Faculty Bibliography

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.

Background: The ability to extinguish the conditioned fear is critical for preventing fear and anxiety. Exploring the neural circuits of extinction learning can facilitate the understanding of the psychopathology underlying fear-and anxiety-related disorders. The field has focused on a limited number of brain regions including the medial prefrontal cortex, insular cortex, hippocampus, and amygdala in fear conditioning and extinction, with the other systems overlooked. Here we explored the dynamic changes of large-scale functional connectivity (FC) across the extinction learning, examined how is the FC altered in anxiety disorders.
Method(s): Nighty-one individuals with at least one anxiety disorder (ANX) and 92 controls without an anxiety disorder (CT) underwent a two-day fear conditioning and extinction paradigm in a functional magnetic resonance imaging (fMRI) scanner. We estimated the trial-by-trial functional connectivity across the brain during extinction learning and compared the two groups using network-based statistic analysis. We conducted correlation analysis to link the extinction learning-induced functional connectivity with neural data during extinction memory recall and with clinical measures (anxiety sensitivity index, beck anxiety inventory, beck depression inventory, and state trait anxiety inventory-trait form). The reported p-values were familywise error-corrected.
Result(s): The CT exhibited increased FC from early to late extinction learning specifically to a conditioned stimulus. The ANX group, in contrast, showed widespread dysconnectivity compared with CT (cluster-level p < 0.001), with the reductions predominantly affecting interactions between the default mode network, somatomotor network, frontoparietal control network, and the rest of the brain. The increase of extinction-induced FC negatively correlated with FC principally within the same systems in ANX (r = -0.63, p < 0.001), and positively correlated with ventromedial prefrontal cortex activation in CT (r = 0.37, cluster-level p < 0.05), during extinction recall in next day. The increased FC during extinction learning correlated with clinical measures (canonical correlation analysis r = 0.51, p = 0.002).
Conclusion(s): These findings provide evidence supporting recent studies implicating distributed brain regions in attention, conscious processes, learning and consolidation of fear extinction memory in the human brain. The disfunction of anxiety disorder may associate with the widespread altered functional connectivity across different stages of extinction learning

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.

INTRODUCTION/BACKGROUND: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.

STUDY OBJECTIVES/OBJECTIVE: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 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:24 ID age- and sex-matched to 24 healthy, good sleeper controls (GS) completed up to two 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 24h 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/CONCLUSIONS: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.

Importance/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED:A 2-day threat conditioning and extinction protocol. Main Outcomes and Measures/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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.

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.