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1.
Behav Brain Res ; 402: 113105, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33417995

RESUMO

Safety signals predict the non-occurrence of an aversive event, thereby inhibiting fear responses. Previous research has shown that conditioned safety learning is impaired in patients suffering from post-traumatic stress disorder (PTSD). Using a translational approach, the present study aimed to investigate whether individual responses to an aversive unconditioned stimulus (US) in rats (basic science), non-traumatized (pre-clinical) or traumatized humans (clinical) predicts their response to a conditioned fear or safety stimulus. Using three different archival datasets, the unconditioned response (UCR) to the US during fear or safety conditioning was assessed in rats, non-traumatized humans, and trauma-exposed humans. The response to learned fear (CS+; context) and safety (CS-) was measured by the modulation of the startle response (rats, traumatized humans) or skin conductance response (non-traumatized humans). Our results showed that all groups with low UCR and those with high UCR from the rodent or non-traumatized human samples displayed lower fear response to the CS- than to the CS+ . Traumatized humans with high UCR showed similarly high responses to the CS+ and CS-. While all groups showed a positive association between the UCR and CS+ response, the UCR correlated positively with the CS- response in traumatized humans only. Our findings suggest that an elevated response to aversive stimuli predicts deficits in conditioned safety memory in those at risk for trauma-related disorders and confirms that impaired safety learning could be a valid biomarker for these diseases.

2.
Transl Psychiatry ; 11(1): 46, 2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441547

RESUMO

Translational models of fear conditioning and extinction have elucidated a core neural network involved in the learning, consolidation, and expression of conditioned fear and its extinction. Anxious or trauma-exposed brains are characterized by dysregulated neural activations within regions of this fear network. In this study, we examined how the functional MRI activations of 10 brain regions commonly activated during fear conditioning and extinction might distinguish anxious or trauma-exposed brains from controls. To achieve this, activations during four phases of a fear conditioning and extinction paradigm in 304 participants with or without a psychiatric diagnosis were studied. By training convolutional neural networks (CNNs) using task-specific brain activations, we reliably distinguished the anxious and trauma-exposed brains from controls. The performance of models decreased significantly when we trained our CNN using activations from task-irrelevant brain regions or from a brain network that is irrelevant to fear. Our results suggest that neuroimaging data analytics of task-induced brain activations within the fear network might provide novel prospects for development of brain-based psychiatric diagnosis.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33279459

RESUMO

BACKGROUND: We assessed the impact of total and partial sleep loss on neural correlates of fear conditioning, extinction learning, and extinction recall in healthy young adults. METHODS: Participants (56.3% female, age 24.8 ± 3.4 years) were randomized to a night of normal sleep (NS) (n = 48), sleep restriction (SR) (n = 53), or sleep deprivation (SD) (n = 53). All completed fear conditioning and extinction learning phases the following morning. Extinction recall was tested in the evening of the same day. Task-based contrasts were modeled at the beginning of, at the end of, and across the fear conditioning and extinction learning phases, and at the beginning of extinction recall. These contrasts were compared among the 3 groups by means of analysis of variance. Nonparametric permutation corrected analyses using a cluster-determining threshold of p < .005 and a familywise error of p < .05. RESULTS: At the end of fear conditioning, NS activated medial prefrontal regions, SR activated motor areas, and participants in the SD group showed no significant activations. Across extinction learning, only NS activated both salience (fear) and extinction (regulatory) areas. For extinction recall, SD activated similar regions as NS across extinction learning, while SR activated salience and motor areas. During early fear conditioning, compared with NS, SD activated more medial prefrontal and SR activated more salience network areas. For extinction recall, NS activated more prefrontal areas and SD activated more of both salience- and extinction-related areas than SR. CONCLUSIONS: Relative to NS, SR may enhance fear-related and diminish extinction-related activity, whereas SD may delay engagement of extinction learning. Findings may have clinical implications for populations and occupations in which sleep loss is common.

5.
Front Psychol ; 11: 579514, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33162918

RESUMO

Observational fear learning can contribute to the development of fear-related psychopathologies, such as anxiety disorders and post-traumatic stress disorder. Observational fear learning is especially relevant during childhood. Parent-child attachment and anxiety sensitivity modulate fear reactions and fear learning but their impact on observational fear learning has not been investigated. This study investigated how these factors contribute to observational fear learning in children. We examined this question among 55 healthy parent-child dyads. Children (8-12 years old) watched a video of their parent undergoing a direct fear conditioning protocol, where one stimulus (CS+Parent) was paired with a shock and one was not (CS-), and a video of a stranger for whom a different stimulus was reinforced (CS+Stranger). Subsequently, all stimuli were presented to children (without shocks) while skin conductance responses were recorded to evaluate fear levels. Our results showed that children more sensitive to anxiety and who had lower father-child relationship security levels exhibited higher skin conductance responses to the CS+Parent. Our data suggest that the father-child relationship security influences vicarious fear transmission in children who are more sensitive to anxiety. This highlights the importance of the father-child relationship security as a potential modulator of children's vulnerability to fear-related psychopathologies.

6.
Sci Rep ; 10(1): 17130, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-33051522

RESUMO

The biological mechanisms involved in fear transmission within families have been scarcely investigated in humans. Here we studied (1) how children acquired conditioned fear from observing their parent, or a stranger, being exposed to a fear conditioning paradigm, and (2) the subsequent fear extinction process in these children. Eighty-three child-parent dyads were recruited. The parent was filmed while undergoing a conditioning procedure where one cue was paired with a shock (CS + Parent) and one was not (CS -). Children (8 to 12 years old) watched this video and a video of an adult stranger who underwent conditioning with a different cue reinforced (CS + Stranger). Children were then exposed to all cues (no shocks were delivered) while skin conductance responses (SCR) were recorded. Children exhibited higher SCR to the CS + Parent and CS + Stranger relative to the CS -. Physiological synchronization between the child's SCR during observational learning and the parent's SCR during the actual process of fear conditioning predicted higher SCR for the child to the CS + Parent. Our data suggest that children acquire fear vicariously and this can be measured physiologically. These data lay the foundation to examine observational fear learning mechanisms that might contribute to fear and anxiety disorders transmission in clinically affected families.

7.
Brain Behav ; 10(9): e01766, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32700828

RESUMO

INTRODUCTION: Mindfulness meditation has successfully been applied to cultivate skills in self-regulation of emotion, as it employs the unbiased present moment awareness of experience. This heightened attention to and awareness of sensory experience has been postulated to create an optimal therapeutic exposure condition and thereby improve extinction learning. We recently demonstrated increased connectivity in hippocampal circuits during the contextual retrieval of extinction memory following mindfulness training. METHODS: Here, we examine the role of structural changes in hippocampal subfields following mindfulness training in a randomized controlled longitudinal study using a two-day fear-conditioning and extinction protocol. RESULTS: We demonstrate an association between mindfulness training-related increases in subiculum and decreased hippocampal connectivity to lateral occipital regions during contextual retrieval of extinguished fear. Further, we demonstrate an association between decreased connectivity and decreases in self-reported anxiety following mindfulness training. CONCLUSIONS: The results highlight the role of the subiculum in gating interactions with contextual stimuli during memory retrieval and, also, the mechanisms through which mindfulness training may foster resilience.

8.
Hum Brain Mapp ; 2020 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-32596977

RESUMO

The ENIGMA group on Generalized Anxiety Disorder (ENIGMA-Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega-analysis of a large number of brain structural scans. In this process, the group was confronted with many methodological challenges related to study planning and implementation, between-country transfer of subject-level data, quality control of a considerable amount of imaging data, and choices related to statistical methods and efficient use of resources. This report summarizes the background information and rationale for the various methodological decisions, as well as the approach taken to implement them. The goal is to document the approach and help guide other research groups working with large brain imaging data sets as they develop their own analytic pipelines for mega-analyses.

9.
JAMA Psychiatry ; 77(6): 618-627, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32022832

RESUMO

Importance: The Research Domain Criteria project of the National Institute of Mental Health aims to guide neuropsychiatry toward precision medicine. Its inception was partly in response to the overlap of clinical manifestations between different DSM-IV diagnoses within a category. For example, anxiety disorders comprise a DSM-IV category that includes diagnoses that differ from each other but are all characterized by dysregulated fear levels. Whether DSM-IV-based and Research Domain Criteria-based analytic approaches provide distinct or similar information with regard to the fear circuitry of individuals with anxiety disorders has not been directly tested. Objective: To use a threat conditioning and extinction protocol to conduct categorical (DSM-IV-based) and dimensional (Research Domain Criteria-based) assessments of psychophysiological, neural, and psychometric responses in individuals with and without anxiety disorders. Design, Setting, and Participants: This cross-sectional study was conducted at the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital in Boston between March 2013 and May 2015. Functional magnetic resonance imaging was used to assess psychophysiological, neural, and psychometric responses among adults aged 18 to 65 years with specific phobia, generalized anxiety disorder, social anxiety disorder, and panic disorder as well as a control group of adults without anxiety disorders. Data were analyzed between May 2018 and April 2019. Exposures: A 2-day threat conditioning and extinction protocol. Main Outcomes and Measures: Skin conductance responses and blood oxygenated level-dependent responses were measured during the threat and extinction protocol. The categorical analysis was performed by grouping participants based on their primary DSM-IV diagnosis. The dimensional analysis was performed by regrouping participants, irrespective of their diagnoses, based on their skin conductance responses to shock delivery during threat conditioning. Results: This cross-sectional study of 114 adults aged 18 to 65 years included 93 participants (34 men and 59 women; mean [SD] age, 29.7 [11.1] years) with at least 1 anxiety disorder (specific phobia, generalized anxiety disorder, social anxiety disorder, or panic disorder) and 21 participants (11 men and 10 women) without an anxiety disorder. The categorical DSM-IV-based approach indicated that all anxiety disorder groups exhibited hypoactivation in the ventromedial prefrontal cortex during extinction recall (ηp2 = 0.15; P = .004). The Research Domain Criteria-based approach revealed that higher arousal to the unconditioned stimulus was associated with higher threat responses during extinction recall (for skin conductance responses, ηp2 = 0.21; P = .01 and in functional magnetic resonance imaging results, ηp2 = 0.12; P = .02). The direct comparison of DSM-IV-based vs Research Domain Criteria-based results did not yield significant findings (ηp2 values ranged from 0.02 to 0.078; P values ranged from .09 to .98), suggesting no overlap between the approaches. Conclusions and Relevance: The data obtained from both approaches indicated complementary yet distinct findings. The findings highlight the validity and importance of using both categorical and dimensional approaches to optimize understanding of the etiology and treatment of anxiety symptoms.

10.
Sleep ; 43(7)2020 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-31993652

RESUMO

STUDY OBJECTIVES: Formation and maintenance of fear-extinction memories are disrupted in post-traumatic stress disorder (PTSD) and anxiety disorders. Sleep contributes to emotional memory consolidation and emotion regulation. Insomnia disorder (ID) is characterized by persistent sleep disturbance as well as rapid eye movement (REM) sleep abnormalities and often precedes or develops in parallel with PTSD and anxiety disorders. Here, we explore the impact of chronic poor sleep and sleep immediately following fear conditioning and extinction learning on preservation of extinction memories. METHODS: Twenty-four ID age- and sex-matched to 24 healthy, good sleeper controls (GS) completed up to 2 weeks of habitual sleep monitoring with daily sleep-wake diaries and actigraphy, and then participated in a two-session fear conditioning, extinction learning and extinction recall procedure. Fear Conditioning and Extinction Learning occurred during session 1, followed by Extinction Recall approximately 24 hours later. Skin-conductance responses (SCR) and shock expectancies were recorded throughout all experimental phases to evaluate associative learning and memory. Overnight sleep between sessions 1 and 2 was recorded using ambulatory polysomnography. RESULTS: ID showed greater physiological reactivity during Fear Conditioning. REM sleep physiology was associated with poorer extinction memory in ID but better extinction memory in GS. CONCLUSION: REM sleep physiology may differentially support emotional memory retention and expression in ID and GS. In the former, REM may enhance retention of fear memories, while in the later, REM may enhance the expression of extinction memories.

11.
J Neuroendocrinol ; 32(1): e12800, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31595559

RESUMO

The accumulating evidence regarding the impact of estradiol on learning and memory synergized studies to examine its influence on enhancing animal's ability to quell fear and anxiety. In this review, we first provide a foundational platform regarding the impact of oestradiol on cellular mechanisms of learning and memory and we review recent advances from rodent and human data showing that oestrogen enhances extinction learning across species. We then propose clinical application to these data. We discuss the potential role of oestradiol variance on the aetiology, maintenance and treatment for post-traumatic stress disorder. Specifically, we argue that the use of oestradiol as an adjunct to prolonged exposure (PE) therapy for PTSD may provide a new treatment approach for enhancing the efficacy of PE in women with PTSD. This could advance our understanding of the mechanisms of PTSD and help tailor sex-specific treatments for this disorder.

12.
Psychophysiology ; 57(1): e13350, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30758048

RESUMO

Skin conductance response (SCR) is often used as an index of conditioned fear. SCR has been shown to be highly variable, and absence of SC reactivity is sometimes used as criteria for excluding data. It is, however, possible that low or no SC reactivity is the result of a distinct biological signature that underlies individual differences in SCR reactivity. This study examined neural correlates associated with the near absence of SCR conditionability. Archival data from 109 healthy adults aged 18-60 years were pooled. All individuals had participated in a fear conditioning protocol in a fMRI environment, during which two cues were partially reinforced (CS+) with a shock and a third cue was not (CS-). Using SCR to the conditioned stimuli and differential SCR (CS+ minus CS-), we created two groups of 30 individuals: low conditioners (defined as those showing the smallest SCR to the CS+ and smallest differential SCR) and high conditioners (defined as those showing the largest SCR to the CS+ and largest differential SCR). Our analyses showed differences in patterns of brain activations between these two groups during conditioning in the following regions: dorsal anterior cingulate cortex, amygdala, subgenual anterior cingulate cortex, and insular cortex. Our findings suggest that low or absent SCR conditionability is associated with hypoactivation of brain regions involved in fear learning and expression. This highlights the need to be cautious when excluding SCR nonconditioners and to consider the potential implications of such exclusion when interpreting the findings from studies of conditioned fear.

13.
Biol Psychiatry ; 86(9): 693-702, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31303261

RESUMO

BACKGROUND: The role of hippocampus in context-dependent recall of extinction is well recognized. However, little is known about how intervention-induced changes in hippocampal networks relate to improvements in extinction learning. In this study, we hypothesized that mindfulness training creates an optimal exposure condition by heightening attention and awareness of present moment sensory experience, leading to enhanced extinction learning, improved emotion regulation, and reduced anxiety symptoms. METHODS: We tested this hypothesis in a randomized controlled longitudinal study design using a 2-day fear conditioning and extinction protocol. The mindfulness training group included 42 participants (28 women) and the control group included 25 participants (15 women). RESULTS: We show that mindfulness training is associated with differential engagement of the right supramarginal gyrus as well as hippocampal-cortical reorganization. We also report enhanced hippocampal connectivity to the primary sensory cortex during retrieval of extinguished stimuli following mindfulness training. CONCLUSIONS: These findings suggest hippocampal-dependent changes in contextual retrieval as one plausible neural mechanism through which mindfulness-based interventions enhance fear extinction and foster stress resilience.


Assuntos
Extinção Psicológica , Medo/fisiologia , Hipocampo/fisiologia , Rememoração Mental/fisiologia , Atenção Plena/métodos , Adolescente , Adulto , Animais , Ansiedade/terapia , Mapeamento Encefálico , Condicionamento Clássico/fisiologia , Regulação Emocional , Feminino , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Neuropsychopharmacology ; 44(10): 1769-1777, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31096264

RESUMO

The neural mechanisms and durability of Δ9-tetrahydrocannabinol (THC) impact on threat processing in humans are not fully understood. Herein, we used functional MRI and psychophysiological tools to examine the influence of THC on the mechanisms of conditioned threat extinction learning, and the effects of THC on extinction memory retention when assessed 1 day and 1 week from learning. Healthy participants underwent threat conditioning on day 1. On day 2, participants were randomized to take one pill of THC or placebo (PBO) 2-h before threat extinction learning. Extinction memory retention was assessed 1 day and 1 week after extinction learning. We found that THC administration increased amygdala and ventromedial prefrontal cortex (vmPFC) activation during early extinction learning with no significant impact on skin conductance responses (SCR). When extinction memory retention was tested 24 h after learning, the THC group exhibited lower SCRs to the extinguished cue with no significant extinction-induced activations within the extinction network. When extinction memory retention was tested 1 week after learning, the THC group exhibited significantly decreased responses to the extinguished cues within the vmPFC and amygdala, but significantly increased functional coupling between the vmPFC, hippocampus, and dorsal anterior cingulate cortex during this extinction retention test. Our results are the first to report a long-term impact of one dose of THC on the functional activation of the threat extinction network and unveil a significant change in functional connectivity emerging after a week from engagement. We highlight the need for further investigating the long-term impact of THC on threat and anxiety circuitry.


Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Agonistas de Receptores de Canabinoides/farmacologia , Dronabinol/farmacologia , Extinção Psicológica/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Retenção Psicológica/efeitos dos fármacos , Adulto , Tonsila do Cerebelo/diagnóstico por imagem , Feminino , Neuroimagem Funcional , Resposta Galvânica da Pele/efeitos dos fármacos , Humanos , Imagem por Ressonância Magnética , Masculino , Memória/efeitos dos fármacos , Adulto Jovem
15.
Psychoneuroendocrinology ; 104: 219-227, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30889471

RESUMO

BACKGROUND: We have previously demonstrated that pre-scan salivary cortisol is associated with attentuated frontal-subcortical brain activation during emotion processesing and semantic list-learning paradigms in depressed subjects. Additionally, altered functional connectivity is observed after remission of acute depression symptoms (rMDD). It is unknown whether cortisol also predicts altered functional connectivity during remission. METHODS: Participants were 47 healthy controls (HC) and 73 rMDD, 18-30 years old who provided salivary cortisol samples before and after undergoing resting-state fMRI. We tested whether salivary cortisol by diagnosis interactions were associated with seed-based resting connectivity of the default mode (DMN) and salience and emotion (SN) networks using whole-brain, cluster-level corrected (p < .01) regression in SPM8. RESULTS: Pre-scan cortisol predicted decreased (HC) and increased (rMDD) cross-network connectivity to the dorsal anterior cingulate, dorso-medial and lateral- prefrontal cortex, brain stem and cerebellum (all seeds) and precuneus (DMN seeds). By and large, pre/post-scan cortisol change predicted the same pattern of findings. In network analyses, cortisol predominantly predicted enhanced cross-network connectivity to cognitive control network regions in rMDD. CONCLUSIONS: The association of cortisol with connections of default and salience networks to executive brain networks differs between individuals with and without a history of depression. Further investigation is needed to better understand the role of cortisol and related stress hormones as a potential primary and interactive driver of network coherence in depression.


Assuntos
Cognição/fisiologia , Depressão/metabolismo , Recuperação de Função Fisiológica/fisiologia , Adolescente , Adulto , Encéfalo/fisiologia , Mapeamento Encefálico , Transtorno Depressivo/metabolismo , Transtorno Depressivo/fisiopatologia , Transtorno Depressivo Maior/fisiopatologia , Intervalo Livre de Doença , Emoções/fisiologia , Feminino , Giro do Cíngulo/fisiopatologia , Humanos , Hidrocortisona/análise , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Masculino , Vias Neurais/fisiologia , Córtex Pré-Frontal/fisiopatologia , Descanso , Saliva/química , Adulto Jovem
16.
Neuroimage ; 188: 445-455, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30572112

RESUMO

The generalization of conditioned fear responses has been shown to decrease as a function of perceptual similarity. However, generalization may also extend beyond the perceptual discrimination threshold, ostensibly due to contributions from processes other than perception. Currently the neural mechanisms that mediate perceptual and non-perceptual aspects of fear generalization are unclear. To investigate this question, we conducted a Pavlovian fear conditioning and generalization experiment, collecting functional magnetic resonance imaging (fMRI), skin conductance and explicit shock likelihood ratings, in 37 healthy subjects. Face stimuli were initially paired (CS+) or not paired (CS) with an electrical shock. During the generalization phase, responses were measured to the CS+, CS and a range of CS + -toCS morphs (generalization stimuli), selected for each participant based on that participant's discrimination ability. Across multiple measurements, we found that fear generalization responses were limited to stimuli that could not be distinguished from the CS + stimulus, thus following a gradient closely linked to perceptual discriminability. These measurements, which were correlated with one another, included skin conductance responses, behavioral ratings, and fMRI responses of anterior insula and superior frontal gyrus. In contrast, responses in areas of the default network, including the posterior cingulate gyrus, angular gyrus and hippocampus, showed a negative generalization function extending to stimuli that were more likely to be distinguished from the CS+. In addition, the generalization gradients of the anterior insula and the behavioral ratings showed some evidence for extension beyond perceptual limits. Taken together, these results suggest that distinct brain areas are involved in perceptual and non-perceptual components of fear generalization.


Assuntos
Mapeamento Encefálico , Córtex Cerebral/fisiologia , Condicionamento Clássico/fisiologia , Discriminação Psicológica/fisiologia , Medo/fisiologia , Resposta Galvânica da Pele/fisiologia , Generalização da Resposta/fisiologia , Adulto , Córtex Cerebral/diagnóstico por imagem , Reconhecimento Facial/fisiologia , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Adulto Jovem
17.
Front Psychiatry ; 9: 365, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30150944

RESUMO

Connectomics is a framework that models brain structure and function interconnectivity as a network, rather than narrowly focusing on select regions-of-interest. MRI-derived connectomes can be structural, usually based on diffusion-weighted MR imaging, or functional, usually formed by examining fMRI blood-oxygen-level-dependent (BOLD) signal correlations. Recently, we developed a novel method for assessing the hierarchical modularity of functional brain networks-the probability associated community estimation (PACE). PACE uniquely permits a dual formulation, thus yielding equivalent connectome modular structure regardless of whether positive or negative edges are considered. This method was rigorously validated using the 1,000 functional connectomes project data set (F1000, RRID:SCR_005361) (1) and the Human Connectome Project (HCP, RRID:SCR_006942) (2, 3) and we reported novel sex differences in resting-state connectivity not previously reported. (4) This study further examines sex differences in regard to hierarchical modularity as a function of age and clinical correlates, with findings supporting a basal configuration framework as a more nuanced and dynamic way of conceptualizing the resting-state connectome that is modulated by both age and sex. Our results showed that differences in connectivity between men and women in the 22-25 age range were not significantly different. However, these same non-significant differences attained significance in both the 26-30 age group (p = 0.003) and the 31-35 age group (p < 0.001). At the most global level, areas of diverging sex difference include parts of the prefrontal cortex and the temporal lobe, amygdala, hippocampus, inferior parietal lobule, posterior cingulate, and precuneus. Further, we identified statistically different self-reported summary scores of inattention, hyperactivity, and anxiety problems between men and women. These self-reports additionally divergently interact with age and the basal configuration between sexes.

18.
Sleep ; 41(8)2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29860407

RESUMO

Study Objectives: Insomnia increases the risk for anxiety disorders that are also associated with fear-extinction deficits. We compared activation of fear and extinction networks between insomnia disorder (ID) without comorbidity and good sleepers (GS). Methods: Twenty-three ID participants age- and sex-matched to 23 GS participants completed 14 days of actigraphy and diaries, three nights of ambulatory polysomnography and a 2-day fear conditioning and extinction paradigm. Fear conditioning and extinction learning occurred on the first day, followed 24 hours later by extinction recall. Blood-oxygen-level-dependent functional magnetic resonance imaging (fMRI) signal and skin conductance responses (SCR) were recorded. Nineteen participants per group produced usable fMRI data. Beta weights from areas where activation differed between groups were regressed against sleep and psychophysiological measures. SCR was compared between groups at various stages of the paradigm. Results: During fear conditioning, both ID (N = 19) and GS (N = 19) activated fear-related structures. Across extinction learning, ID (N = 19) demonstrated little change, whereas GS (N = 16) activated both fear and extinction-related areas, including the hippocampus, insula, dorsal anterior cingulate (dACC), and ventromedial prefrontal (vmPFC) cortices. During extinction recall, while GS (N = 17) demonstrated limited activation, ID (N = 16) activated regions similar to those previously activated in GS (vmPFC, dACC, insula). Sleep quality was predictive of activations seen at various stages of the paradigm. SCR data suggested ID were more physiologically reactive than GS. Conclusions: Across extinction learning, GS but not ID activated both fear and extinction-related networks. At extinction recall, ID engaged similar regions whereas GS no longer did so. Individuals with ID may show a delayed acquisition of fear extinction memories.


Assuntos
Transtornos de Ansiedade/fisiopatologia , Condicionamento Clássico/fisiologia , Extinção Psicológica/fisiologia , Medo/psicologia , Rememoração Mental/fisiologia , Distúrbios do Início e da Manutenção do Sono/fisiopatologia , Actigrafia , Adolescente , Adulto , Idoso , Medo/fisiologia , Feminino , Giro do Cíngulo/fisiologia , Hipocampo/fisiologia , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Polissonografia , Córtex Pré-Frontal/fisiologia , Adulto Jovem
19.
Biol Psychiatry ; 84(2): 129-137, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29246436

RESUMO

BACKGROUND: Animal fear conditioning studies have illuminated neuronal mechanisms of learned associations between sensory stimuli and fear responses. In rats, brief electrical stimulation of the infralimbic cortex has been shown to reduce conditioned freezing during recall of extinction memory. Here, we translated this finding to humans with magnetic resonance imaging-navigated transcranial magnetic stimulation (TMS). METHODS: Subjects (N = 28) were aversively conditioned to two different cues (day 1). During extinction learning (day 2), TMS was paired with one of the conditioned cues but not the other. TMS parameters were similar to those used in rat infralimbic cortex: brief pulse trains (300 ms at 20 Hz) starting 100 ms after cue onset, total of four trains (28 TMS pulses). TMS was applied to one of two targets in the left frontal cortex, one functionally connected (target 1) and the other unconnected (target 2, control) with a human homologue of infralimbic cortex in the ventromedial prefrontal cortex. Skin conductance responses were used as an index of conditioned fear. RESULTS: During extinction recall (day 3), the cue paired with TMS to target 1 showed significantly reduced skin conductance responses, whereas TMS to target 2 had no effect. Further, we built group-level maps that weighted TMS-induced electric fields and diffusion magnetic resonance imaging connectivity estimates with fear level. These maps revealed distinct cortical regions and large-scale networks associated with reduced versus increased fear. CONCLUSIONS: The results showed that spatiotemporally focused TMS may enhance extinction learning and/or consolidation of extinction memory and suggested novel cortical areas and large-scale networks for targeting in future studies.


Assuntos
Condicionamento Clássico , Extinção Psicológica , Medo , Córtex Pré-Frontal/fisiologia , Estimulação Magnética Transcraniana , Animais , Humanos , Imagem por Ressonância Magnética , Rememoração Mental , Ratos , Análise de Regressão
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