001) and CSF volumes significantly larger (p < 0.001) in preterm than in term born infants, while cortical and subcortical gray matter volumes were not significantly different between groups. Amygdala volumes showed significant correlation with the intensity of the escape response to a fearsome toy (rs = 0.38, p = 0.013), and were larger in infants showing an escape response compared to the infants showing no escape response (mean difference 120.97 mm3, p = 0.005). Amygdala volumes were not significantly correlated with the intensity of facial fear, distress vocalizations, bodily fear and positive motor activity in the fear episode. Conclusion: Our results indicate that premature birth is associated with a reduction in amygdala volumes and white matter volumes at TEA, suggesting that altered amygdala development might be linked to alterations in white matter connectivity reported in premature infants. Moreover, our data suggests that such alterations might affect infants’ fear-processing capabilities.
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Affiliation(s)
- Anca Liliana Cismaru
- Division of Development and Growth, Department of Pediatrics, Hospital of Geneva Geneva, Switzerland
| | - Laura Gui
- Division of Development and Growth, Department of Pediatrics, Hospital of Geneva Geneva, Switzerland
| | - Lana Vasung
- Division of Development and Growth, Department of Pediatrics, Hospital of Geneva Geneva, Switzerland
| | - Fleur Lejeune
- Child Clinical Neuropsychology Unit, University of Geneva Geneva, Switzerland
| | - Koviljka Barisnikov
- Child Clinical Neuropsychology Unit, University of Geneva Geneva, Switzerland
| | - Anita Truttmann
- Division of Neonatology, University Hospital of Lausanne Lausanne, Switzerland
| | - Cristina Borradori Tolsa
- Division of Development and Growth, Department of Pediatrics, Hospital of Geneva Geneva, Switzerland
| | - Petra S Hüppi
- Division of Development and Growth, Department of Pediatrics, Hospital of Geneva Geneva, Switzerland
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Schultz DH, Balderston NL, Baskin-Sommers AR, Larson CL, Helmstetter FJ. Psychopaths Show Enhanced Amygdala Activation during Fear Conditioning. Front Psychol 2016; 7:348. [PMID: 27014154 PMCID: PMC4785144 DOI: 10.3389/fpsyg.2016.00348] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 02/25/2016] [Indexed: 11/27/2022] Open
Abstract
Psychopathy is a personality disorder characterized by emotional deficits and a failure to inhibit impulsive behavior and is often subdivided into “primary” and “secondary” psychopathic subtypes. The maladaptive behavior related to primary psychopathy is thought to reflect constitutional “fearlessness,” while the problematic behavior related to secondary psychopathy is motivated by other factors. The fearlessness observed in psychopathy has often been interpreted as reflecting a fundamental deficit in amygdala function, and previous studies have provided support for a low-fear model of psychopathy. However, many of these studies fail to use appropriate screening procedures, use liberal inclusion criteria, or have used unconventional approaches to assay amygdala function. We measured brain activity with BOLD imaging in primary and secondary psychopaths and non-psychopathic control subjects during Pavlovian fear conditioning. In contrast to the low-fear model, we observed normal fear expression in primary psychopaths. Psychopaths also displayed greater differential BOLD activity in the amygdala relative to matched controls. Inverse patterns of activity were observed in the anterior cingulate cortex (ACC) for primary versus secondary psychopaths. Primary psychopaths exhibited a pattern of activity in the dorsal and ventral ACC consistent with enhanced fear expression, while secondary psychopaths exhibited a pattern of activity in these regions consistent with fear inhibition. These results contradict the low-fear model of psychopathy and suggest that the low fear observed for psychopaths in previous studies may be specific to secondary psychopaths.
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Affiliation(s)
- Douglas H Schultz
- Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee WI, USA
| | | | | | - Christine L Larson
- Department of Psychology, University of Wisconsin-Milwaukee, MilwaukeeWI, USA; Department of Neurology, Medical College of Wisconsin, MilwaukeeWI, USA
| | - Fred J Helmstetter
- Department of Psychology, University of Wisconsin-Milwaukee, MilwaukeeWI, USA; Department of Neurology, Medical College of Wisconsin, MilwaukeeWI, USA
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Harnett NG, Wheelock MD, Wood KH, Ladnier JC, Mrug S, Knight DC. Affective state and locus of control modulate the neural response to threat. Neuroimage 2015. [PMID: 26196669 DOI: 10.1016/j.neuroimage.2015.07.034] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The ability to regulate the emotional response to threat is critical to healthy emotional function. However, the response to threat varies considerably from person-to-person. This variability may be partially explained by differences in emotional processes, such as locus of control and affective state, which vary across individuals. Although the basic neural circuitry that mediates the response to threat has been described, the impact individual differences in affective state and locus of control have on that response is not well characterized. Understanding how these factors influence the neural response to threat would provide new insight into processes that mediate emotional function. Therefore, the present study used a Pavlovian conditioning procedure to investigate the influence individual differences in locus of control, positive affect, and negative affect have on the brain and behavioral responses to predictable and unpredictable threats. Thirty-two healthy volunteers participated in a fear conditioning study in which predictable and unpredictable threats (i.e., unconditioned stimulus) were presented during functional magnetic resonance imaging (fMRI). Locus of control showed a linear relationship with learning-related ventromedial prefrontal cortex (PFC) activity such that the more external an individual's locus of control, the greater their differential response to predictable versus unpredictable threat. In addition, positive and negative affectivity showed a curvilinear relationship with dorsolateral PFC, dorsomedial PFC, and insula activity, such that those with high or low affectivity showed reduced regional activity compared to those with an intermediate level of affectivity. Further, activity within the PFC, as well as other regions including the amygdala, were linked with the peripheral emotional response as indexed by skin conductance and electromyography. The current findings demonstrate that the neural response to threat within brain regions that mediate the peripheral emotional response is modulated by an individual's affective state as well as their perceptions of an event's causality.
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Affiliation(s)
| | | | - Kimberly H Wood
- Department of Psychology, University of Alabama at Birmingham, USA
| | - Jordan C Ladnier
- Department of Psychology, University of Alabama at Birmingham, USA
| | - Sylvie Mrug
- Department of Psychology, University of Alabama at Birmingham, USA
| | - David C Knight
- Department of Psychology, University of Alabama at Birmingham, USA.
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Wood KH, Wheelock MD, Shumen JR, Bowen KH, Ver Hoef LW, Knight DC. Controllability modulates the neural response to predictable but not unpredictable threat in humans. Neuroimage 2015; 119:371-81. [PMID: 26149610 DOI: 10.1016/j.neuroimage.2015.06.086] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Revised: 06/12/2015] [Accepted: 06/14/2015] [Indexed: 01/15/2023] Open
Abstract
Stress resilience is mediated, in part, by our ability to predict and control threats within our environment. Therefore, determining the neural mechanisms that regulate the emotional response to predictable and controllable threats may provide important new insight into the processes that mediate resilience to emotional dysfunction and guide the future development of interventions for anxiety disorders. To better understand the effect of predictability and controllability on threat-related brain activity in humans, two groups of healthy volunteers participated in a yoked Pavlovian fear conditioning study during functional magnetic resonance imaging (fMRI). Threat predictability was manipulated by presenting an aversive unconditioned stimulus (UCS) that was either preceded by a conditioned stimulus (i.e., predictable) or by presenting the UCS alone (i.e., unpredictable). Similar to animal model research that has employed yoked fear conditioning procedures, one group (controllable condition; CC), but not the other group (uncontrollable condition; UC) was able to terminate the UCS. The fMRI signal response within the dorsolateral prefrontal cortex (PFC), dorsomedial PFC, ventromedial PFC, and posterior cingulate was diminished during predictable compared to unpredictable threat (i.e., UCS). In addition, threat-related activity within the ventromedial PFC and bilateral hippocampus was diminished only to threats that were both predictable and controllable. These findings provide insight into how threat predictability and controllability affects the activity of brain regions (i.e., ventromedial PFC and hippocampus) involved in emotion regulation, and may have important implications for better understanding neural processes that mediate emotional resilience to stress.
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Affiliation(s)
- Kimberly H Wood
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Muriah D Wheelock
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Joshua R Shumen
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Kenton H Bowen
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Lawrence W Ver Hoef
- Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Birmingham VA Medical Center, Birmingham, AL 35294, USA
| | - David C Knight
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
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Gilpin NW, Herman MA, Roberto M. The central amygdala as an integrative hub for anxiety and alcohol use disorders. Biol Psychiatry 2015; 77:859-69. [PMID: 25433901 PMCID: PMC4398579 DOI: 10.1016/j.biopsych.2014.09.008] [Citation(s) in RCA: 340] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Revised: 08/22/2014] [Accepted: 09/08/2014] [Indexed: 12/29/2022]
Abstract
The central amygdala (CeA) plays a central role in physiologic and behavioral responses to fearful stimuli, stressful stimuli, and drug-related stimuli. The CeA receives dense inputs from cortical regions, is the major output region of the amygdala, is primarily GABAergic (inhibitory), and expresses high levels of prostress and antistress peptides. The CeA is also a constituent region of a conceptual macrostructure called the extended amygdala that is recruited during the transition to alcohol dependence. We discuss neurotransmission in the CeA as a potential integrative hub between anxiety disorders and alcohol use disorder, which are commonly co-occurring in humans. Imaging studies in humans and multidisciplinary work in animals collectively suggest that CeA structure and function are altered in individuals with anxiety disorders and alcohol use disorder, the end result of which may be disinhibition of downstream "effector" regions that regulate anxiety-related and alcohol-related behaviors.
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Affiliation(s)
- Nicholas W Gilpin
- Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, Louisiana; Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
| | - Melissa A Herman
- Committee on the Neurobiology of Addictive Disorders (MAH, MR), The Scripps Research Institute, La Jolla, California
| | - Marisa Roberto
- Committee on the Neurobiology of Addictive Disorders (MAH, MR), The Scripps Research Institute, La Jolla, California
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43
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Balderston NL, Schultz DH, Hopkins L, Helmstetter FJ. Functionally distinct amygdala subregions identified using DTI and high-resolution fMRI. Soc Cogn Affect Neurosci 2015; 10:1615-22. [PMID: 25969533 DOI: 10.1093/scan/nsv055] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 05/07/2015] [Indexed: 11/13/2022] Open
Abstract
Although the amygdala is often directly linked with fear and emotion, amygdala neurons are activated by a wide variety of emotional and non-emotional stimuli. Different subregions within the amygdala may be engaged preferentially by different aspects of emotional and non-emotional tasks. To test this hypothesis, we measured and compared the effects of novelty and fear on amygdala activity. We used high-resolution blood oxygenation level-dependent (BOLD) imaging and streamline tractography to subdivide the amygdala into three distinct functional subunits. We identified a laterobasal subregion connected with the visual cortex that responds generally to visual stimuli, a non-projecting region that responds to salient visual stimuli, and a centromedial subregion connected with the diencephalon that responds only when a visual stimulus predicts an aversive outcome. We provide anatomical and functional support for a model of amygdala function where information enters through the laterobasal subregion, is processed by intrinsic circuits in the interspersed tissue, and is then passed to the centromedial subregion, where activation leads to behavioral output.
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Affiliation(s)
- Nicholas L Balderston
- Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA, and
| | - Douglas H Schultz
- Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA, and
| | - Lauren Hopkins
- Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA, and
| | - Fred J Helmstetter
- Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA, and Department of Neurology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
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Abstract
Patients with heart failure (HF) exhibit a wide range of symptoms, including dyspnea, sleep-disordered breathing, autonomic abnormalities, cognitive dysfunction, and neuropsychological disturbances. These symptoms, which affect quality of life and morbidity and mortality in the condition, are largely related to structural and functional changes in the brain. There are increasing reports of brain abnormalities in HF, but often the linkages between brain injury and common HF clinical symptomatology are not clearly described. In this review, we will discuss the current evidence of brain injury and the associated clinical symptoms in HF, focusing on those brain regions that are commonly damaged in the condition. We will also provide a brief exploration of some potential mechanisms for brain injury in HF.
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Affiliation(s)
- Jennifer A Ogren
- UCLA School of Nursing, 700 Tiverton Ave., Los Angeles, CA, 90095-1702, USA,
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45
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Neural correlates of individual differences in fear learning. Behav Brain Res 2015; 287:34-41. [PMID: 25819422 DOI: 10.1016/j.bbr.2015.03.035] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Revised: 03/15/2015] [Accepted: 03/17/2015] [Indexed: 01/25/2023]
Abstract
Variability in fear conditionability is common, and clarity regarding the neural regions responsible for individual differences in fear conditionability could uncover brain-based biomarkers of resilience or vulnerability to trauma-based psychopathologies (e.g., post-traumatic stress disorder). In recent years, neuroimaging work has yielded a detailed understanding of the neural mechanisms underlying fear conditioning common across participants, however only a minority of studies have investigated the brain basis of inter-individual variation in fear learning. Moreover, the majority of these studies have employed small sample sizes (mean n=17; range n=5-27) and all have failed to meet the minimum recommended sample size for functional magnetic resonance imaging (fMRI) studies of individual differences. Here, using fMRI, we analyzed blood-oxygenation level dependent (BOLD) response recorded simultaneously with skin conductance response (SCR) and ratings of unconditioned stimulus (US) expectancy in 49 participants undergoing Pavlovian fear conditioning. On average, participants became conditioned to the conditioned stimulus (CS+; higher US expectancy ratings and SCR for the CS+ compared to the unpaired conditioned stimulus, CS-); the CS+ also robustly increased activation in the bilateral insula. Amygdala activation was revealed from a regression analysis that incorporated individual differences in fear conditionability (i.e., a between-subjects regressor of mean CS+>CS- SCR). By replicating results observed using much smaller sample sizes, the results confirm that variation in amygdala reactivity covaries with individual differences in fear conditionability. The link between behavior (SCR) and brain (amygdala reactivity) may be a putative endophenotype for the acquisition of fear memories.
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46
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Ahrens LM, Mühlberger A, Pauli P, Wieser MJ. Impaired visuocortical discrimination learning of socially conditioned stimuli in social anxiety. Soc Cogn Affect Neurosci 2014; 10:929-37. [PMID: 25338634 DOI: 10.1093/scan/nsu140] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Accepted: 10/20/2014] [Indexed: 12/18/2022] Open
Abstract
In search of causative factors of social anxiety disorder (SAD), classical conditioning has been discussed as a potential trigger mechanism for many years. Recent findings suggest that the social relevance of the unconditioned stimulus (US) might play a major role in learning theories of SAD. Thus, this study applied a social conditioning paradigm with disorder-relevant US to examine the electrocortical correlates of affective learning. Twenty-four high socially anxious (HSA) and 23 age- and gender-matched low socially anxious (LSA) subjects were conditioned to 3 different faces flickering at a frequency of 15 Hz which were paired with auditory insults, compliments or neutral comments (US). The face-evoked electrocortical response was measured via steady-state visually evoked potentials and subjective measures of valence and arousal were obtained. Results revealed a significant interaction of social anxiety and conditioning, with LSA showing highest cortical activity to faces paired with insults and lowest activity to faces paired with compliments, while HSA did not differentiate between faces. No group differences were discovered in the affective ratings. The findings indicate a potentially impaired ability of HSA to discriminate between relevant and irrelevant social stimuli, which may constitute a perpetuating factor of SAD.
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Affiliation(s)
- Lea M Ahrens
- Department of Psychology, University of Würzburg, Würzburg, Germany, and Department of Clinical Psychology and Psychotherapy, University of Regensburg, Regensburg, Germany
| | - Andreas Mühlberger
- Department of Psychology, University of Würzburg, Würzburg, Germany, and Department of Clinical Psychology and Psychotherapy, University of Regensburg, Regensburg, Germany
| | - Paul Pauli
- Department of Psychology, University of Würzburg, Würzburg, Germany, and Department of Clinical Psychology and Psychotherapy, University of Regensburg, Regensburg, Germany
| | - Matthias J Wieser
- Department of Psychology, University of Würzburg, Würzburg, Germany, and Department of Clinical Psychology and Psychotherapy, University of Regensburg, Regensburg, Germany
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Mosig C, Merz CJ, Mohr C, Adolph D, Wolf OT, Schneider S, Margraf J, Zlomuzica A. Enhanced discriminative fear learning of phobia-irrelevant stimuli in spider-fearful individuals. Front Behav Neurosci 2014; 8:328. [PMID: 25324745 PMCID: PMC4181334 DOI: 10.3389/fnbeh.2014.00328] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Accepted: 09/03/2014] [Indexed: 01/01/2023] Open
Abstract
Avoidance is considered as a central hallmark of all anxiety disorders. The acquisition and expression of avoidance, which leads to the maintenance and exacerbation of pathological fear is closely linked to Pavlovian and operant conditioning processes. Changes in conditionability might represent a key feature of all anxiety disorders but the exact nature of these alterations might vary across different disorders. To date, no information is available on specific changes in conditionability for disorder-irrelevant stimuli in specific phobia (SP). The first aim of this study was to investigate changes in fear acquisition and extinction in spider-fearful individuals as compared to non-fearful participants by using the de novo fear conditioning paradigm. Secondly, we aimed to determine whether differences in the magnitude of context-dependent fear retrieval exist between spider-fearful and non-fearful individuals. Our findings point to an enhanced fear discrimination in spider-fearful individuals as compared to non-fearful individuals at both the physiological and subjective level. The enhanced fear discrimination in spider-fearful individuals was neither mediated by increased state anxiety, depression, nor stress tension. Spider-fearful individuals displayed no changes in extinction learning and/or fear retrieval. Surprisingly, we found no evidence for context-dependent modulation of fear retrieval in either group. Here, we provide first evidence that spider-fearful individuals show an enhanced discriminative fear learning of phobia-irrelevant (de novo) stimuli. Our findings provide novel insights into the role of fear acquisition and expression for the development and maintenance of maladaptive responses in the course of SP.
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Affiliation(s)
- Carina Mosig
- Mental Health Research and Treatment Center, Ruhr-University Bochum , Bochum , Germany
| | - Christian J Merz
- Department of Cognitive Psychology, Institute of Cognitive Neuroscience, Ruhr-University Bochum , Bochum , Germany
| | - Cornelia Mohr
- Mental Health Research and Treatment Center, Ruhr-University Bochum , Bochum , Germany
| | - Dirk Adolph
- Mental Health Research and Treatment Center, Ruhr-University Bochum , Bochum , Germany
| | - Oliver T Wolf
- Department of Cognitive Psychology, Institute of Cognitive Neuroscience, Ruhr-University Bochum , Bochum , Germany
| | - Silvia Schneider
- Mental Health Research and Treatment Center, Ruhr-University Bochum , Bochum , Germany
| | - Jürgen Margraf
- Mental Health Research and Treatment Center, Ruhr-University Bochum , Bochum , Germany
| | - Armin Zlomuzica
- Mental Health Research and Treatment Center, Ruhr-University Bochum , Bochum , Germany
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48
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VanElzakker MB, Dahlgren MK, Davis FC, Dubois S, Shin LM. From Pavlov to PTSD: the extinction of conditioned fear in rodents, humans, and anxiety disorders. Neurobiol Learn Mem 2014; 113:3-18. [PMID: 24321650 PMCID: PMC4156287 DOI: 10.1016/j.nlm.2013.11.014] [Citation(s) in RCA: 329] [Impact Index Per Article: 29.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Revised: 10/31/2013] [Accepted: 11/24/2013] [Indexed: 01/08/2023]
Abstract
Nearly 100 years ago, Ivan Pavlov demonstrated that dogs could learn to use a neutral cue to predict a biologically relevant event: after repeated predictive pairings, Pavlov's dogs were conditioned to anticipate food at the sound of a bell, which caused them to salivate. Like sustenance, danger is biologically relevant, and neutral cues can take on great salience when they predict a threat to survival. In anxiety disorders such as posttraumatic stress disorder (PTSD), this type of conditioned fear fails to extinguish, and reminders of traumatic events can cause pathological conditioned fear responses for decades after danger has passed. In this review, we use fear conditioning and extinction studies to draw a direct line from Pavlov to PTSD and other anxiety disorders. We explain how rodent studies have informed neuroimaging studies of healthy humans and humans with PTSD. We describe several genes that have been linked to both PTSD and fear conditioning and extinction and explain how abnormalities in fear conditioning or extinction may reflect a general biomarker of anxiety disorders. Finally, we explore drug and neuromodulation treatments that may enhance therapeutic extinction in anxiety disorders.
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Affiliation(s)
- Michael B VanElzakker
- Tufts University Psychology, 490 Boston Avenue, Medford, MA 02155, USA; Massachusetts General Hospital Psychiatry, 149 Thirteenth Street, Charlestown, MA 02129, USA.
| | - M Kathryn Dahlgren
- Tufts University Psychology, 490 Boston Avenue, Medford, MA 02155, USA; Massachusetts General Hospital Psychiatry, 149 Thirteenth Street, Charlestown, MA 02129, USA
| | - F Caroline Davis
- Massachusetts General Hospital Psychiatry, 149 Thirteenth Street, Charlestown, MA 02129, USA
| | - Stacey Dubois
- Tufts University Psychology, 490 Boston Avenue, Medford, MA 02155, USA
| | - Lisa M Shin
- Tufts University Psychology, 490 Boston Avenue, Medford, MA 02155, USA; Massachusetts General Hospital Psychiatry, 149 Thirteenth Street, Charlestown, MA 02129, USA
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Wheelock MD, Sreenivasan KR, Wood KH, Ver Hoef LW, Deshpande G, Knight DC. Threat-related learning relies on distinct dorsal prefrontal cortex network connectivity. Neuroimage 2014; 102 Pt 2:904-12. [PMID: 25111474 DOI: 10.1016/j.neuroimage.2014.08.005] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Revised: 07/23/2014] [Accepted: 08/02/2014] [Indexed: 10/24/2022] Open
Abstract
Conditioned changes in the emotional response to threat (e.g. aversive unconditioned stimulus; UCS) are mediated in part by the prefrontal cortex (PFC). Unpredictable threats elicit large emotional responses, while the response is diminished when the threat is predictable. A better understanding of how PFC connectivity to other brain regions varies with threat predictability would provide important insights into the neural processes that mediate conditioned diminution of the emotional response to threat. The present study examined brain connectivity during predictable and unpredictable threat exposure using a fear conditioning paradigm (previously published in Wood et al., 2012) in which unconditioned functional magnetic resonance imaging data were reanalyzed to assess effective connectivity. Granger causality analysis was performed using the time series data from 15 activated regions of interest after hemodynamic deconvolution, to determine regional effective connectivity. In addition, connectivity path weights were correlated with trait anxiety measures to assess the relationship between negative affect and brain connectivity. Results indicate the dorsomedial PFC (dmPFC) serves as a neural hub that influences activity in other brain regions when threats are unpredictable. In contrast, the dorsolateral PFC (dlPFC) serves as a neural hub that influences the activity of other brain regions when threats are predictable. These findings are consistent with the view that the dmPFC coordinates brain activity to take action, perhaps in a reactive manner, when an unpredicted threat is encountered, while the dlPFC coordinates brain regions to take action, in what may be a more proactive manner, to respond to predictable threats. Further, dlPFC connectivity to other brain regions (e.g. ventromedial PFC, amygdala, and insula) varied with negative affect (i.e. trait anxiety) when the UCS was predictable, suggesting that stronger connectivity may be required for emotion regulation in individuals with higher levels of negative affect.
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Affiliation(s)
- M D Wheelock
- Department of Psychology, University of Alabama at Birmingham, USA
| | - K R Sreenivasan
- AU MRI Research Center, Department of Electrical and Computer Engineering, Auburn University, Auburn, AL, USA
| | - K H Wood
- Department of Psychology, University of Alabama at Birmingham, USA
| | - L W Ver Hoef
- Department of Neurology, University of Alabama at Birmingham, School of Medicine, Birmingham VA Medical Center, USA
| | - Gopikrishna Deshpande
- AU MRI Research Center, Department of Electrical and Computer Engineering, Auburn University, Auburn, AL, USA; Department of Psychology, Auburn University, Auburn, AL, USA
| | - D C Knight
- Department of Psychology, University of Alabama at Birmingham, USA.
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Meier ML, de Matos NMP, Brügger M, Ettlin DA, Lukic N, Cheetham M, Jäncke L, Lutz K. Equal pain-Unequal fear response: enhanced susceptibility of tooth pain to fear conditioning. Front Hum Neurosci 2014; 8:526. [PMID: 25100974 PMCID: PMC4103082 DOI: 10.3389/fnhum.2014.00526] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2014] [Accepted: 06/28/2014] [Indexed: 01/11/2023] Open
Abstract
Experimental fear conditioning in humans is widely used as a model to investigate the neural basis of fear learning and to unravel the pathogenesis of anxiety disorders. It has been observed that fear conditioning depends on stimulus salience and subject vulnerability to fear. It is further known that the prevalence of dental-related fear and phobia is exceedingly high in the population. Dental phobia is unique as no other body part is associated with a specific phobia. Therefore, we hypothesized that painful dental stimuli exhibit an enhanced susceptibility to fear conditioning when comparing to equal perceived stimuli applied to other body sites. Differential susceptibility to pain-related fear was investigated by analyzing responses to an unconditioned stimulus (UCS) applied to the right maxillary canine (UCS-c) vs. the right tibia (UCS-t). For fear conditioning, UCS-c and USC-t consisted of painful electric stimuli, carefully matched at both application sites for equal intensity and quality perception. UCSs were paired to simple geometrical forms which served as conditioned stimuli (CS+). Unpaired CS+ were presented for eliciting and analyzing conditioned fear responses. Outcome parameter were (1) skin conductance changes and (2) time-dependent brain activity (BOLD responses) in fear-related brain regions such as the amygdala, anterior cingulate cortex, insula, thalamus, orbitofrontal cortex, and medial prefrontal cortex. A preferential susceptibility of dental pain to fear conditioning was observed, reflected by heightened skin conductance responses and enhanced time-dependent brain activity (BOLD responses) in the fear network. For the first time, this study demonstrates fear-related neurobiological mechanisms that point toward a superior conditionability of tooth pain. Beside traumatic dental experiences our results offer novel evidence that might explain the high prevalence of dental-related fears in the population.
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Affiliation(s)
- Michael L. Meier
- Center of Dental Medicine, Clinic for Removable Prosthodontics, Masticatory Disorders and Special Care Dentistry, University of ZurichZurich, Switzerland
- Chiropractic Medicine, Balgrist University HospitalZurich, Switzerland
| | - Nuno M. P. de Matos
- Center of Dental Medicine, Clinic for Removable Prosthodontics, Masticatory Disorders and Special Care Dentistry, University of ZurichZurich, Switzerland
| | - Mike Brügger
- Center of Dental Medicine, Clinic for Removable Prosthodontics, Masticatory Disorders and Special Care Dentistry, University of ZurichZurich, Switzerland
- MRI Technology, Institute for Biomedical Engineering, Swiss Federal Institute of Technology and the University of ZurichZurich, Switzerland
| | - Dominik A. Ettlin
- Center of Dental Medicine, Clinic for Removable Prosthodontics, Masticatory Disorders and Special Care Dentistry, University of ZurichZurich, Switzerland
| | - Nenad Lukic
- Center of Dental Medicine, Clinic for Removable Prosthodontics, Masticatory Disorders and Special Care Dentistry, University of ZurichZurich, Switzerland
| | - Marcus Cheetham
- Institute of Psychology, Department of Neuropsychology, University of ZurichZurich, Switzerland
| | - Lutz Jäncke
- Institute of Psychology, Department of Neuropsychology, University of ZurichZurich, Switzerland
| | - Kai Lutz
- Institute of Psychology, Department of Neuropsychology, University of ZurichZurich, Switzerland
- Center for Neurology and Rehabilitation CereneoVitznau, Switzerland
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