ArticleLiterature Review

Functional Neuroanatomy of Emotion and Its Regulation in PTSD

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Abstract

Posttraumatic stress disorder (PTSD) is a devastating disorder, linked to profound mental, physical, occupational, and functional impairment. In addition, it is a highly complex disorder, characterized by symptom heterogeneity across multiple domains. Nevertheless, emotion dysregulation arising from the exaggerated response to threat or from the inability to regulate negative emotional states plays a defining role in the pathophysiology of PTSD. In order to improve our understanding of how emotion dysregulation manifests in this illness, functional neuroimaging research over the past 20 years provides great insight into underlying neuroanatomy of each component of emotion dysregulation in the context of PTSD. While prior reviews exist on the topic of neuroimaging findings in PTSD, the present review synthesizes that work through the lens of emotion and its regulation. Studies that employed tasks of emotional responding and symptom provocation, implicit regulation (e.g., emotional Stroop and interference), explicit regulation (e.g., cognitive reappraisal), and fear conditioning/extinction were reviewed. Findings demonstrate that emotion dysregulation in PTSD arises from complications within a large neurocircuitry involving the amygdala, insula, hippocampus, anterior cingulate cortex, and prefrontal cortex. Although an exaggerated response in the amygdala and insula to negative emotional triggers is pervasive, PTSD is also marked by deficient appraisal, resolution, and management of negative emotional states subserved by the anterior cingulate cortex and prefrontal cortex during regulation. These findings further support the importance of studying emotion-regulation deficits in tandem with exaggerated symptom provocation in order to better understand the constellation of symptoms present in those with PTSD.

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... In this regard, one of the most replicable findings in fMRI studies of PTSD refers to increased amygdala activity across different task paradigms in comparison to TC and HC groups (for reviews see, Fitzgerald et al., 2018;Henigsberg et al., 2019;Sheynin & Liberzon, 2017;Stark et al., 2015). As the amygdala region is highly involved in emotional processes, such as salience detection (especially stimuli associated with danger) it is reasonable to assume that hyperactivity in this system may potentially place an individual at greater risk of developing maladaptive behaviors (McCrory et al., 2017). ...
... Nevertheless, a meta-analysis by Stark et al. (2015) that separated studies by type of control group, (PTSD vs. TC vs. HC) found changes in activity in the amygdala and parahippocampal cortex to distinguish PTSD from both control groups (Stark et al., 2015). With regard to the anterior insula, an amount of studies have found increased activation in PTSD patients across different emotional and cognitive paradigms compared to TC groups (for review see, Akiki et al., 2017;Fitzgerald et al., 2018). As already mentioned, the anterior insula is considered to be involved in cognitive-emotional network interactions and may be important for effective modulation of attention in the presence of emotional stimuli during executive control tasks (Akiki et al., 2017;Smith et al., 2014). ...
... As already mentioned, the anterior insula is considered to be involved in cognitive-emotional network interactions and may be important for effective modulation of attention in the presence of emotional stimuli during executive control tasks (Akiki et al., 2017;Smith et al., 2014). Exaggerated insula activation when challenged with emotional stimuli has further been considered to specifically contribute to states of emotional undermodulation, including hypervigilance, re-experience and hyperarousal symptoms (Fitzgerald et al., 2018;Lanius et al., 2015). ...
Thesis
Approximately 70% of the general population experience a traumatic event during lifetime. However, only a small proportion develop Posttraumatic Stress Disorder (PTSD) (5.6%). Considerable efforts have been made to investigate individual differences as well as characteristics of the trauma itself that both may contribute to the development of PTSD. The experience of child maltreatment (CM) in contrast to the experience of a traumatic event during adulthood has repeatedly found to be correlated to significant higher rates of PTSD. On a neurocognitive level, cognitive dysfunctions together with functional and structural brain alterations seem to characterize individuals with PTSD compared to traumatized healthy subjects. Although a cumulative effect of trauma can be assumed, the role of type and timing of CM has become of particular interest when investigating neurocognitive correlates contributing to the development of PTSD. Emerging evidence points to sensitive periods and specificity of CM-subtypes to differentially impact neurocognitive correlates in individuals with and without PTSD. However, research is still at a very early stage. The development of PTSD in the aftermath of prolonged and severe CM is often associated with clinical features that extend beyond classic PTSD symptoms such as affective dysregulation, negative self-concept and disturbances in relationships. This complex form of PTSD (cPTSD) has therefore been included in the 11th revision of the World Health Organization’s International Classification of Diseases (ICD-11). Numerous studies in PTSD patients related to various trauma types have already provided evidence for neurocognitive alterations. However, the empirical database on neurocognitive correlates of cPTSD is quite limited at this time. Understanding alterations in cognitive and neural processes could optimize treatments in order to improve long-term outcomes of individuals with cPTSD. Several psychotherapeutic approaches have been developed for PTSD treatment and have been shown to be successful in treating PTSD symptoms as well as neurocognitive alterations. However, those treatments have mostly been developed for survivors of adult-trauma PTSD. Meta-analyses demonstrated substantially lower effect sizes of psychotherapeutic treatments in CM-related cPTSD indicating poorer treatment response. Even though preliminary data point to the effectiveness of psychotherapy on normalizing neurocognitive correlates in cPTSD patients, these data are in clear need of replication. To fill this gap, the aim of the doctoral thesis was to examine the long-term sequelea of CM with an emphasis on neurocognitive correlates of CM-related PTSD and cPTSD and the impact of psychotherapy on these measures. For this purpose, three experimental studies were conducted. Two studies investigated the role of cPTSD and CM history on neurocognitive correlates. Study I investigated the role of psychopathology and CM history on functional correlates of cognitive control and emotional interference. Study II focused on the effects of CM on structural brain correlates with an emphasis on type and timing of traumatization. The third study aimed to examine whether 12 months of psychotherapy (DBT-PTSD or CPT) lead to an improvement of neurocognitive alterations in patients with cPTSD. In study I, patients with cPTSD showed poorer behavioral outcome and an increased need for activation within prefrontal cognitive control networks, while confronted with trauma-related stimuli as compared to healthy controls with and without CM history. After 12 months of psychotherapy (study III), the pathologically increased emotional interference in cPTSD patients was found to be “normalized” on both neuronal and behavioral measures (reflected in faster reaction times, less errors and decreased activation within limbic and prefrontal brain regions). It can be concluded that psychotherapy helped patients by working with trauma-related memories, cognitions and emotions to integrate new adaptive information to distinguish between threat and safety to habituate towards trauma-related material. Regarding structural brain correlates of CM, study II demonstrated a negative correlation between global CM severity and bilateral amygdala volume. Interestingly, this effect was driven by the severity of neglect. Moreover, results point to an effect of timing of CM exposure at 10-11 years of age and 13 years of age, for both bilateral amygdala and hippocampal volume. Regarding type x timing analyses, results revealed sensitive periods during 10-12 years of age and 13-14 years of age for the severity of neglect, affecting right amygdala volume. Moreover, results point to a sensitive period during 14 - 16 years of age for the severity of neglect affecting left amygdala volume. Likewise, a sensitive time window for the severity of neglect were identified during 9-13 years of age, affecting bilateral hippocampal volume. The results of the present thesis provide further support that exposure to CM lead to long-term stress-induced cumulative changes in the neurobiological system. Moreover, the results provide further evidence for a type and timing model of CM, as a complementary approach in the understanding of the impact of CM across the entire lifespan on neurocognitive correlates. Longitudinal studies, however, are needed to get insight on causal relationships.
... Починає превалювати «звична» пам'ять, залежна від смугастого мозку, а не «когнітивна» пам'ять, що визначається гіпокампом. Підвищений страх і збудження є корелятами гіперактивності мигда лини та дорсальної передньої поясної звивини, імовірно через втрату контролю «зверху -вниз» через гіпоактивність префронтальної кори, а також через порушення зникнення страху внаслі док дисфункції медіальної префронтальної кори і гіпокампу [28]. ...
... Мережа пасивної роботи мозку (мережа режиму за замовчуванням) (рис.1) просторово охоплює важливі області в задній поясній корі, медіальній префронтальній корі і медіальній скро невій частці, включаючи гіпокамп [28]. Відомо, що в осіб із ПТСР режим за замовчуванням є гіпо активним і слабко взаємопов'язаним, що, мож ливо, визначає симптоми дисоціації, уникнення та нав'язливості. ...
... Зміни мигдалини, острівця, гіпокампу, пере дньої цингулярної кори та префронтальної кори демонструють, що порушення регуляції емоцій при ПТСР виникає внаслідок ускладнень у вели кій нейромережі. Хоча ПТСР характеризується підвищеним виявленням негативних емоцій, це принципове порушення існує поряд із недоліком в оцінці, розв'язанні та управлінні негативними емоційними станами [28]. ...
Article
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Relevance. Posttraumatic stress disorder (PTSD) occurs in people who have suffered a traumatic event (during war, natural disaster, domestic violence, etc.) sometimes even many years after the injury, causing changes in psychological and behavioral levels. Objective is to consider current data on the prevalence, pathophysiology and therapy of patients with PTSD. Methods. Analysis of data presented by PubMed by keywords "posttraumatic stress", "prevalence", "pathophysiology", "psychotherapy", "psychopharmacology". Results. PTSD is observed in 5-10% of the population, twice as often in women than in men, among children PTSD is found in 10%, in girls 4 times more often than in boys. During the war, PTSD is most often associated with stressful events such as bombing, homelessness, sieges, and combat. The highest prevalence of PTSD was among widows and widowers, divorcees, the unemployed and retirees. Hereditary sources of PTSD risk are shown on the basis of general genomic and epigenomic associations, transcriptomic and neuroimaging studies. Changes in the amygdala, islet, hippocampus, anterior cingulate cortex, and prefrontal cortex demonstrate that emotional dysregulation in PTSD occurs due to complications in the large neural network. Methods of non-pharmacological therapy of PTSD are presented and the effectiveness of drugs of different groups (antidepressants; antipsychotics; drugs that affect sympathetic activity, endocannabinoid system, etc.) is described. Conclusions. Posttraumatic stress disorder is a common disorder that is often undiagnosed, leading to significant psychological and behavioral disorders, increasing the risk of suicide. The review presents modern ideas about its pathophysiology and treatment options.
... Threat-related modulation of the LPP in those with post-traumatic stress symptoms (PTSS) or PTSD has been examined in several studies (Fitzgerald et al., 2018;Grasso and Simons, 2012;Lobo et al., 2014;Macatee et al., 2020;MacNamara et al., 2013). Although the expected within-subject LPP enhancement during threat processing was found in each study, associations between individual differences in threat-related LPP modulation and PTSD were inconsistent, with negative (MacNamara et al., 2013), positive (Fitzgerald et al., 2018;Lobo et al., 2014;Macatee et al., 2020), null (Grasso and Simons, 2012), and even quadratic (Macatee et al., 2020) relations reported. ...
... Threat-related modulation of the LPP in those with post-traumatic stress symptoms (PTSS) or PTSD has been examined in several studies (Fitzgerald et al., 2018;Grasso and Simons, 2012;Lobo et al., 2014;Macatee et al., 2020;MacNamara et al., 2013). Although the expected within-subject LPP enhancement during threat processing was found in each study, associations between individual differences in threat-related LPP modulation and PTSD were inconsistent, with negative (MacNamara et al., 2013), positive (Fitzgerald et al., 2018;Lobo et al., 2014;Macatee et al., 2020), null (Grasso and Simons, 2012), and even quadratic (Macatee et al., 2020) relations reported. In addition to heterogeneity in trauma-exposed samples, these inconsistencies may be due in part to variability in tasks and stimuli used to elicit the LPP. ...
... In addition to heterogeneity in trauma-exposed samples, these inconsistencies may be due in part to variability in tasks and stimuli used to elicit the LPP. Two of the five studies used a task that involved matching threatening facial expressions to quantify the LPP (Macatee et al., 2020;MacNamara et al., 2013), whereas the other three used more complex, threatening scene stimuli and asked participants to view, maintain, and/or reappraise their emotional response (Fitzgerald et al., 2018;Grasso and Simons, 2012;Lobo et al., 2014). If threat-related modulation of the LPP is a neurophysiological indicator of a single construct (i.e., motivated attention towards threat), it should be correlated across tasks, but to our knowledge this has never been examined in healthy or trauma-exposed samples. ...
Article
Trauma exposure is prevalent, associated with multiple forms of psychopathology, and thought to alter the neurobiological substrates of threat processing. The late positive potential (LPP) is an event-related potential (ERP) that may be a clinically useful probe of the neurobiology of threat processing. Despite evidence that combat-exposed veterans exhibit aberrant threat modulation of the LPP, no studies to date have tested the psychometric properties of the LPP in combat trauma-exposed, symptomatic veterans. The primary aim of the current study was to evaluate the reliability (internal consistency, retest reliability) and convergent validity of LPP modulation by threatening faces and scenes in two common tasks among combat-exposed veterans. Participants included 82 combat-exposed veterans who completed face-matching and emotion regulation tasks during EEG recording at baseline and twelve weeks. Internal consistencies of the early LPP time windows (<1000 ms) were acceptable in both tasks, whereas they were poor in late time windows (>1000 ms). Twelve-week retest reliabilities were fair for the early window LPPs to threatening scenes and fear faces, as well as in the late time window for fear faces. Reliabilities were better for individual condition compared to difference scores. Finally, LPPs modulated by threatening scenes and faces were unrelated. Together, these results suggest that the LPPs to threatening scenes and faces reflect distinct forms of threat processing in combat-exposed veterans, and their reliabilities for the early window indicate potential clinical utility in this population.
... Pre-trauma protective factors. The amygdala is widely studied in trauma research due to its role in responding to threatening stimuli and the expression of fear (for review, see ref. [13]). It has been hypothesized that individual differences in the structure and function of the amygdala may contribute to stress resilience, such that individuals who show less threat reactivity may be more resilient after trauma [14]. ...
... Similarly, the ventromedial prefrontal cortex (vmPFC) and its connections with the amygdala or hippocampus may be important contributors to adaptive threat responses. The vmPFC implements top-down control over fear-related regions like the amygdala, and helps to adaptively modulate threat responses [13]. A recent study found that greater vmPFC activation pre-combat training positively predicted resilience to stress symptoms post-training [26]. ...
... Amygdala-PFC connectivity, and PFC sub areas, has previously been supported as a resilience factor [60]. The vmPFC is suggested to inhibit fear responses via the amygdala [13]. Concurrently, DTI studies point to greater amygdala-PFC or Uf structural connectivity as a protective factor for resilience, as measured by fewer PTSD symptoms [61]. ...
Article
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Resilience in the face of major life stressors is changeable over time and with experience. Accordingly, differing sets of neurobiological factors may contribute to an adaptive stress response before, during, and after the stressor. Longitudinal studies are therefore particularly effective in answering questions about the determinants of resilience. Here we provide an overview of the rapidly-growing body of longitudinal neuroimaging research on stress resilience. Despite lingering gaps and limitations, these studies are beginning to reveal individual differences in neural circuit structure and function that appear protective against the emergence of future psychopathology following a major life stressor. Here we outline a neural circuit model of resilience to trauma. Specifically, pre-trauma biomarkers of resilience show that an ability to modulate activity within threat and salience networks predicts fewer stress-related symptoms. In contrast, early post-trauma biomarkers of subsequent resilience or recovery show a more complex pattern, spanning a number of major circuits including attention and cognitive control networks as well as primary sensory cortices. This novel synthesis suggests stress resilience may be scaffolded by stable individual differences in the processing of threat cues, and further buttressed by post-trauma adaptations to the stressor that encompass multiple mechanisms and circuits. More attention and resources supporting this work will inform the targets and timing of mechanistic resilience-boosting interventions.
... This is supported by previous research examining PTSD brain correlates during both scriptdriven imagery and the recall of trauma-related autobiographical memories in PTSD (Hopper et al., 2007a;Lanius et al., 2007;Frewen et al., 2011;Mickleborough et al., 2011;Ramage et al., 2013;Liberzon and Abelson, 2016;Fenster et al., 2018;Thome et al., 2019). Interestingly, in the current study, we found evidence to suggest that downregulating the PCC during trauma word presentation resulted in a normalization of this PTSD neural signature, with decreased activation in aforementioned DMN regions involved in self-related and autobiographical memory processing (bilateral dmPFC and hippocampus) as well as in SN areas involved in emotional arousal, emotion evaluation, salience monitoring and innate fight-or-flight defensive responses (amygdala and mid-cingulate cortex) (Liddell et al., 2005;Etkin et al., 2011;Lanius et al., 2015Lanius et al., , 2017Fitzgerald et al., 2018;Hinojosa et al., 2019). Activation in the dmPFC occurs during self-related emotion processing and exposure to negative content, and additionally, is involved in evaluating self-related emotional experience (Fitzgerald et al., 2018). ...
... Interestingly, in the current study, we found evidence to suggest that downregulating the PCC during trauma word presentation resulted in a normalization of this PTSD neural signature, with decreased activation in aforementioned DMN regions involved in self-related and autobiographical memory processing (bilateral dmPFC and hippocampus) as well as in SN areas involved in emotional arousal, emotion evaluation, salience monitoring and innate fight-or-flight defensive responses (amygdala and mid-cingulate cortex) (Liddell et al., 2005;Etkin et al., 2011;Lanius et al., 2015Lanius et al., , 2017Fitzgerald et al., 2018;Hinojosa et al., 2019). Activation in the dmPFC occurs during self-related emotion processing and exposure to negative content, and additionally, is involved in evaluating self-related emotional experience (Fitzgerald et al., 2018). Moreover, the dmPFC has been shown generally to subserve functions related to the appraisal and expression of fear and anxiety (Etkin et al., 2011). ...
... Recent meta-analyses have also reported that the mid-cingulate cortex is hyperactive in PTSD, with both correlations to PTSD severity and trauma exposure (Hayes et al., 2012;Patel et al., 2012;Hinojosa et al., 2019). Furthermore, several studies have found evidence of enhanced hippocampal engagement during exposure to trauma-specific images, as well as increased activation during reexperiencing and retrieval of trauma-related autobiographical memories (Hou et al., 2007;Nilsen et al., 2016;Fitzgerald et al., 2018;Thome et al., 2019). With respect to the amygdala, due to its hyperactivity in close association with symptoms of PTSD and hyperarousal (Hayes et al., 2012;Fenster et al., 2018;Fitzgerald et al., 2018;Henigsberg et al., 2018) and its involvement with the innate alarm system in the salient detection of threat (Liddell et al., 2005;Lanius et al., 2017), this limbic region has been a frequent target of previous rt-fMRI-NFB studies in PTSD (Gerin et al., 2016;Nicholson et al., 2016aNicholson et al., , 2018Misaki et al., 2018bMisaki et al., , 2019Zotev et al., 2018;Chiba et al., 2019). ...
Article
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Background Intrinsic connectivity networks, including the default mode network (DMN), are frequently disrupted in individuals with posttraumatic stress disorder (PTSD). The posterior cingulate cortex (PCC) is the main hub of the posterior DMN, where the therapeutic regulation of this region with real-time fMRI neurofeedback (NFB) has yet to be explored. Methods We investigated PCC downregulation while processing trauma/stressful words over 3 NFB training runs and a transfer run without NFB (total n = 29, PTSD n = 14, healthy controls n = 15). We also examined the predictive accuracy of machine learning models in classifying PTSD versus healthy controls during NFB training. Results Both the PTSD and healthy control groups demonstrated reduced reliving symptoms in response to trauma/stressful stimuli, where the PTSD group additionally showed reduced symptoms of distress. We found that both groups were able to downregulate the PCC with similar success over NFB training and in the transfer run, although downregulation was associated with unique within-group decreases in activation within the bilateral dmPFC, bilateral postcentral gyrus, right amygdala/hippocampus, cingulate cortex, and bilateral temporal pole/gyri. By contrast, downregulation was associated with increased activation in the right dlPFC among healthy controls as compared to PTSD. During PCC downregulation, right dlPFC activation was negatively correlated to PTSD symptom severity scores and difficulties in emotion regulation. Finally, machine learning algorithms were able to classify PTSD versus healthy participants based on brain activation during NFB training with 80% accuracy. Conclusions This is the first study to investigate PCC downregulation with real-time fMRI NFB in both PTSD and healthy controls. Our results reveal acute decreases in symptoms over training and provide converging evidence for EEG-NFB targeting brain networks linked to the PCC.
... After accounting for all covariates, the observed task activation during anticipation and stimulus presentation periods was consistent with the literature on trauma-exposed populations, with greater activation to negative than to neutral stimuli in the occipital and frontal cortices (41)(42)(43)(44). Some studies have found that hypervigilance to threat-related stimuli in PTSD can bias attention resources or require additional effort to disengage (42,(45)(46)(47)(48)(49). However, others have found this same pattern for those who have experienced trauma broadly, regardless of PTSD diagnosis (41)(42)(43)(44). ...
... Although common posttrauma outcomes such as PTSD have frequently been shown to lead to hyperactivity in threat processing (47,48), this body of work has largely overlooked factors related to preexisting functioning and adaptations of threat-processing neural circuitry (4). The inclusion of pretrauma context (i.e., neighborhood disadvantage) and PTSD symptom severity as covariates in this study may help explain why we observed less activation in threat-related neural circuitry compared with the existing literature. ...
... Further analysis of stimulus presentation effects showed that for predictable negative and neutral stimuli, higher ADI rankings were related to less activation of the ACC and posterior cingulate cortex, respectively. The ACC is critical for prediction of stimuli and execution of decision making in uncertainty (47,51). The posterior cingulate cortex is a critical node of the default mode network shown to be vulnerable to stress wherein reduced activity impairs top-down emotion regulation (52). ...
Article
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Background: Individuals residing in more socioeconomically disadvantaged neighborhoods experience greater uncertainty through insecurity of basic needs such as food, employment, and housing, compared with more advantaged neighborhoods. Although the neurobiology of uncertainty has been less frequently examined in relation to neighborhood disadvantage, there is evidence that neighborhood disadvantage is associated with widespread neural alterations. Methods: Recently traumatically injured participants (n = 90) completed a picture anticipation task in the magnetic resonance imaging scanner, in which they viewed images presented in a temporally predictable or unpredictable manner. We investigated how neighborhood disadvantage (via area deprivation index [ADI]) was related to neural activation during anticipation and presentation of negative and neutral images after accounting for individual factors (i.e., age, gender, income, acute posttraumatic stress symptoms). Results: There was a significant interaction during the anticipation period such that higher ADI rankings were related to greater activation of the right anterior cingulate cortex to predictable versus unpredictable neutral stimuli. Although no other robust interactions emerged related to ADI, we note several novel simple effects of ADI during anticipation and presentation periods in the hippocampus and prefrontal, cingulate, and occipital cortices. Conclusions: Together, these results may represent an adaptive response to predictable and/or negative stimuli, stemming from chronic exposure to socioeconomic-based uncertainties. Although effects were modest, future work should continue to examine pretrauma context on posttrauma outcomes. To better understand trauma outcomes, it is imperative that researchers consider the broader context in which trauma survivors reside.
... T he ability to control emotional responses is crucial for adaptive behaviour, especially when one is confronted with adverse or stressful situations. PTSD is characterized by reduced prefrontal activation and aberrant emotion regulation abilities [1][2][3] . However, it is currently unclear to what extent prefrontal emotion regulation capabilities form a predisposing factor, protecting against the development of post-traumatic stress symptoms after trauma, or whether individual differences in emotion regulation are rather acquired, forming a consequence of trauma exposure. ...
... Also, structural and functional abnormalities in the vmPFC and changes in its connectivity with the hippocampus have been suggested to be acquired rather than predisposing 5 . However, these studies investigated threat/reward anticipation 37 or passive processing of emotional stimuli 36,38 but did not test active emotion regulation by the prefrontal cortex, despite its key role in PTSD 2,3 . Therefore, the aim of the present prospective longitudinal study is to test whether relatively high frontal activation and relatively low amygdala activation during emotional action control constitute resilience factors against the development of post-traumatic stress symptoms. ...
Article
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Regulating social emotional actions is essential for coping with life stressors and is associated with control by the anterior prefrontal cortex (aPFC) over the amygdala. However, it remains unclear to what extent prefrontal emotion regulation capacities contribute to resilience against developing post-traumatic stress disorder (PTSD) symptoms. Here, 185 police recruits who experienced their core trauma in the line of duty participated in a prospective longitudinal study. Pre- and post-trauma, they performed a well-established functional magnetic resonance imaging (fMRI) approach–avoidance task, mapping impulsive and controlled emotional actions. Higher baseline aPFC, dorsal and medial frontal pole activity was related to lower PTSD symptoms after trauma exposure. aPFC activity predicted symptom development over and above self-reported and behavioural measures. Trauma exposure, but not trauma symptoms, predicted amygdala activation at follow-up. These findings suggest that prefrontal emotion regulation activity predicts increased resilience against developing post-traumatic stress symptoms and may provide fruitful starting points for prediction and intervention studies.
... The hippocampus shows a decline in volume in PTSD but may be more metabolically active nonetheless [5]. This activity seems to be related to stimulus type, as there is less engagement of the hippocampus in response to positive images [6]. Stress in both humans and animal models plays a significant role in sculpting all of these regions from the level of regional volumes down to the relative exuberance of dendritic arbors or the birth of new neurons [7,8]. ...
... Accelerated development of fear learning has an obvious relationship with PTSD and other stress and anxiety disorders, as PTSD is characterized by impaired capacity to extinguish fear learning [20]. In healthy individuals, exposure to negative stimuli predominantly activates the amygdala, insula, hippocampus, anterior cingulate cortex (ACC), and ventromedial prefrontal cortex (vmPFC) [6]. In addition to dysfunction of brain regions, white matter abnormalities and reduced regional volumes are also present in PTSD, particularly in the anterior cingulate cortex (ACC) and hippocampus (regions vital to contextual fear conditioning and extinction learning), with the amygdala showing a more complex response to accumulated trauma. ...
Chapter
Post-Traumatic Stress Disorder is characterized by low levels of cortisol and high HPA reactivity to stress although most individuals exposed to trauma will not develop the disorder. Childhood trauma and abuse is significantly associated with risk of PTSD and those with a history of abuse may represent a biologically distinct subtype of the disorder. Risk of PTSD can be transmitted across generations as exemplified by the survivors of the Holocaust and Dutch hunger winter. Epigenetic effects are present in the brain and other tissues in response to stress and trauma. New research is exploring novel therapies like mindfulness-based stress reduction, MDMA, cannabinoids, and other pharmaceuticals to target the epigenetic patterns present in PTSD.
... Importantly, a wide body of evidence suggests a dynamic interplay among cognitive dysfunction, difficulties with ER, and symptoms of PTSD, where numerous studies have identified overlapping patterns of alterations in activation among neuroanatomical regions [15,[47][48][49][50][51][52][53] and large-scale neural circuitry [54][55][56][57]. Here, reductions in activation of pre-frontal cortical regions, such as the medial pre-frontal cortex and the rostral anterior cingulate cortex, have been associated with decreases in top-down control of emotion processing and regulation centres of the brain, such as the amygdala and other limbic regions [15,50,51]. ...
... Disruption to these networks may confer difficulties with top-down cognitive control and bottom-up regulation, subsequently disrupting both cognitive function and ER [52,[55][56][57]. In many instances, for example, the ability to successfully regulate emotions is dependent on the ability to inhibit a pre-potent response and executive control [80,81]. ...
Article
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Post-traumatic stress disorder (PTSD) is a severe psychiatric illness that disproportionately affects military personnel, veterans, and public safety personnel (PSP). Evidence demonstrates that PTSD is significantly associated with difficulties with emotion regulation (ER) and difficulties with cognitive functioning, including difficulties with attention, working memory, and executive functioning. A wide body of evidence suggests a dynamic interplay among cognitive dysfunction, difficulties with ER, and symptoms of PTSD, where numerous studies have identified overlapping patterns of alterations in activation among neuroanatomical regions and neural circuitry. Little work has examined interventions that may target these symptoms collectively. The primary objective of this pilot randomized controlled trial (RCT) with a parallel experimental design was to assess the effectiveness of goal management training (GMT), a cognitive remediation intervention, in reducing difficulties with cognitive functioning, and to determine its effects on PTSD symptoms and symptoms associated with PTSD, including difficulties with ER, dissociation, and functioning among military personnel, veterans, and PSP. Forty-two military personnel, veterans, and PSP between the ages of 18 and 70 with symptoms of PTSD were recruited across Ontario, Canada between October 2017 and August 2019. Participants were randomized to either the waitlist (WL) (n = 18) or the GMT (n = 22) condition. Participants in both conditions received self-report measures and a comprehensive neuropsychological assessment at baseline, post-intervention, and 3-month follow-up. Following their completion of the 3-month follow-up, participants in the WL condition were given the opportunity to participate in GMT. Assessors and participants were blind to intervention allocation during the initial assessment. A series of 2 (time) × 2 (group) ANOVAs were conducted to assess the differences between the WL and GMT conditions from pre- to post-intervention for the self-report and neuropsychological measures. The results demonstrated significant improvements in measures of executive functioning (e.g., verbal fluency, planning, impulsivity, cognitive shifting, and discrimination of targets) and trending improvements in short-term declarative memory for participants in the GMT condition. Participants in the GMT condition also demonstrated significant improvements from pre- to post-testing in measures of subjective cognition, functioning, PTSD symptom severity, difficulties with ER, dissociative symptom severity, and depression and anxiety symptoms. No adverse effects were reported as a result of participating in GMT. The results of this pilot RCT show promise that GMT may be a useful intervention to improve symptoms of cognitive dysfunction, symptoms of PTSD, and symptoms associated with PTSD within military personnel, veterans, and PSP. Future work is needed to address the small sample size and the durability of these findings.
... Other cortical regions, like the insula cortex, which receives interoceptive information from the viscera and body, are also important (Fitzgerald et al., 2018) and have reciprocal connections with the amygdala. The insula cortex is hyperactive in anxiety and trauma disorders to provocation (Fitzgerald et al., 2018). ...
... Other cortical regions, like the insula cortex, which receives interoceptive information from the viscera and body, are also important (Fitzgerald et al., 2018) and have reciprocal connections with the amygdala. The insula cortex is hyperactive in anxiety and trauma disorders to provocation (Fitzgerald et al., 2018). Evidence from kindling studies indicates that development of kindled seizures is first propagated from amygdala to the insula cortex during the early stages of kindling when only arrest/immobile behavior is generated (O'Shea et al., 2000;Foster et al., 2004), suggesting amygdala hyperexcitability readily recruits the insula cortex, which then also becomes hyperresponsive to threatening stimuli. ...
Article
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Hyperexcitability in fear circuits is suggested to be important for development of pathological anxiety and trauma from adaptive mechanisms of fear. Hyperexcitability is proposed to be due to acquired sensitization in fear circuits that progressively becomes more severe over time causing changing symptoms in early and late pathology. We use the metaphor and mechanisms of kindling to examine gains and losses in function of one excitatory and one inhibitory neuropeptide, corticotrophin releasing factor and somatostatin, respectively, to explore this sensitization hypothesis. We suggest amygdala kindling induced hyperexcitability, hyper-inhibition and loss of inhibition provide clues to mechanisms for hyperexcitability and progressive changes in function initiated by stress and trauma.
... When shown negative stimuli, hippocampal/parahippocampal activity is heightened [17,18], and this increased activity is correlated with increased amygdala activation in some instances [12,19], though overall, there may be decreased coupling of the hippocampus and amygdala in PTSD [20]. Together, these findings indicate that in PTSD, individuals view negative stimuli as excessively important or salient, have increased reactivity to them, have less frontal lobe mitigation of this reactivity, and may experience stimuli as having more personal or autobiographical significance [21]. Such alterations result in downstream effects including abnormal stress response mechanisms as evidenced by alterations in urinary free cortisol and catecholamine levels [22]. ...
... Because Default Mode Network (DMN) activity is heightened during internally-focused processes such as autobiographical memory and mind-wandering, it has become a focus of study in a variety of psychiatric illnesses including PTSD [92][93][94]. As also discussed in Section 1, specific network alterations in PTSD include a poorly integrated DMN which is destabilized by increased Salience Network activity that assigns excess importance to given stimuli [95], and negative stimuli in particular [17,18,21]. It is not yet studied how psychedelics affect this particular network relationship in PTSD. ...
Article
Post-traumatic stress disorder (PTSD) is a debilitating mental illness with limited treatment options and a high treatment dropout rate. Psychedelics, often in combination with psychotherapy, are now under investigation as a potential treatment option for a variety of psychiatric conditions including PTSD. This paper reviews the proposed mechanism of action for 3,4-Methylenedioxymethamphetamine (MDMA) and classical psychedelics such as psilocybin in treating PTSD, along with available clinical evidence, safety and side effects. MDMA-assisted psychotherapy is in FDA phase III clinical trials for PTSD and is purported to work by way of increased empathy and decreased amygdala activation during the therapeutic encounter and trauma processing. Classical psychedelics may create change by a subjective transformative experience along with an observable process of brain network alterations, though these substances have not been clinically studied in the context PTSD. In recent human-subject studies MDMA-assisted therapy resulted in significant improvement in PTSD symptoms with a good safety and side effect profile. There is not yet direct clinical evidence for classical psychedelics in treating PTSD, but the evidence supports such a trial. The studies to date have been relatively small, and participants are wellscreened for potential co-morbidities which could increase the risks of psychedelic treatment. Nonetheless, the data is promising for psychedelic-assisted treatment to become a much-needed treatment option for PTSD.
... Overall, the identification of separable, individual-specific coupling from the Frontoparietal network and Language network to the DMN suggests that the DMN does not operate in isolation but may be instantiated or regulated by inputs from control and Language networks. This conceptualization paves the way for testing hypotheses about these Frontoparietal network-DMN and Language-DMN interactions in disorders such as posttraumatic stress disorder (PTSD), in which lateral prefrontal-mediated top-down regulation of emotions is deficient (80), but verbal processing of memories can reduce intrusive symptoms (81). It also suggests that these network-network interactions may be specifically modifiable via treatments such as transcranial magnetic stimulation that can target individual-specific DMN subnetworks. ...
Article
The human brain is organized into large-scale networks identifiable using resting-state functional connectivity (RSFC). These functional networks correspond with broad cognitive domains; for example, the Default-mode network (DMN) is engaged during internally oriented cognition. However, functional networks may contain hierarchical substructures corresponding with more specific cognitive functions. Here, we used individual-specific precision RSFC to test whether network substructures could be identified in 10 healthy human brains. Across all subjects and networks, individualized network subdivisions were more valid—more internally homogeneous and better matching spatial patterns of task activation—than canonical networks. These measures of validity were maximized at a hierarchical scale that contained ∼83 subnetworks across the brain. At this scale, nine DMN subnetworks exhibited topographical similarity across subjects, suggesting that this approach identifies homologous neurobiological circuits across individuals. Some DMN subnetworks matched known features of brain organization corresponding with cognitive functions. Other subnetworks represented separate streams by which DMN couples with other canonical large-scale networks, including language and control networks. Together, this work provides a detailed organizational framework for studying the DMN in individual humans.
... The authors collate extensive evidence for the strong associations between psychopathology and emotion dysregulation (Aldao, Gee, De Los Reyes, & Seager, 2016;Beauchaine, 2015;Cline et al., 2015;Cole, Hall, & Hajal, 2017;Silk, Steinberg, & Morris, 2003). Difficulties with emotion regulation have been consistently described in relation to many diagnosed conditions: substance abuse (Weiss, Williams, & Connolly, 2015), eating disorders (Seidel et al., 2018;Svaldi, Griepenstroh, Tuschen-Caffier, & Ehring, 2012), depression (Lopez, Luby, Belden, & Barch, 2018), anxiety (Kircanski et al., 2018), posttraumatic stress disorder (Fitzgerald, DiGangi, & Phan, 2018), attention-deficit hyperactivity disorder (Steinberg & Drabick, 2015), conduct disorder (Beauchaine, Gatzke-Kopp, & Mead, 2007), borderline personality disorder (Herpertz, Schneider, Schmahl, & Bertsch, 2018;van Zutphen et al., 2018), and psychotic disorders (Kring & Caponigro, 2010;Nook, Dodell-Feder, Germine, Hooley, DeLisi, & Hooker, 2018). ...
Article
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In this article I will discuss, departing from the usual disintegration of the newborn’s experiences, how one can model the integration of different forms of memory, sensory channels, and mode of representation of these early experiences. Based on the inborn semiotics of the affect system, I pursue the idea that the affect expression of the mother comprises the organizational nucleus of the child’s future personality, and that the representational format of the very young child comprises the mother’s faces and vocalizations. In the aftermath of parental projections, the baby is confronted with plenty of dominant affect expressions, for example contempt, disgust, anger, and fear. These act in contrast to happiness in terms of guiding the affect expression of secure attachment. Following Tomkins, I call these interaction schemes “emotional scripts” and demonstrate that they are carried on into adulthood. Here I launch and discuss four clinical vignettes that can be characterized as being governed by such an “emotional script.” I try to show that these scripts can be redrafted if the governing affect can be exchanged with a different one. These considerations have led to a revised form of the procedure called “splitting.” In addition, implications for treatment techniques are depicted.
... Importantly, among different types of childhood trauma, emotional abuse was most strongly associated with negative affectivity and emotion dysregulation in later life (28)(29)(30). Finally, prior work supports the role of emotion dysregulation as a possible mechanism by which early emotional and physical maltreatment impacts later substance use disorder (31,32). ...
Article
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Introduction: Several studies have confirmed that the experience of childhood trauma, poor emotion regulation, as well as the experience of physical pain may contribute to the development and poor treatment outcomes of alcohol use disorder (AUD). However, little is known about how the joint impact of these experiences may contribute to AUD. Objectives: To analyze associations between childhood trauma, emotion regulation, and pain in individuals with AUD. Methods: The study sample included 165 individuals diagnosed with AUD. The Childhood Trauma Questionnaire (CTQ) was used to investigate different types of trauma during childhood (physical, emotional, and sexual abuse and neglect), the Brief Symptom Inventory was used to assess anxiety symptoms, the Difficulties in Emotion Regulation Scale (DERS) was used to assess emotional dysregulation, and the Pain Resilience Scale and Pain Sensitivity Questionnaire were used to measure self-reported pain tolerance and sensitivity. Results: Childhood emotional abuse (CTQ subscale score) was positively associated with anxiety, anxiety was positively associated with emotional dysregulation, and emotional dysregulation was negatively associated with pain tolerance. Accordingly, there was support for a significant indirect negative association between childhood emotional abuse and pain tolerance. The serial mediation statistical procedure demonstrated that anxiety and emotional dysregulation mediated the effect of childhood emotional abuse on pain resilience among individuals with AUD. Conclusions: Targeting emotional dysregulation and physical pain that can result from childhood trauma may have particular therapeutic utility among individuals treated for AUD.
... Since, the insula is commonly associated with social cognition, empathy and emotion processing in TD individuals it has been suggested that the insula play a generic role in the evaluation of emotional stimuli and the general production and regulation of affective states and interoceptive awareness (Craig, 2009;Fan et al., 2011;Phan et al., 2002;Phillips et al., 2003;Singer et al., 2009). Additionally, hyper-responsivity of the insula has been linked to post-traumatic stress disorder during processing of fearful and angry faces, indicating a role for exaggerated salience detection (Fitzgerald et al., 2018;Fonzo et al., 2010). The observed reduction in insula activity during emotional face processing in individuals with CD might therefore be linked to a weaker salience detection and insensitivity to affective stimuli, especially considering the insula's role in affective empathy (Fan et al., 2011). ...
Article
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Abstract Background Conduct disorder (CD) is characterized by severe aggressive and antisocial behavior. Initial evidence suggests neural deficits and aberrant eye gaze pattern during emotion processing in CD; both concepts, however, have not yet been studied simultaneously. The present study assessed the functional brain correlates of emotional face processing with and without consideration of concurrent eye gaze behavior in adolescents with CD compared to typically developing (TD) adolescents. Methods 58 adolescents (23CD/35TD; average age=16 years/range=14-19 years) underwent an implicit emotional face processing task. Neuroimaging analyses were conducted for a priori-defined regions of interest (insula, amygdala, and medial orbitofrontal cortex) and using a full-factorial design assessing the main effects of emotion (neutral, anger, fear), group and the interaction thereof (cluster-level, p<.05 FWE-corrected) with and without consideration of concurrent eye gaze behavior (i.e., time spent on the eye region). Results Adolescents with CD showed significant hypo-activations during emotional face processing in right anterior insula compared to TD adolescents, independent of the emotion presented. In-scanner eye-tracking data revealed that adolescents with CD spent significantly less time on the eye, but not mouth region. Correcting for eye gaze behavior during emotional face processing reduced group differences previously observed for right insula. Conclusions Atypical insula activation during emotional face processing in adolescents with CD may partly be explained by attentional mechanisms (i.e., reduced gaze allocation to the eyes, independent of the emotion presented). An increased understanding of the mechanism causal for emotion processing deficits observed in CD may ultimately aid the development of personalized intervention programs.
... Although not directly connected to the amygdala as much as ventral and medial portions of the PFC, the DLPFC modulates amygdala response in healthy individuals (Barbas, 2000;Ghashghaeia, Hilgetag, & Barbas, 2007;Stefanacci & Amaral, 2002). Therefore, atypical connectivity between the amygdala and the DLPFC as a predictor of PTSD severity substantiates the notion that PTSD is a disorder that is not just defined by aberrant bottom-up generation of emotional states, but also disruption in the ability to regulate emotion through top-down control (Fitzgerald, DiGangi, & Phan, 2018). ...
Article
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Introduction Resting state functional magnetic resonance imaging (rsfMRI) studies demonstrate that individuals with posttraumatic stress disorder (PTSD) exhibit atypical functional connectivity (FC) between the amygdala, involved in the generation of emotion, and regions responsible for emotional appraisal (e.g., insula, orbitofrontal cortex [OFC]) and regulation (prefrontal cortex [PFC], anterior cingulate cortex). Consequently, atypical amygdala FC within an emotional processing and regulation network may be a defining feature of PTSD, although altered FC does not seem constrained to one brain region. Instead, altered amygdala FC involves a large, distributed brain network in those with PTSD. The present study used a machine‐learning data‐driven approach, multi‐voxel pattern analysis (MVPA), to predict PTSD severity based on whole‐brain patterns of amygdala FC. Methods Trauma‐exposed adults (N = 90) completed the PTSD Checklist‐Civilian Version to assess symptoms and a 5‐min rsfMRI. Whole‐brain FC values to bilateral amygdala were extracted and used in a relevance vector regression analysis with a leave‐one‐out approach for cross‐validation with permutation testing (1,000) to obtain significance values. Results Results demonstrated that amygdala FC predicted PCL‐C scores with statistically significant accuracy (r = .46, p = .001; mean sum of squares = 130.46, p = .001; R ² = 0.21, p = .001). Prediction was based on whole‐brain amygdala FC, although regions that informed prediction (top 10%) included the OFC, amygdala, and dorsolateral PFC. Conclusion Findings demonstrate the utility of MVPA based on amygdala FC to predict individual severity of PTSD symptoms and that amygdala FC within a fear acquisition and regulation network contributed to accurate prediction.
... This finding reflects the generally observed inability to control affective states in personality disorders 25 and PTSD. 26 Intense inner pain, represented by dysphoric affects and cognitions, has been reported to be at the core of borderline personality disorder. 27 Emotional flooding could reflect the importance of affective component in personality disorders and PTSD, while suffering related cognitions might be a shared trait among many individuals seeking EAS. ...
Article
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Objectives Euthanasia and assisted suicide (EAS) of individuals with mental disorders is a growing practice in several countries, including the Netherlands. Here, we aimed to identify the most frequent dimensions of and associated factors to psychological pain, which has been associated with suicidality, in individuals undergoing psychiatric EAS. Methods An exploratory retrospective content analysis of the English translation of 66 digital case records of individuals who died by EAS in the Netherlands between 2011 and 2014 was performed. Nine standard psychological pain dimensions (irreversibility, loss of control, emptiness, emotional flooding, freezing, social distancing, narcissistic wounds, confusion, and self-estrangement), illness, and sociodemographic variables were evaluated by 2 independent raters using a premade data abstraction form (Kohen κ > 0.8 in all cases). Results The mean number of dimensions was 4.64 ± 1.20 (median = 5), out of 9. The most frequent dimensions were irreversibility, loss of control, emptiness, and emotional flooding, in decreasing order. Past treatment refusal and the mention of social connections in case descriptions were related to the higher number of psychological pain dimensions (4.89 ± 1.24 vs. 4.31 ± 1.07, P = 0.03 and 5.05 ± 1.17 vs. 4.43 ± 1.17, P = 0.03, respectively). Emotional flooding was the only dimension specifically associated with specific psychiatric conditions, namely posttraumatic phenomena and personality disorders. Conclusions Numerous psychological pain dimensions were detected in case descriptions of individuals who underwent EAS before the procedure. Subjective nature of the study precludes definite conclusions but suggest that future studies should explore psychological pain and the role of interventions targeting it in patients requesting EAS.
... Ces éléments sont d'ailleurs aujourd'hui soutenus par de nouvelles recherches en épigénétique (Tarquinio, 2019). Pour le deuxième aspect, les sensations physiques de peur émaneraient de la réponse exagérée de peur amygdalienne et l'absence de son extinction liée à la dérégulation émotionnelle induite par l'exposition traumatique (Fitzgerald et al., 2018 ;Pitman et al., 2012). En effet, au niveau amygdalien, les neurones qui codent le trauma sont constamment sous l'inhibition GABAergique. ...
Article
Lors des attaques terroristes du 11 septembre 2015, les services d’urgence ont dû faire face à un afflux important de victimes souffrant d’un Trouble de Stress Aigu (TSA). L’objectif de notre étude était de trouver des indicateurs simples et fiables pour identifier les victimes les plus à risque de développer à un mois un Trouble de Stress Post Traumatique (TSPT). Notre cohorte comprenait 82 patients à 6 mois, 127 à 18 mois et 115 (en cours de recrutement au moment de la rédaction du résumé) à 30 mois. Tous étaient présents dans la salle du Bataclan au moment des faits. Nous avons recherché tous les facteurs de risques classiquement retrouvés dans la littérature. Dans notre cohorte, 74 % des victimes souffraient d’un TSA sévère. 17 % ont été blessés physiquement pendant les attentats. La prévalence du TSPT dans la cohorte est supérieure à 60 % aux 3 étapes de l’évaluation. 3 facteurs de risques principaux sont retrouvés : un TSA sévère (RR = 3.1), un bas niveau de capacités de pleine conscience (RR = 2.4) et un soutien social faible. Les attaques terroristes induisent une prévalence de TSPT très élevée. Dans les suites d’un attentat, un niveau de stress aigu élevé devrait amener à proposer un suivi post-urgence. La prévention du TSPT passe par l’optimisation des ressources externes (soutien social) et internes (aptitude à la pleine conscience) afin d’augmenter les capacités de résilience des patients face à l’événement tragique.
... The authors collate extensive evidence for the strong associations between psychopathology and emotion dysregulation (Aldao, Gee, De Los, Reyes & Seager, 2016;Beauchaine, 2015;Cline et al., 2015;Cole, Hall & Hajal, 2017;Silk, Steinberg & Morris, 2003). Difficulties with emotion regulation have been consistently described in relation to many diagnosed conditions: substance abuse (Weiss, Williams & Connolly, 2015), eating disorder (Seidel et al., 2018;Svaldi, Griepenstroh, Tuschen-Caffier & Ehring, 2012), depression (Lopez, Luby, Belden & Barch, 2018), anxiety (Kircanski et al., 2018), post-traumatic stress disorder (Fitzgerald, DiGangi & Phan, 2018), attentiondeficit/hyperactivity disorder (Steinberg & Drabick, 2015), conduct disorder (Beauchaine, Mentalizing and emotion regulation 6 Gatzke- Kopp & Mead, 2007), borderline personality disorder (Herpertz, Schneider, Schmahl & Bertsch, 2018;van Zutphen et al., 2018) and psychotic disorders (Kring & Caponigro, 2010;Nook et al., 2018). ...
Article
Theoretical conceptualizations of mentalizing postulate a close relationship between the ability to mentalize and the regulation of emotional states. The former is viewed as a key process to modulate the latter, with the origins of the link between the two established in early attachment relationships. However, there is a lack of research testing this association empirically. In the present cross-sectional study, the hypothesis of a positive relationship between the two constructs was tested based on data collected on more than 500 nonclinical adult participants. Various self-assessments and an experimentally derived instrument of mentalizing were employed to this end. Correlational analyses confirmed the expected associations between emotion regulation and mentalizing. In addition, regression models showed that adaptive as well as maladaptive emotion regulation, independent of age, gender, and native language, could be predicted only by self-focused mentalizing.
... Lastly, there was a temporally graded pattern of task-based functional connectivity between the hippocampus and amygdala that was stronger during early training trials but then dissipated in late trials [9]. Importantly, these neural circuits have been broadly implicated in functional studies of fear conditioning, symptom provocation, and emotion regulation in PTSD [10][11][12][13] . These studies generally report a hyper-reactive salience network in PTSD, including the amygdala, anterior cingulate cortex, and insula, coupled with poor contextual and cognitive regulation of this circuit via the hippocampus and prefrontal cortex (PFC), respectively. ...
Article
Posttraumatic stress disorder (PTSD) may develop when mechanisms for making accurate distinctions about threat relevance have gone awry. Generalization across conceptually related objects has been hypothesized based on clinical observation in PTSD, but the neural mechanisms remain unexplored. Recent trauma-exposed military veterans (n = 46) were grouped into PTSD (n = 23) and non-PTSD (n = 23). Participants learned to generalize fear across conceptual categories (animals or tools) of semantically related items that were partially reinforced by shock during functional magnetic resonance imaging. Conditioned fear learning was quantified by shock expectancy and skin conductance response (SCR). Relative to veteran controls, PTSD subjects exhibited a stronger neural response associated with fear generalization to the reinforced object category in the striatum, anterior cingulate cortex, amygdala, occipitotemporal cortex, and insula (Z > 2.3; p < 0.05; whole-brain corrected). Based on SCR, both groups generalized the shock contingency to the reinforced conceptual category, but learning was not significantly different between groups. We found that PTSD was associated with an enhanced neural response in fronto-limbic, midline, and occipitotemporal regions to a learned representation of threat that is based on previously established conceptual knowledge of the relationship between basic-level exemplars within a semantic category. Behaviorally, veterans with PTSD were somewhat slower to differentiate threat and safety categories as compared with trauma-exposed veteran controls owing in part to an initial overgeneralized behavioral response to the safe category. These results have implications for understanding how fear spreads across semantically related concepts in PTSD.
... Importantly, these exacerbated responses in stress reactivity (burying and immobility) occurred 7 weeks after the initial stressful experience and did not involve exposure to the primary stressor. This detail is relevant in regard to PTSD-type behaviors because often symptomatic episodes do not result from the primary stressor but from conditioned stimuli or "triggers" associated with the original stressor that evoke memories, psychological distress, or physiological responses (Fitzgerald et al. 2018;Maren et al. 2013). Coping strategies in response to CS or "triggers" influence PTSD development. ...
Article
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RationaleThere is a robust relationship between anxiety disorders, including post-traumatic stress disorder (PTSD) and substance abuse. In fact, 30–50% of people seeking treatment for substance abuse have a comorbid diagnosis for PTSD. Heroin use is at epic proportions in the USA and is commonly used by people with co-occurring PTSD symptoms and substance use disorder.Objectives Here, we combined animal assays of acute restraint stress and contingent heroin self-administration (SA) to study comorbidity between stress disorders and opioid use disorder and identify shifts in anxiety-like behaviors following stress and/or heroin in response to a stress-conditioned cue. Our objective for this approach was to determine the long-term impact of acute restraint stress and heroin self-administration on stress reactivity and basic reward processes.Methods We used 2-h acute restraint stress paired with an odor stimulus to condition a stress cue (CS) for testing of subsequent stress reactivity in a burying task and reinstatement and extinction to heroin seeking. Rats were also tested for social place preference for measures of social reward and anxiety-like behaviors.ResultsStress rats exhibited multiple levels of disrupted behavior including enhanced acquisition of heroin intake and reinstatement in response to the stress CS, as well as delayed extinction in response to the stress CS. All rats developed a social place preference, but stress rats spent more time in nose-to-nose contact with the unfamiliar rat while heroin rats spent time exploring the chamber. In the burying task, stress shortened latencies to bury the CS and increased burying and immobility in male and female rats relative to sham counterparts.Conclusions Acute restraint stress results in anxiety-like behaviors and a stress-associated cue is sufficient to reinstate extinguished heroin seeking. This project has the potential to elucidate the complex relationship between stress/anxiety disorders, including some PTSD-like characteristics, and the onset, maintenance, and relapse to heroin seeking.
... A Communicated by Sreedharan Sajikumar. growing body of research highlights the fact that encoding of fear extinction involves different important brain areas: the medial prefrontal cortex (mPFC), the hippocampus and amygdala (Knapska et al. 2012;Fitzgerald et al. 2018). A well-known suppressive pathway of fear is the one that originates from the infralimbic cortex of the mPFC (IL-mPFC) and terminates in amygdaloid nuclei such as; the basomedial nucleus, the lateral central nucleus, and the ventral region of the lateral amygdala. ...
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Several brain regions, including the medial prefrontal cortex (mPFC), are important in the process of fear extinction learning. Ketamine is a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, which is shown to play a role in extinction modulation. Ketamine and calcineurin (CN), an intracellular protein phosphatase, have several common targets in the cells. Therefore, in the present study, our aim is to investigate the possible role of calcineurin in the mPFC on the enhancing effects of ketamine in fear extinction. First, different doses of a CN inhibitor, cyclosporine-A (CsA), were micro-injected into the infralimbic (IL) region of the mPFC prior to extinction training in a classical conditioning model in rats. Next, sub-effective doses of CsA (Intra-mPFC) and ketamine (i.p.) were co-administered in another cohort of rats to find their possible interactions. Enzymatic activity of calcineurin was measured in the IL-mPFC following drug administration. We used the elevated plus-maze (EPM) and open field (OF) test for further behavioral assessments. The results showed that CsA can enhance the extinction of conditioned fear and inhibit the enzyme CN at a dose of 20 nM. The combination of sub-effective doses of CsA (5 nM) and ketamine (10 mg/kg) could again enhance the extinction of fear and reduce CN activity in the region. Our results propose that inhibition of CN in the IL-mPFC is involved in the extinction of fear and ketamine enhancement of extinction is probably mediated by reducing CN activity in this part of the brain.
... The role of the amygdala in activating fear and of the relation between amygdala and the pre-frontal cortex areas in suppressing fear was found to be crucial; e.g., (Admon et al., 2013;Panksepp & Biven, 2012). If the emotion regulation strategy based on suppression is strengthened, this leads to a decrease in physiological and experiential effects of negative emotions; e.g., (Fitzgerald, 2018;Ochsner & Gross, 2014;Webb, Miles, Sheeran, 2012). ...
Conference Paper
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In this paper, a second-order adaptive model is introduced for simulation of the formation of a mental model of a traumatic course of events and its emotional responses, and learning processes of how a stimulus can become a trigger to activate this mental model. Furthermore, the influence of therapy on the ability of an individual to learn to control the emotional responses to the traumatic mental model was modeled. To unblock and activate this learning ability, a form of second-order adaptation was applied.
... Since most of the highly NA-innervated nuclei in the thalamus are related to limbic circuits or to circuits involving the prefrontal cortex (e.g., MD nucleus), disease mechanisms and treatments might involve the thalamus, and particularly the thalamic NA system. For example, PTSD is associated with impaired prefrontal regulation of emotion (Liberzon and Abelson 2016;Fitzgerald et al. 2018), and prazosin, an Alpha-1 adrenergic receptor antagonist, is commonly used to treat the condition (Boehnlein and Kinzie 2007;Simon and Rousseau 2017). We have shown high Alpha-1 densities in the midline nuclei, with important limbic connections, and in the MD nucleus, connected with the prefrontal cortex (Fig. 6, Table 3). ...
Article
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Noradrenaline (NA) in the thalamus has important roles in physiological, pharmacological, and pathological neuromodulation. In this work, a complete characterization of NA axons and Alpha adrenoceptors distributions is provided. NA axons, revealed by immunohistochemistry against the synthesizing enzyme and the NA transporter, are present in all thalamic nuclei. The most densely innervated ones are the midline nuclei, intralaminar nuclei (paracentral and parafascicular), and the medial sector of the mediodorsal nucleus (MDm). The ventral motor nuclei and most somatosensory relay nuclei receive a moderate NA innervation. The pulvinar complex receives a heterogeneous innervation. The lateral geniculate nucleus (GL) has the lowest NA innervation. Alpha adrenoceptors were analyzed by in vitro quantitative autoradiography. Alpha-1 receptor densities are higher than Alpha-2 densities. Overall, axonal densities and Alpha adrenoceptor densities coincide; although some mismatches were identified. The nuclei with the highest Alpha-1 values are MDm, the parvocellular part of the ventral posterior medial nucleus, medial pulvinar, and midline nuclei. The nucleus with the lowest Alpha-1 receptor density is GL. Alpha-2 receptor densities are highest in the lateral dorsal, centromedian, medial and inferior pulvinar, and midline nuclei. These results suggest a role for NA in modulating thalamic involvement in consciousness, limbic, cognitive, and executive functions.
... Patients suffering from this psychiatric condition, however, often present extinction impairments [10,13] accompanied by a hypoactive vmPFC [14,15], hyperactive dACC and amygdala [14,[16][17][18], and a smaller and hypofunctional hippocampus [14,18,19]. The abnormal functioning of these brain regions could explain not only the hyperarousal and extinction deficits but also the increased responsiveness to trauma-unrelated stimuli leading to fear overgeneralization [20][21][22]. Noteworthy, over time, the original aversive/traumatic memory can spontaneously reemerge, which also limits the efficacy of the extinction approach [23]. ...
Article
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Background: Posttraumatic stress disorder (PTSD) may stem from the formation of aberrant and enduring aversive memories. Some PTSD patients have recreationally used Cannabis, probably aiming at relieving their symptomatology. However, it is still largely unknown whether and how Cannabis or its psychotomimetic compound Δ9-tetrahydrocannabinol (THC) attenuates the aversive/traumatic memory outcomes. Here, we seek to review and discuss the effects of THC on aversive memory extinction and anxiety in healthy humans and PTSD patients. Methods: Medline, PubMed, Cochrane Library, and Central Register for Controlled Trials databases were searched to identify peer-reviewed published studies and randomized controlled trials in humans published in English between 1974 and July 2020, including those using only THC and THC combined with cannabidiol (CBD). The effect size of the experimental intervention under investigation was calculated. Results: At low doses, THC can enhance the extinction rate and reduce anxiety responses. Both effects involve the activation of cannabinoid type-1 receptors in discrete components of the corticolimbic circuitry, which could couterbalance the low "endocannabinoid tonus" reported in PTSD patients. The advantage of associating CBD with THC to attenuate anxiety while minimizing the potential psychotic or anxiogenic effect produced by high doses of THC has been reported. The effects of THC either alone or combined with CBD on aversive memory reconsolidation, however, are still unknown. Conclusions: Current evidence from healthy humans and PTSD patients supports the THC value to suppress anxiety and aversive memory expression without producing significant adverse effects if used in low doses or when associated with CBD. Future studies are guaranteed to address open questions related to their dose ratios, administration routes, pharmacokinetic interactions, sex-dependent differences, and prolonged efficacy.
... Beauchaine & Cicchetti, 2019) including: substance abuse(Weiss, Williams, & Connolly, 2015), eating disorder(Seidel et al., 2018;Svaldi, Griepenstroh, Tuschen-Caffier, & Ehring, 2012), depression(Lopez, Luby, Belden, & Barch, 2018), anxiety(Kircanski et al., 2018), PTSD(Fitzgerald, DiGangi, & Phan, 2018), ADHD(Steinberg & Drabick, 2015), conduct disorder(Beauchaine, Gatzke-Kopp, & Mead, 2007), borderline personality disorder(Herpertz, Schneider, Schmahl, & Bertsch, 2018;van Zutphen et al., 2018), and psychotic disorders ...
Chapter
This chapter covers contextual, individual, biological, and genetic risk factors as well as protective factors that act transdiagnostically, or across disorders. Comorbidity transcends diagnoses and overlap is observed between most symptoms known to be associated with mental disorder. Behaviour genetic studies on families and twins tend to show that genetic risk is not specific to particular disorders, rather it is largely a transdiagnostic vulnerability. A singular model of mental disorder most commonly invokes dysfunction of the prefrontal cortex. Pharmaceutical therapies are mostly focused around specific symptoms and the co‐occurrence of symptoms in severe disorders accounts for the high prevalence of polypharmacy, relatively more common in groups at greatest social disadvantage. The chapter also presents some closing thoughts on the key concepts discussed in the preceding chapters of this book.
... Neurobiological factors implicated in PTSD include activation of the monoamine system, changes in the neuroendocrine system, and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis [8][9][10]. In other words, it is caused by traumatic stress-induced emotional fear memory and anxiety-like symptoms, arising through an imbalance among neurotransmitters, such as serotonin (5-HT), dopamine, and norepinephrine (NE), in the fear circuit regions (e.g., the medial prefrontal cortex (PFC), hippocampus (HIP), and amygdala (AMY)) [11]. Decreased 5-HT and increased NE were observed in the PFC and HIP of PTSD patients [9]. ...
Article
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Posttraumatic stress disorder (PTSD) is a stress-related psychiatric or mental disorder characterized by experiencing a traumatic stress. The cause of such PTSD is dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and imbalance of monoamines. Myricetin (MYR) is a common natural flavonoid that has various pharmacological activities. We investigated the effects of MYR on fear, depression, and anxiety following monoamine imbalance and hyperactivation of HPA axis in rats exposed to a single prolonged stress (SPS). Male rats were dosed with MYR (10 and 20 mg/kg, i.p.) once daily for 14 days after exposure to SPS. Administration of MYR reduced freezing responses to extinction recall, depression, and anxiety-like behaviors and decreased increase of plasma corticosterone and adrenocorticotropic hormone levels. Also, administration of MYR restored decreased serotonin and increased norepinephrine in the fear circuit regions, medial prefrontal cortex, and hippocampus. It also increased the reduction in the brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B mRNA expression and the ratio of p-ERK/extracellular signal-regulated kinase (ERK) in the hippocampus. Thus, MYR exerted antidepressant and anxiolytic effects by regulation of HPA axis and activation of the BDNF-ERK signaling pathway. Finally, we suggest that MYR could be a useful therapeutic agent to prevent traumatic stress such as PTSD.
... In PTSD, fear extinction deficits contribute to the persistence of traumatic memories. These impairments are associated with decreased activation in the ventromedial prefrontal cortex (vmPFC) and hippocampus, brain regions involved in fear extinction and recall of extinction learning (i.e., extinction retention), as well as increased activation of the amygdala, an area critical to threat responding (4). Although fear extinction is impaired in patients with PTSD (5), standardized cognitive behavioral therapy approaches that facilitate extinction learning can ameliorate these deficits (6). ...
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The endocannabinoid (eCB) system is one the most ubiquitous signaling systems of the brain and offers a rich pharmacology including multiple druggable targets. Preclinical research shows that eCB activity influences functional connectivity between the prefrontal cortex and amygdala, thereby influences an organism’s ability to cope with threats and stressful experiences. Animal studies show that cannabinoid receptor 1 (CB1) activation within the amygdala is essential for extinction of fear memories. Failure to extinguish traumatic memories is a core symptom of post-traumatic stress disorder, suggesting that potentiating eCB signaling may have a therapeutic potential in this condition. It has, however, been unknown whether animal findings in this domain translate to humans. Data to inform this critical question are now emerging and are the focus of this review. We first briefly summarize the biology of the eCB system and the animal studies that support its role in fear extinction and stress responding. We then discuss the pharmacological eCB-targeting strategies that may be exploited for therapeutic purposes: Direct CB1 activation, using THC or its synthetic analogues; or indirect potentiation, through inhibition of eCB degrading enzymes, the anandamide (N-arachidonoylethanolamine; AEA) degrading enzyme fatty acid amide hydrolase (FAAH); or the 2-arachidonylglycerol degrading enzyme monoacylglycerol lipase. We then review recent human data on direct CB1 activation via THC and AEA potentiation through FAAH blockade. The available human data consistently support a translation of animal findings on fear memories and stress reactivity and suggest a potential therapeutic utility in humans.
... Consequently to the activation of amygdala, a hippocampal increased activity has also been observed, leading to the hypothesis that these two brain structures co-activate at the exposure of the individuals to negative images or when accessing their personal traumatic memories, in comparison with nontraumatized controls. Moreover, a less engagement of these two structures has been indicated as a response to positive images for PTSD patients (for a review, see Fitzgerald et al., [18]). A schematic representation of the main brain regions affected by PTSD is shown in Figure 1. ...
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Objective: Although not highly prevalent among the general population, post-traumatic stress disorder is a serious psychiatric condition, associated with co-morbidities, mortality and high suicide rates. Currently, there are few approved pharmacological therapies, which count as second-line, augmented to psychotherapy. Studies from the literature emphasize the need for novel treatment options, due to high relapse rates and patients that do not achieve remission. This study provides an overview over the pharmacological treatment of post-traumatic stress disorder, from a neurobiological perspective. Methods: A systematic research has been conducted through PubMed, PLOS one, Cochrane library and Google Scholar databases. Results: The neurobiological mechanisms which underlies the symptomatology are not fully elucidated. In the present, some theories involved in the onset/ manifestation are formulated (serotonergic, noradrenergic, glutamatergic, GABA-ergic, endocannabinoid) and the current therapy aims to modulate these neurotransmissions. In light of the studies along the years, a line should be drawn between the drugs acting on reducing the anxiety only and those that exhibit dual effect i.e. reducing the anxiety and affecting the memory reconsolidation processes. Although labelled as recreational drugs rather than compounds with intended therapeutic effects, cannabidiol and 3,4-methylenedioximethamphetamine appear to be the most promising from the perspective of efficacy and benefit-risk ratio. Conclusion: Preclinical studies come with acceptable results, yet clinical trials are controversial and heterogeneous, given the small population size. Given the seriousness of post-traumatic stress disorder, the attempts to find effective and safe treatment in a context that lacks appropriate therapeutic approaches should be encouraged.
... Biologically, brain structure atrophy has independently been associated with psychological trauma, PTSD, depression, head injury, and cognitive decline (Byers & Yaffe, 2011;Childress et al., 2013;Karl et al., 2006;O'Brien et al., 2020;Woon et al., 2010). Similar to brain structure atrophy, functional brain abnormalities could also underlie the relations of PTSD, depression and head injury with cognitive function (Carron et al., 2016;Chau et al., 2017;Elzinga & Bremner, 2002;Fitzgerald et al., 2018). PTSD, depression and head injury have also been associated with inflammatory responses, which can lead to cognitive decline (Dowlati et al., 2010;Gorelick, 2010;Lozano et al., 2015;Sumner et al., 2018). ...
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Background Despite evidence linking posttraumatic stress disorder (PTSD), depression, and head injury, separately, with worse cognitive performance, investigations of their combined effects on cognition are limited in civilian women. Methods The Cogstate Brief Battery assessment was administered in 10,681 women from the Nurses' Health Study II cohort, mean age 64.9 years (SD = 4.6). Psychological trauma, PTSD, depression, and head injury were assessed using online questionnaires. In this cross-sectional analysis, we used linear regression models to estimate mean differences in cognition by PTSD/depression status and stratified by history of head injury. Results History of head injury was prevalent (36%), and significantly more prevalent among women with PTSD and depression (57% of women with PTSD and depression, 21% of women with no psychological trauma or depression). Compared to having no psychological trauma or depression, having combined PTSD and depression was associated with worse performance on psychomotor speed/attention ( = −.15, p = .001) and learning/working memory ( = −.15, p < .001). The joint association of PTSD and depression on worse cognitive function was strongest among women with past head injury, particularly among those with multiple head injuries. Conclusions Head injury, like PTSD and depression, was highly prevalent in this sample of civilian women. In combination, these factors were associated with poorer performance on cognitive tasks, a possible marker of future cognitive health. Head injury should be further explored in future studies of PTSD, depression and cognition in women.
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... Accordingly, disturbed REM sleep is associated with impairments in both conditioned fear and extinction learning [63][64][65]. Similar impairments in fear learning and emotional dysregulation have also been found with PTSD [66,67], along with evidence of REM sleep abnormalities [59,68,69]. This body of evidence supports hypotheses that REM sleep disturbance may play a role in the development and persistence of PTSD. ...
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Obstructive sleep apnea (OSA) and post-traumatic stress disorder (PTSD) are often co-morbid with implications for disease severity and treatment outcomes. OSA prevalence is higher in PTSD sufferers than in the general population, with a likely bidirectional effect of the two illnesses. There is substantial evidence to support the role that disturbed sleep may play in the pathophysiology of PTSD. Sleep disturbance associated with OSA may interfere with normal rapid eye movement (REM) functioning and thus worsen nightmares and sleep-related movements. Conversely, hyperarousal and hypervigilance symptoms of PTSD may lower the arousal threshold and thus increase the frequency of sleep fragmentation related to obstructive events. Treating OSA not only improves OSA symptoms, but also nightmares and daytime symptoms of PTSD. Evidence suggests that positive airway pressure (PAP) therapy reduces PTSD symptoms in a dose-dependent fashion, but also presents challenges to tolerance in the PTSD population. Alternative OSA treatments may be better tolerated and effective for improving both OSA and PTSD. Further research avenues will be introduced as we seek a better understanding of this complex relationship.
... The hippocampus is involved in various processes ranging from learning and memory to control of emotions and motivation [1]. It is also responsive to stress hormones [2] and is implicated in pathogenesis of various disorders such as depression [3], post-traumatic stress disorder [4], schizophrenia [5], epilepsy [6] and neurodegenerative diseases [7]. Therefore, it is not surprising that the hippocampus is one of the most frequently studied brain areas in rodents. ...
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Many research methods applied in molecular neuroscience require the collection of hippocampal samples, but a still poorly recognized problem is contamination with the choroid plexus during brain dissection. Because of a distinct pattern of gene expression, its inclusion in brain samples can obscure or even confound conclusions drawn from molecular studies. Therefore, we tested our dissection method designed for removal of tissue contamination using expression of the transthyretin gene (Ttr) as a marker of the choroid plexus. Additionally, we also validated dissection of the entire hippocampus into its dorsal, intermediate and ventral subdivisions using the expression of Trhr and Lct genes as molecular markers of anatomical subdivisions. The PCR analysis showed that Ttr is expressed at a residual level in hippocampal samples that display an mRNA level several hundred lower than the adjacent control tissue colocalized with the choroid plexus. This indicates that the applied method for dissecting the hippocampus from a fresh brain allows for replicable removal of the majority of choroid plexus from hippocampal samples. In turn, differences in expression of Lct and Trhr confirmed the proper dissection of dorsal, intermediate and ventral subdivisions from fresh brain tissue. Therefore, a special emphasis on the removal of tissue contamination and avoidance of tissue distortions makes our protocol especially suitable for molecular experiments performed either on the entire hippocampus or its subdivisions.
... The role of the amygdala in activating fear and of the relation between amygdala and the pre-frontal cortex areas in suppressing fear was found to be crucial; e.g., (Admon et al. 2013;Panksepp and Biven 2012). If the emotion regulation strategy based on suppression is strengthened, this leads to a decrease in physiological and experiential effects of negative emotions; e.g., (Fitzgerald et al. 2018;Ochsner and Gross 2014;Webb et al. 2012). ...
Chapter
In this chapter, a second-order adaptive network model is introduced for a number of phenomena that occur in the context of PTSD. First of all the model covers simulation of the formation of a mental model of a traumatic course of events and its emotional responses that make replay of flashback movies happen. Secondly, it addresses learning processes of how a stimulus can become a trigger to activate this acquired mental model. Furthermore, the influence of therapy on the ability of an individual to learn to control the emotional responses to the traumatic mental model was modeled. Finally, a form of second-order adaptation was covered to unblock and activate this learning ability.
... The VMPFC is heavily connected to the amygdala and acts to regulate emotion. The activity of the VMPFC is diminished in PTSD leading to increased activation and reactivity of the amygdala since it a role in the inhibitory control over the amygdala (40). Additionally, the VMPFC can alter the original fear that led to the development of PTSD and instead override it with safe memories (9). ...
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Post-traumatic stress disorder (PTSD) is a psychiatric disorder that causes significant functional impairment and is related to altered stress response and reinforced learned fear behavior. PTSD has been found to impact three functional networks in the brain: default mode, executive control, and salience. The executive control network includes the dorsolateral prefrontal cortex (DLPFC) and lateral PPC. The salience network involves the anterior cingulate cortex, anterior insula, and amygdala. This latter network has been found to have increased functional connectivity in PTSD. Transcranial Magnetic Stimulation (TMS) is a technique used in treating PTSD and involves stimulating specific portions of the brain through electromagnetic induction. Currently, high-frequency TMS applied to the left dorsolateral prefrontal cortex (DLPFC) is approved for use in treating major depressive disorder (MDD) in patients who have failed at least one medication trial. In current studies, high-frequency stimulation has been shown to be more effective in PTSD rating scales posttreatment than low-frequency stimulation. The most common side effect is headache and scalp pain treated by mild analgesics. Seizures are a rare side effect and are usually due to predisposing factors. Studies have been done to assess the overall efficacy of TMS. However, results have been conflicting, and sample sizes were small. More research should be done with larger sample sizes to test the efficacy of TMS in the treatment of PTSD. Overall, TMS is a relatively safe treatment. Currently, the only FDA- approved to treat refractory depression, but with the potential to treat many other conditions.
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Objectives Maternal alcohol misuse during the postpartum period is associated with negative maternal and infant outcomes. This study examined whether greater stress exposure in the year before the baby's birth and maternal post-traumatic stress disorder (PTSD) were associated with postpartum alcohol misuse among a sample of women veterans. Maternal PTSD was also examined as a moderator of the association between stress exposure and postpartum alcohol misuse. Methods Data were drawn from the Center for Maternal and Infant Outcomes Research in Translation study, a multisite prospective cohort study of pregnant and postpartum women veterans. Interviews were conducted within 12 weeks after birth. At this post-birth interview, women reported whether they experienced stressful events (e.g., loss of job, military deployment, separation/divorce) in the year before birth during the interview. PTSD diagnosis and postpartum scores on the Alcohol Use Disorders Identification Test (AUDIT-C) were derived from the Department of Veterans Affairs medical records. Results Models testing main and interaction effects showed a statistically significant association of both PTSD (p = .02) and stress exposure (p = .04), as well as significant interaction of PTSD and stress exposure (p = .03) with AUDIT-C scores postpartum, after controlling for marital status, age, and race. Specifically, compared with women without PTSD, those with PTSD had higher overall AUDIT-C scores postpartum, regardless of stress exposure. For women without PTSD, more stress exposure before birth was associated with higher AUDIT-C score during the postpartum phase. Conclusions PTSD diagnosis and life stressors before infant birth predicted maternal alcohol misuse during the postpartum period. Identifying such risk factors is an initial step in preventing alcohol misuse, with the goal of enhancing postpartum health for the birthing parent and infant.
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Objective Post-traumatic stress disorder (PTSD) is a common mental disorder following one or more traumatic events in which patients exhibit behavioural and emotional disturbances. Recent studies report alterations in social cognition with cerebral functioning modifications. While it is now established that brain function can be modified and severely altered following successive childhood traumas, less studies have focused on brain alterations in adults with normal social cognition development. Methods We conducted a selective literature review by querying PubMed and Embase databases for titles of articles research on PTSD adults published from January 2000 to December 2021 focusing on adulthood traumatic events. Results Majority of studies reported frontolimbic rupture, with limbic structures like amygdala missing top-down control of frontal regulation. These cerebral dysfunctions could be observed even without overt behavioural defects on social cognition tests. Conclusion These results can be analyzed in light of intrinsic cerebral networks and we propose an attentional model of social threat information processing opening up perspective of social attentional rehabilitation in adjunction to usual care.
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Introduction: Recently, there has been substantial interest in exploring the heterogeneity of posttraumatic stress disorder (PTSD) on a neurobiological level, as individuals with PTSD, including military members and Veterans, vary in their presentation of symptoms. Methods: Critically, a dissociative subtype of PTSD (PTSD+DS) has been defined, where a large body of evidence suggests that the unique presentation of symptoms among PTSD+DS patients is associated with aberrant neurobiological underpinnings. Results: PTSD+DS is often characterized by emotion overmodulation, with increased top-down activation from emotion regulation areas, which is associated with emotional detachment, depersonalization, and derealization. This is in stark contrast to the symptoms commonly observed in individuals with PTSD, who exhibit emotion undermodulation, which involves decreased top-down regulation of hyperactive emotion generation areas and is associated with vivid re-experiencing of trauma memories and hyperarousal. Discussion: This article examines a clinical case example that clearly illustrates this heterogeneous presentation of PTSD symptomatology and psychopathology. It discusses the implications this evidence base holds for a neurobiologically-informed, personalized medicine approach to treatment for military members and Veterans.
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Neurofeedback is emerging as a psychophysiological treatment where self-regulation is achieved through online feed­back of neural states. Novel personalized medicine approaches are particularly important for the treatment of posttrau­matic stress disorder (PTSD), as symptom presentation of the disorder, as well as responses to treatment, are highly het­erogeneous. Learning to achieve control of specific neural substrates through neurofeedback has been shown to display therapeutic evidence in patients with a wide variety of psychiatric disorders, including PTSD. This article outlines the neural mechanisms underlying neurofeedback and examines converging evidence for the efficacy of neurofeedback as an adjunctive treatment for PTSD via both electroencephalography (EEG) and real-time functional magnetic resonance imaging (f MRI) modalities. Further, implications for the treatment of PTSD via neurofeedback in the military mem­ber and Veteran population is examined.
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Developing accurate subcortical volumetric quantification tools is crucial for neurodevelopmental studies, as they could reduce the need for challenging and time‐consuming manual segmentation. In this study the accuracy of two automated segmentation tools, FSL‐FIRST (with three different boundary correction settings) and FreeSurfer were compared against manual segmentation of the hippocampus and subcortical nuclei, including the amygdala, thalamus, putamen, globus pallidus, caudate and nucleus accumbens, using volumetric and correlation analyses in 80 5‐year‐olds. Both FSL‐FIRST and FreeSurfer overestimated the volume on all structures except the caudate, and the accuracy varied depending on the structure. Small structures such as the amygdala and nucleus accumbens, which are visually difficult to distinguish, produced significant overestimations and weaker correlations with all automated methods. Larger and more readily distinguishable structures such as the caudate and putamen produced notably lower overestimations and stronger correlations. Overall, the segmentations performed by FSL‐FIRST’s Default pipeline were the most accurate, while FreeSurfer’s results were weaker across the structures. In line with prior studies, the accuracy of automated segmentation tools was imperfect with respect to manually defined structures. However, apart from amygdala and nucleus accumbens, FSL‐FIRST’s agreement could be considered satisfactory (Pearson correlation > 0.74, Intraclass correlation coefficient (ICC) > 0.68 and Dice Score coefficient (DSC) > 0.87) with highest values for the striatal structures (putamen, globus pallidus, caudate) (Pearson correlation > 0.77, ICC > 0.87 and DSC > 0.88, respectively). Overall, automated segmentation tools do not always provide satisfactory results, and careful visual inspection of the automated segmentations is strongly advised.
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Intrinsic connectivity networks (ICNs), including the default mode network (DMN), central executive network (CEN), and salience network (SN) have been shown to be aberrant in patients with posttraumatic stress disorder (PTSD). The purpose of the current study was to a) compare ICN functional connectivity between PTSD, dissociative subtype PTSD (PTSD+DS) and healthy individuals; and b) to examine the use of multivariate machine learning algorithms in classifying PTSD, PTSD+DS, and healthy individuals based on ICN functional activation. Our neuroimaging dataset consisted of resting-state fMRI scans from 186 participants [PTSD (n = 81); PTSD + DS (n = 49); and healthy controls (n = 56)]. We performed group-level independent component analyses to evaluate functional connectivity differences within each ICN. Multiclass Gaussian Process Classification algorithms within PRoNTo software were then used to predict the diagnosis of PTSD, PTSD+DS, and healthy individuals based on ICN functional activation. When comparing the functional connectivity of ICNs between PTSD, PTSD+DS and healthy controls, we found differential patterns of connectivity to brain regions involved in emotion regulation, in addition to limbic structures and areas involved in self-referential processing, interoception, bodily self-consciousness, and depersonalization/derealization. Machine learning algorithms were able to predict with high accuracy the classification of PTSD, PTSD+DS, and healthy individuals based on ICN functional activation. Our results suggest that alterations within intrinsic connectivity networks may underlie unique psychopathology and symptom presentation among PTSD subtypes. Furthermore, the current findings substantiate the use of machine learning algorithms for classifying subtypes of PTSD illness based on ICNs.
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There is significant heterogeneity in pain outcomes following motor vehicle crashes (MVCs), such that a sizeable portion of individuals develop symptoms of chronic pain months after injury while others recover. Despite variable outcomes, the pathogenesis of chronic pain is currently unclear. Previous neuroimaging work implicates the dorsal anterior cingulate cortex (dACC) in adaptive control of pain, while prior resting state functional magnetic resonance imaging studies find increased functional connectivity (FC) between the dACC and regions involved in pain processing in those with chronic pain. Hyper-connectivity of the dACC to regions that mediate pain response may therefore relate to pain severity. The present study completed rsfMRI scans on N=22 survivors of MVCs collected within two weeks of the incident to test whole-brain dACC-FC as a predictor of pain severity six months later. At two weeks, pain symptoms were predicted by positive connectivity between the dACC and the premotor cortex. Controlling for pain symptoms at two weeks, pain symptoms at six months were predicted by negative connectivity between the dACC and the precuneus. Previous research implicates the precuneus in the individual subjective awareness of pain. Given a relatively small sample size, approximately half of which did not experience chronic pain at six months, findings warrant replication. Nevertheless, this study provides preliminary evidence of enhanced dACC connectivity with motor regions and decreased connectivity with pain processing regions as immediate and prospective predictors of pain following MVC. Perspective This article presents evidence of distinct neural vulnerabilities that predict chronic pain in motor vehicle crash survivors based on whole-brain connectivity with the dorsal anterior cingulate cortex.
Article
Objective Individuals with posttraumatic stress disorder (PTSD) have been found to exhibit emotional regulation difficulties. However, the specific neural mechanisms that underlie these difficulties remain understudied. This study aimed to use pupillometry as an index function of parasympathetic nervous system activation, to investigate the mechanisms underlying emotional regulation difficulties in individuals with PTSD. Method A total of 87 trauma-exposed mothers (34 with PTSD and 53 non-PTSD controls) completed an eye tracking assessment in which pupillary dilation in response to emotionally valenced stimuli was measured. The participants also completed two self-report measures of emotional regulation, namely the Difficulties in Emotional Regulation Scale and the Emotional Regulations Questionnaire. Linear mixed-effect modelling was used to assess potential group differences. Results The PTSD group exhibited increased pupillary dilation to positively valenced stimuli compared to the non-PTSD group. However, no significant associations between the self-report measures and pupillary response to emotionally valenced stimuli were found. Conclusion Increased pupillary dilation in PTSD may reflect impaired parasympathetic nervous system processes. The lack of association of these measures with self-reported emotion regulation may suggest reporting biases. Larger studies with more generalised populations are required to consolidate these preliminary findings.
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Emotion dysregulation that occurs after trauma conveys risk for multiple disorders, including posttraumatic stress disorder, depression, and anxiety. Psychophysiological data (e.g., skin conductance level [SCL]) may be a useful biomarker for quantifying emotion dysregulation given that autonomic nervous system (ANS)-mediated arousal may underlie this feature. In this longitudinal study, we tested whether SCL collected following a single-incident traumatic injury could predict changes in emotion dysregulation over 6 months. Sixty-six adults were recruited from the emergency department; SCL was quantified during an active trauma narrative, in which participants re-told their traumatic event to a research staff member, as well as a neutral narrative for a control condition. Change in SCL (ΔSCL) was calculated using a maximum activation – minimum activation difference score. Multilevel linear modeling was used to test ΔSCL as a predictor of emotion dysregulation using the Emotion Dysregulation Scale (EDS) over time (3 timepoints over 6 months). Results showed that greater ΔSCL – indicative of increasing arousal– during both the trauma (p = 0.037) and neutral (p = 0.013) narratives was a significant predictor of greater emotion dysregulation at each subsequent timepoint. Further, we found a ΔSCL by time interaction, such that less ΔSCL during the neutral narrative predicted decreased emotion dysregulation over time (b = −1.26, SE = 0.43, t = −2.91, p = 0.004). Results validate the use of lab-based assessments of arousal to study emotion dysregulation in trauma survivors. That recovery from emotion dysregulation was predicted by less arousal during a neutral event underscores the importance of clinically targeting response to safety in trauma survivors.
Article
Background Posttraumatic Stress Disorder (PTSD) is a debilitating disorder and there is no current accurate prediction of who develops it after trauma. Neurobiologically, individuals with chronic PTSD exhibit aberrant resting-state functional connectivity (rsFC) between the hippocampus and other brain regions (e.g., amygdala, prefrontal cortex, posterior cingulate), and these aberrations correlate with severity of illness. Prior small-scale research (n < 25) has also shown that hippocampal-rsFC measured acutely after trauma is predictive of future severity using an ROI-based approach. While a promising biomarker, to-date no study has employed a data-driven approach to test whole-brain hippocampal-FC patterns in forecasting the development of PTSD symptoms. Methods Ninety-eight adults at risk of PTSD were recruited from the emergency department following traumatic injury and completed resting functional magnetic resonance imaging (rsfMRI; 8min) within 1-month; 6-months later they completed the Clinician-Administered PTSD Scale (CAPS-5) for assessment of PTSD symptom severity. Whole-brain rsFC values with bilateral hippocampi were extracted (CONN) and used in a machine learning kernel ridge regression analysis (PRoNTo); both a k-folds (k=10) and 70/30 testing vs. training split approach were used for cross-validation (1,000 iterations to bootstrap confidence intervals for significance values). Results Acute hippocampal-rsFC significantly predicted CAPS-5 scores at 6-months (r=0.30, p=0.006; MSE=120.58, p=0.006; R²=0.09, p=0.025). In post-hoc analyses, hippocampal-rsFC remained significant after controlling for demographics, PTSD symptoms at baseline, and depression, anxiety, and stress severity at 6-months (B=0.59, SE=0.20, p=0.003). Conclusions Findings suggest functional connectivity of the hippocampus across the brain acutely after traumatic injury is associated with prospective PTSD symptom severity.
Article
Introduction: Comorbid mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) are common in military service members. The aim of this study is to investigate brain metabolic inter-relationships in service members with and without persistent PTSD symptoms following mTBI using 18F-fluorodeoxyglucose positron emission tomography. Methods: Service members (n=408) diagnosed with mTBI were studied retrospectively. Principal component analysis was applied to identify latent metabolic systems, and the associations between metabolic latent systems and self-report measures of post-concussive and PTSD symptoms were evaluated. Participants were divided into two groups based on DSM-IV-TR criteria for PTSD, and structural equation modeling was performed to test a priori hypotheses on metabolic inter-relationships among the brain regions in the cortico-limbic circuitry responsible for top-down control and bottom-up emotional processing. The differences in metabolic inter-relationships between age-matched PTSD-absent (n=204) and PTSD-present (n=204) groups were evaluated. Results: FDG uptake in the temporo-limbic system was positively correlated with post-concussive and hyperarousal symptoms. For the bottom-up emotional processing, the insula and amygdala-hippocampal complex in PTSD-present group had stronger metabolic inter-relationships with the bilateral rostral anterior cingulate, left lingual, right lateral occipital, and left superior temporal cortices, but a weaker relationship with the right precuneus cortex, compared to PTSD-absent group. For the top-down control, PTSD-present group had decreased metabolic engagements of the dorsolateral prefrontal cortex on the amygdala. Discussion: Our results suggest altered metabolic inter-relationships in the cortico-limbic circuitry in mTBI subjects with persistent PTSD symptoms, which may underlie the pathophysiological mechanisms of comorbid mTBI and PTSD.
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Background Meta-analytic results indicate that posttraumatic stress disorder (PTSD) is associated with hypoactivation of the medial prefrontal cortex (mPFC), hyperactivation of the amygdala, and volume reductions of the hippocampus. Effective psychotherapeutic treatments were hypothesized to normalize these neural patterns via upregulation of prefrontal structures, which in turn downregulate limbic regions. Objective To gain a sound understanding of the effects of successful psychotherapy on the brain, neural changes from pre- to post-treatment in PTSD patients will be aggregated. Method A systematic literature search identified 24 original studies employing structural or functional MRI measurements both before and after treatment of patients diagnosed with PTSD. Results In conjunction, the review returned little evidence of an activation increase in the mPFC/rostral anterior cingulate cortex (rACC) following successful treatment. Five out of 12 studies observed such an increase (especially during emotion processing tasks), albeit in partially non-overlapping brain regions. Conversely, neither the putative related activation decrease in the amygdala nor volumetric changes or altered activation during the resting state could be convincingly established. Conclusion Successful psychological treatments might potentially work via upregulation of the mPFC, which thus may be involved in symptom reduction. However, the role of the amygdala in recovery from PTSD remains unclear. There is currently no indication that the various PTSD treatment approaches employed by the reviewed studies differ regarding their action mechanisms, but further research on this topic is needed.
Article
The psychological trauma associated with events resulting in traumatic brain injury (TBI) is an important and frequently overlooked factor that may impede brain recovery and worsen mental health following a TBI. Indeed, individuals with comorbid post-traumatic stress disorder (PTSD) and TBI have significantly poorer clinical outcomes than individuals with a sole diagnosis. Emotion dysregulation is a common factor leading to poor cognitive and affective outcomes following TBI. Here we synthesize how acute post-injury molecular processes stemming either from physical or emotional trauma may adversely impact circuitry subserving emotion regulation, and ultimately yield long-term systems-level functional and structural changes that are common to TBI and PTSD. In the immediate aftermath of traumatic injury, glucocorticoids stimulate excess glutamatergic activity, particularly in prefrontal cortex-subcortical circuitry implicated in emotion regulation. In human neuroimaging work, assessing this same circuitry well after the acute injury, TBI and PTSD show similar impacts on prefrontal and subcortical connectivity and activation. These neural profiles indicate that emotion regulation may be a useful target for treatment, including for early intervention to prevent the adverse sequelae of TBI. Ultimately, the success of future TBI and PTSD early interventions depends on the fields’ ability to address both the physical and emotional impact of physical injury.
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Introduction Following a case study on scopolamine butyl bromide, an anticholinergic drug, we studied the effect of a central anticholinergic drug on post‐traumatic stress disorder (PTSD)‐related flashbacks and nightmares. Methods We administered trihexyphenidyl (TP) to 34 patients with refractory PTSD‐related nightmares and flashbacks (open‐label trial [n = 22]; single‐blind trial [n = 12]), who had previously received psychiatric treatment for approximately 2–15 years, without therapeutic benefits. The effect of TP was determined using the Clinician‐Administered PTSD Scale (CAPS) and the Impact of Event Scale‐Revised (IES‐R). Results Overall, most patients reported an improvement to none or mild on the CAPS for nightmares (88%) and flashbacks (79%). Conclusion This study is the first to demonstrate the potential efficacy of TP in the treatment of refractory PTSD‐related nightmares and flashbacks. Further double‐blind, randomized control trials are needed to explore the potential clinical benefits of TP in PTSD.
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Losing one’s only child is a major traumatic life event that may lead to posttraumatic stress disorder (PTSD); however, not all parents who experience this trauma develop PTSD. Genetic variants are associated with the risk of developing PTSD. Catechol-O-methyltransferase (COMT) rs4680 and brain-derived neurotrophic factor (BDNF) rs6265 are two most well-described single-nucleotide polymorphisms that relate to stress response; however, the neural mechanism underlying their effects on adults who lost an only child remains poorly understood. Two hundred and ten Han Chinese adults who had lost their only child (55 with PTSD and 155 without PTSD) were included in this imaging genetics study. Participants were divided into subgroups according to their COMT rs4680 and BDNF rs6265 genotypes. Degree Centrality (DC)—a resting-state fMRI index reflecting the brain network communication—was compared with a three-way (PTSD diagnosis, COMT, and BDNF polymorphisms) analysis of covariance. Diagnosis state had a significant effect on DC in bilateral inferior parietal lobules and right middle frontal gyrus (MFG), where PTSD adults showed weaker DC. BDNF × diagnosis interaction effect was found in the right MFG and hippocampus, and these two regions were reversely modulated. Also, there was a significant COMT × BDNF interaction effect in left cuneus, middle temporal gyrus, right inferior occipital gyrus, and bilateral putamen, independent of PTSD diagnosis. These findings suggest that the modulatory effect of BDNF polymorphism on the MFG and hippocampus may contribute to PTSD development in bereaved adults. Interactions of COMT × BDNF polymorphisms modulate some cortices and basal ganglia, irrespective of PTSD development.
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Over the past two decades, evidence has accumulated that the human amygdala exerts some of its functions also when the observer is not aware of the content, or even presence, of the triggering emotional stimulus. Nevertheless, there is as of yet no consensus on the limits and conditions that affect the extent of amygdala’s response without focused attention or awareness. Here we review past and recent studies on this subject, examining neuroimaging literature on healthy participants as well as brain-damaged patients, and we comment on their strengths and limits. We propose a theoretical distinction between processes involved in attentional unawareness, wherein the stimulus is potentially accessible to enter visual awareness but fails to do so because attention is diverted, and in sensory unawareness, wherein the stimulus fails to enter awareness because its normal processing in the visual cortex is suppressed. We argue this distinction, along with data sampling amygdala responses with high temporal resolution, helps to appreciate the multiplicity of functional and anatomical mechanisms centered on the amygdala and supporting its role in non-conscious emotion processing. Separate, but interacting, networks relay visual information to the amygdala exploiting different computational properties of subcortical and cortical routes, thereby supporting amygdala functions at different stages of emotion processing. This view reconciles some apparent contradictions in the literature, as well as seemingly contrasting proposals, such as the dual stage and the dual route model. We conclude that evidence in favor of the amygdala response without awareness is solid, albeit this response originates from different functional mechanisms and is driven by more complex neural networks than commonly assumed. Acknowledging the complexity of such mechanisms can foster new insights on the varieties of amygdala functions without awareness and their impact on human behavior.
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In recent years, an explosion of neuroimaging studies has examined cognitive reappraisal, an emotion regulation strategy that involves changing the way one thinks about a stimulus in order to change its affective impact. Existing models broadly agree that reappraisal recruits frontal and parietal control regions to modulate emotional responding in the amygdala, but they offer competing visions of how this is accomplished. One view holds that control regions engage ventromedial prefrontal cortex (vmPFC), an area associated with fear extinction, that in turn modulates amygdala responses. An alternative view is that control regions modulate semantic representations in lateral temporal cortex that indirectly influence emotion-related responses in the amygdala. Furthermore, while previous work has emphasized the amygdala, whether reappraisal influences other regions implicated in emotional responding remains unknown. To resolve these questions, we performed a meta-analysis of 48 neuroimaging studies of reappraisal, most involving downregulation of negative affect. Reappraisal consistently 1) activated cognitive control regions and lateral temporal cortex, but not vmPFC, and 2) modulated the bilateral amygdala, but no other brain regions. This suggests that reappraisal involves the use of cognitive control to modulate semantic representations of an emotional stimulus, and these altered representations in turn attenuate activity in the amygdala.
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Background Previous research suggests that individuals with posttraumatic stress disorder (PTSD) preferentially attend to trauma-related emotional stimuli and have difficulty completing unrelated concurrent tasks. Compared to trauma-exposed control groups, individuals with PTSD also exhibit lower rostral anterior cingulate cortex (rACC) activation during tasks involving interference from trauma-related stimuli. However, it is not clear whether relatively diminished rACC activation in PTSD also occurs during interference tasks involving trauma-unrelated emotional stimuli. The present study employed functional magnetic resonance imaging (fMRI) and an interference task that involves emotional facial expressions and elicits rACC activation in healthy participants. Findings While performing a trauma-unrelated emotional interference task, participants with PTSD (n=17) showed less rACC activation than trauma-exposed non-PTSD (TENP; n=18) participants. In the PTSD group, rACC activation was negatively correlated with the severity of re-experiencing symptoms. The two groups did not significantly differ on behavioral measures (i.e., response times and error rates). Conclusions These findings suggest that relatively diminished rACC activation in PTSD can be observed in interference tasks involving trauma-unrelated emotional stimuli, indicating a more general functional brain abnormality in this disorder. Future neuroimaging studies need not employ trauma-related stimuli in order to detect rACC abnormalities in PTSD.