Cannabinoid modulation of corticolimbic activation during extinction learning and fear renewal in adults with posttraumatic stress disorder.

Failure to successfully extinguish fear is a hallmark of trauma-related disorders, like posttraumatic stress disorder (PTSD). PTSD is also characterized by dysfunctional corticolimbic activation and connectivity. The endocannabinoid system is a putative system to target for rescuing these behavioral and neural deficits. In healthy adults, acute, low-dose delta-9-tetrahydrocannabinol (THC) facilitates fear extinction and increases cortico-limbic activation and connectivity in response to threat. The present study determines the effect of acute, low-dose THC on fear-related brain activation and connectivity during fear extinction in trauma-exposed adults with (PTSD = 19) and without PTSD [trauma-exposed controls (TEC) = 26] and non-trauma-exposed [healthy controls (HC) = 26]. We used a Pavlovian fear conditioning and extinction paradigm, where we measured concurrent functional magnetic resonance imaging (fMRI) and behavioral responses (i.e., skin conductance responding and expectancy ratings). Using a randomized, double-blind, placebo-controlled design, N = 71 subjects were randomized to receive placebo (PBO, n = 37) or THC (n = 34) prior to fear extinction learning. During early extinction learning, individuals with PTSD given THC had greater vmPFC activation than their TEC counterparts. During a test of the return of fear (i.e., renewal), HC and individuals with PTSD given THC had greater vmPFC activation compared to TEC. Individuals with PTSD given THC also had greater amygdala activation compared to those given PBO. We found no effects of trauma group or THC on behavioral fear indices during extinction learning, recall, and fear renewal. These data suggest that low dose, oral THC can affect neural indices of fear learning and memory in adults with trauma-exposure; this may be beneficial for future therapeutic interventions seeking to improve fear extinction learning and memory.

A common genetic variant in fatty acid amide hydrolase is linked to alterations in fear extinction neural circuitry in a racially diverse, nonclinical sample of adults.

Poor fear extinction learning and recall are linked to the development of fear-based disorders, like posttraumatic stress disorder, and are associated with aberrant activation of fear-related neural circuitry. This includes greater amygdala activation during extinction learning and lesser hippocampal and ventromedial prefrontal cortex (vmPFC) activation during recall. Emerging data indicate that genetic variation in fatty acid amide hydrolase (FAAH C385A; rs324420) is associated with increased peripheral endocannabinoid (eCB) levels and lesser threat-related amygdala reactivity. Preclinical studies link increased eCB signaling to better extinction learning and recall, thus FAAH C385A may protect against the development of trauma-related psychopathology by facilitating extinction learning. However, how this FAAH variant affects fear extinction neural circuitry remains unknown. In the present study, we used a novel, immersive-reality fear extinction paradigm paired with functional neuroimaging to assess FAAH C385A effects on fear-related neural circuitry and conditioned fear responding (US expectancy ratings, subjective units of distress, and skin conductance responding) in healthy adults from an urban area (Detroit, MI; N = 59; C/C = 35, A-carrier = 24). We found lesser amygdala activation in A-allele carriers, compared to C/C homozygotes, during early extinction recall. Likewise, we found lesser dorsal anterior cingulate cortex and greater hippocampus activation in early extinction learning in A-carriers compared to C/C homozygotes. We found no effects of FAAH C385A on vmPFC activation or behavioral fear indices. These data support and extend previous findings that FAAH genetic variation, associated with increased eCB signaling and subsequent enhanced fear extinction, may predict individual differences in successful fear learning.

Meditation reduces brain activity in the default mode network in children with active cancer and survivors.

BACKGROUND: Mounting evidence demonstrates that meditation can lower pain and emotional distress in adults, and more recently, in children. Children may benefit from meditation given its accessibility across a variety of settings (e.g., surgical preparation). Recent neuroimaging studies in adults suggest that meditation techniques are neurobiologically distinct from other forms of emotion regulation, such as distraction, that rely on prefrontal control mechanisms, which are underdeveloped in youth. Rather, meditation techniques may not rely on "top-down" prefrontal control and may therefore be utilized across the lifespan. PROCEDURE: We examined neural activation in children with cancer, a potentially distressing diagnosis. During neuroimaging, children viewed distress-inducing video clips while using martial arts-based meditation (focused attention, mindful acceptance) or non-meditation (distraction) emotion regulation techniques. In a third condition (control), participants passively viewed the video clip. RESULTS: We found that meditation techniques were associated with lower activation in default mode network (DMN) regions, including the medial frontal cortex, precuneus, and posterior cingulate cortex, compared to the control condition. Additionally, we found evidence that meditation techniques may be more effective for modulating DMN activity than distraction. There were no differences in self-reported distress ratings between conditions. CONCLUSION: Together, these findings suggest that martial arts-based meditation modulates negative self-referential processing associated with the DMN, and may have implications for the management of pediatric pain and negative emotion.

Community and household-level socioeconomic disadvantage and functional organization of the salience and emotion network in children and adolescents.

Socioeconomic disadvantage (SED) during childhood has been linked to disparities in physical and mental health. A growing body of research has focused on identifying neurodevelopmental consequences of SED, commonly measured using within-household factors (e.g., household income), to better understand the processes underlying SED-related disparities. These studies suggest that childhood SED has a widespread impact on brain development, altering development of multiple brain regions simultaneously. These findings also raise the possibility that childhood SED impacts development of key brain systems, such as the salience and emotion network (SEN), which is positioned at the intersection of brain systems involved in cognitive and emotion-related functioning and is thought to mediate information flow within and between these networks. The present study tests for associations between household- and community-level SED, as well as their interaction, and measures of SEN-based functional neural organization in 57 children and adolescents (ages 6-17). We applied graph theoretical analyses to resting-state functional magnetic resonance imaging (fMRI) data to examine SEN-based functional network topology. Results showed that youth residing in more distressed communities demonstrate lower hub-like properties (i.e., less efficient global information transfer and fewer connections) of two core SEN nodes - the anterior cingulate cortex and the left supramarginal gyrus. Similarly, lower household income was associated with lower efficiency of the anterior cingulate, but had no effect on the supramarginal gyrus. There was, however, an interaction between income and community SED in the rostral prefrontal cortex, such that higher income was associated with higher clustering coefficient and lower betweenness centrality, suggesting greater local processing and lower influence of this region on information flow across the network. These effects were significant only among youth living in low (but not high) SED communities, suggesting that within-household SED factors may not protect against the detrimental effects of a disadvantaged community context. Similarly, the age-related increase in average path length of the left rostral prefrontal cortex was only significant among youth living in low (but not high) SED communities. Given that maturation of the SEN is considered to be a critical functional backbone supporting the development of more flexible cognitive and emotional processes into adulthood, we tested for links between SEN graph metrics and measures of cognitive and emotion-related functioning. We found that higher community SED and lower income were both associated with lower IQ. Lower IQ, in turn, was associated with global efficiency of the left supramarginal gyrus. Observed effects of SED on SEN-based functional neural organization may help to explain the strong and pervasive link between childhood SED and disparities in cognitive and emotional outcomes.

Emotion-related brain organization and behavioral responses to socioemotional stimuli in pediatric cancer survivors with posttraumatic stress symptoms.

BACKGROUND: Pediatric cancer is a life-changing, stressful experience for children and their families. Although most children adjust well, psychologically, a significant subset report posttraumatic stress symptoms (PTSS), with nearly 75% reexperiencing traumatic parts of cancer and/or its treatment. However, little research has examined the effects of pediatric cancer and related PTSS on emotional processing, and on functional properties of key emotional centers in the brain (e.g., amygdala). PROCEDURE: We examined cancer-related PTSS, behavioral responses during an emotion-processing task, and resting-state functional connectivity of the amygdala in 17 pediatric cancer survivors (ages 6-11) and 17 age- and sex-matched controls. RESULTS: Cancer survivors, relative to controls, were more likely to rate ambiguous (i.e., neutral) faces as negative (i.e., "negativity bias"). Higher reexperiencing PTSS was associated with faster responses to neutral faces. Although there were no group differences in amygdala centrality, within survivors, both higher reexperiencing PTSS and faster reaction times were associated with increased centrality of the amygdala-a functional property associated with hubs of information processing in the brain. In an exploratory mediation analysis, we found that amygdala centrality mediated the link between reaction time and PTSS, suggesting that changes in the brain may be a proximal marker of the expression of emotion-related symptomology. CONCLUSIONS: Negativity bias in cancer survivors may reflect their stressful experiences with cancer and/or its treatment. This negativity bias may represent a susceptibility to changes in emotion-related brain functioning, which may, in turn, lead to PTSS.

Neurodevelopmental consequences of pediatric cancer and its treatment: applying an early adversity framework to understanding cognitive, behavioral, and emotional outcomes.

Today, children are surviving pediatric cancer at unprecedented rates, making it one of modern medicine's true success stories. However, we are increasingly becoming aware of several deleterious effects of cancer and the subsequent "cure" that extend beyond physical sequelae. Indeed, survivors of childhood cancer commonly report cognitive, emotional, and psychological difficulties, including attentional difficulties, anxiety, and posttraumatic stress symptoms (PTSS). Cognitive late- and long-term effects have been largely attributed to neurotoxic effects of cancer treatments (e.g., chemotherapy, cranial irradiation, surgery) on brain development. The role of childhood adversity in pediatric cancer - namely, the presence of a life-threatening disease and endurance of invasive medical procedures - has been largely ignored in the existing neuroscientific literature, despite compelling research by our group and others showing that exposure to more commonly studied adverse childhood experiences (i.e., domestic and community violence, physical, sexual, and emotional abuse) strongly imprints on neural development. While these adverse childhood experiences are different in many ways from the experience of childhood cancer (e.g., context, nature, source), they do share a common element of exposure to threat (i.e., threat to life or physical integrity). Therefore, we argue that the double hit of early threat and cancer treatments likely alters neural development, and ultimately, cognitive, behavioral, and emotional outcomes. In this paper, we (1) review the existing neuroimaging research on child, adolescent, and adult survivors of childhood cancer, (2) summarize gaps in our current understanding, (3) propose a novel neurobiological framework that characterizes childhood cancer as a type of childhood adversity, particularly a form of early threat, focusing on development of the hippocampus and the salience and emotion network (SEN), and (4) outline future directions for research.

Dose-dependent effect of acute THC on extinction memory recall and fear renewal: a randomized, double-blind, placebo-controlled study.

RATIONALE: Prior work from our lab and others demonstrates that the endocannabinoid system is a promising avenue for improving fear memory deficits in posttraumatic stress disorder (PTSD). Specifically, 7.5 mg of delta-9-tetrahydrocannabinol (THC) decreases fear responding in healthy adults and increases prefrontal cortex activation during extinction learning and fear renewal in adults with PTSD. OBJECTIVES: The present study will determine whether there is a dose-dependent effect of THC on short-term (24 h) and long-term (one week) fear learning and memory in adults with PTSD. METHODS: Using a randomized, double-blind, placebo-controlled design, N = 36 adults with PTSD completed the study and were randomized to receive placebo (PBO, n = 11), 5 mg of THC (n = 11), or 10 mg of THC (n = 14) prior to fear extinction learning. Participants completed a Pavlovian conditioning paradigm with extinction recall and fear renewal occurring 24 h and one week later, where we measured concurrent functional imaging and behavioral responses. RESULTS: Twenty-four hours after drug administration, individuals with PTSD given 5 mg of THC exhibited greater anterior cingulate cortex and prefrontal cortex activation during early fear renewal. One week later, individuals given 10 mg of THC exhibited greater hippocampus activation during extinction recall and prefrontal cortex activation during fear renewal. CONCLUSIONS: These data suggest that dosing and timing are critical for facilitating fear memory processes in PTSD, and that low-dose oral THC prior to extinction learning can affect brain indices of fear learning and memory both acutely and one week after administration.

Smaller Hippocampal Volume Is Associated With Reduced Posttraumatic Stress Symptoms in Children With Cancer and Survivors Following a Brief Novel Martial Arts-Based Intervention.

PURPOSE: Children with cancer and survivors frequently report posttraumatic stress symptoms (PTSS), which are associated with volumetric changes in stress-sensitive brain regions, including the hippocampus. METHODS: We examined the impact of a novel, 4-week martial-arts-based meditative intervention on cancer-related PTSS in 18 pediatric patients and survivors and whether baseline hippocampal volumes correlate with PTSS severity and/or PTSS changes over time. RESULTS: Overall, PTSS did not significantly change from baseline to post-intervention. Smaller hippocampal volume was correlated with more severe re-experiencing PTSS at baseline, and greater reductions in PTSS post-intervention. CONCLUSIONS: Together, hippocampal volume may be a biomarker of PTSS severity and intervention response. Identifying hippocampal volume as a potential biomarker for PTSS severity and intervention response may allow for more informed psychosocial treatments.

Comparison of behavioral and brain indices of fear renewal during a standard vs. novel immersive reality Pavlovian fear extinction paradigm in healthy adults.

Pavlovian conditioning paradigms model the learned fear associations inherent in posttraumatic stress disorder, including the renewal of inappropriate fear responses following extinction learning. However, very few studies in humans investigate the underlying neural mechanisms involved in fear renewal despite its clinical importance. To address this issue, our lab designed a novel, immersive-reality Pavlovian fear acquisition, extinction, recall, and renewal paradigm. We utilized an ecological threat - a snake striking towards the participant - as the unconditioned stimulus (US). Context and background were dynamic and included both visual and auditory cues that are relevant to everyday life. Using functional magnetic resonance imaging and behavioral measures (US expectancy ratings), we examined the validity of this Novel paradigm in healthy adults (n = 49) and compared it to a Standard, well-validated 2D paradigm (n = 28). The Novel paradigm, compared to the Standard, was associated with greater hippocampal activation throughout the task. Participants who underwent the Standard paradigm, compared to the Novel, also displayed insula activation; however, this was not specific to stimulus or time. During fear renewal, the Novel paradigm was associated with dorsal anterior cingulate cortex activation to CS+ (> CS-). Overall, we found that our Novel, immersive-reality paradigm, which features an ecologically relevant US, elicited greater corticolimbic activation. These results suggest that immersive Pavlovian fear conditioning paradigms paired with innately fearful stimuli may improve translatability of preclinical paradigms to clinical interventions for fear-based disorders.

Cannabinoid modulation of brain activation during volitional regulation of negative affect in trauma-exposed adults.

Emotion dysregulation is considered a core component of posttraumatic stress disorder (PTSD). Cognitive reappraisal is one therapeutic emotion regulation strategy that has been widely studied among individuals with mood and anxiety disorders, and numerous differences in brain activation patterns have been shown between individuals with and without PTSD during tasks of cognitive reappraisal. Prior research among healthy subjects suggests that an acute, low dose of Δ9-tetrahydrocannabinol (THC) could attenuate the neurophysiological discrepancies that exist between individuals with and without PTSD during tasks of emotional processing; however, the effect of an acute, low dose of THC on corticolimbic activity during emotion regulation among individuals with PTSD has not yet been studied. The present study aimed to investigate the effect of THC on negative affect and brain activation in a priori regions of interest during cognitive reappraisal among trauma-exposed individuals with and without PTSD. Using a double-blind design, 51 individuals were randomized to receive THC or placebo (PBO) before participating in a well-established emotion regulation task during functional magnetic resonance imaging (fMRI). THC but not PBO reduced negative affect during reappraisal, and THC increased dorsomedial prefrontal cortex (dmPFC) activation in response to neutral images. Individuals with PTSD displayed less activation in the angular gyrus, overall, compared to the trauma-exposed control (TEC) group, however THC increased angular gyrus activation in the PTSD group so that there was no significant difference in angular gyrus activation between the TEC and PTSD groups that received THC. Compared to PBO, THC also increased cerebellar activation during exposure to neutral images in individuals with PTSD. Lastly, in participants that received THC, greater posterior cingulate cortex (PCC)/precuneus activation during reappraisal was associated with less self-reported negative affect following reappraisal blocks. Together these findings suggest that THC may prove to be a beneficial pharmacological adjunct to cognitive reappraisal therapy in the treatment of PTSD.

Alterations in fear extinction neural circuitry and fear-related behavior linked to trauma exposure in children.

Exposure to childhood trauma is extremely common (>60 %) and is a leading risk factor for fear-based disorders, including anxiety and posttraumatic stress disorder. These disorders are characterized by deficits in fear extinction and dysfunction in underlying neural circuitry. Given the strong and pervasive link between childhood trauma and the development of psychopathology, fear extinction may be a key mechanism. The present study tests the impact of childhood trauma exposure on fear extinction and underlying neural circuitry. Children (N = 44, 45 % trauma-exposed; 6-11 yrs) completed a novel two-day virtual reality fear extinction experiment. On day one, participants underwent fear conditioning and extinction. Twenty-four hours later, participants completed a test of extinction recall during fMRI. Conditioned fear was measured throughout the experiment using skin conductance and fear-related behavior, and activation in fear-related brain regions was estimated during recall. There were no group differences in conditioned fear during fear conditioning or extinction learning. During extinction recall, however, trauma-exposed children kept more distance from both the previously extinguished and the safety cue, suggesting poor differentiation between threat and safety cues. Trauma-exposed youth also failed to approach the previously extinguished cue over the course of extinction recall. The effects on fear-related behavior during extinction recall were accompanied by higher activation to the previously extinguished cue in fear-relevant brain regions, including the dorsal anterior cingulate cortex and anterior insula, in trauma-exposed relative to control children. Alterations in fear-related brain regions and fear-related behavior may be a core mechanism through which childhood trauma confers heightened vulnerability to psychopathology.

Cannabinoid modulation of corticolimbic activation to threat in trauma-exposed adults: a preliminary study.

RATIONALE: Excessive fear and anxiety, coupled with corticolimbic dysfunction, are core features of stress- and trauma-related psychopathology, such as posttraumatic stress disorder (PTSD). Interestingly, low doses of ∆9-tetrahydrocannabinol (THC) can produce anxiolytic effects, reduce threat-related amygdala activation, and enhance functional coupling between the amygdala and medial prefrontal cortex and adjacent rostral cingulate cortex (mPFC/rACC) during threat processing in healthy adults. Together, these findings suggest the cannabinoid system as a potential pharmacological target in the treatment of excess fear and anxiety. However, the effects of THC on corticolimbic functioning in response to threat have not be investigated in adults with trauma-related psychopathology. OBJECTIVE: To address this gap, the present study tests the effects of an acute low dose of THC on corticolimbic responses to threat in three groups of adults: (1) non-trauma-exposed healthy controls (HC; n = 25), (2) trauma-exposed adults without PTSD (TEC; n = 27), and (3) trauma-exposed adults with PTSD (n = 19). METHODS: Using a randomized, double-blind, placebo-controlled, between-subjects design, 71 participants were randomly assigned to receive either THC or placebo (PBO) and subsequently completed a well-established threat processing paradigm during functional magnetic resonance imaging. RESULTS: In adults with PTSD, THC lowered threat-related amygdala reactivity, increased mPFC activation during threat, and increased mPFC-amygdala functional coupling. CONCLUSIONS: These preliminary data suggest that THC modulates threat-related processing in trauma-exposed individuals with PTSD, which may prove advantageous as a pharmacological approach to treating stress- and trauma-related psychopathology.

Martial Arts-Based Therapy Reduces Pain and Distress Among Children with Chronic Health Conditions and Their Siblings.

OBJECTIVE: Test whether a martial arts-based therapy, Kids Kicking Cancer (KKC), can reduce pain and emotional distress in children with cancer, other chronic health conditions (e.g., sickle cell), and healthy siblings. METHODS: This study surveyed children's pain and distress levels immediately before and after a 1-hr in-person KKC class. Eligible participants were enrolled in standard KKC classes, were diagnosed with a chronic health condition (e.g., cancer, sickle cell) or were the sibling of a child diagnosed and were between the ages of 5-17 years (inclusive). Children reported on their pain and distress using Likert-style scales (Coloured Analog Scale and modified FACES scale, respectively). Friedman test was used to test for overall changes in pain and distress, and within subgroups. Age and sex effects were evaluated using Spearman's rank-order correlation. Additional Yes/No questions were administered regarding KKC satisfaction and use of techniques. RESULTS: Fifty-nine youth (19 cancer patients, 17 non-cancer patients, 23 siblings; 5-17 yrs, 26 females) completed this study. Overall, there was a significant reduction in pain (p = 0.033) and emotional distress (p < 0.001) after a 1-hr class, with 50% and 89% of youth reporting a reduction in pain and distress, respectively. On average, pain levels remained within the mild/moderate range on average (i.e., pre vs. post levels; pre: M = 1.67, post: M = 1.33) and emotional distress went from mild/moderate to none/mild distress, on average (pre: M = 1.92, post: M = 1.08). Youth with higher pre-class pain and distress reported greater reductions (p = 0.001 and p < 0.001, respectively). The reduction in pain appeared to be most pronounced with cancer and non-cancer patients. In contrast, the reduction in distress appeared to be most pronounced among healthy siblings. However, overall, reductions in pain and distress did not significantly differ among subgroups (i.e., cancer patients, non-cancer patients, siblings), and change in pain and distress was not associated with age or sex. Ninety-six percent of youth would recommend KKC to others and 81% reported using KKC techniques (e.g., the Breath BrakeTM or other martial arts techniques) outside of class, such as at home. CONCLUSION: Results support the more widespread application of KKC as a psychosocial intervention for reducing pain and distress in various pediatric populations.

Distinct neural correlates of trait resilience within core neurocognitive networks in at-risk children and adolescents.

Background: Most children who are exposed to threat-related adversity (e.g., violence, abuse, neglect) are resilient - that is, they show stable trajectories of healthy psychological development. Despite this, most research on neurodevelopmental changes following adversity has focused on the neural correlates of negative outcomes, such as psychopathology. The neural correlates of trait resilience in pediatric populations are unknown, and it is unclear whether they are distinct from those related to adversity exposure and the absence of negative outcomes (e.g., depressive symptomology). Methods: This functional magnetic resonance imaging (fMRI) study reports on a diverse sample of 55 children and adolescents (ages 6-17 years) recruited from a range of stressful environments (e.g., lower income, threat-related adversity exposure). Participants completed a multi-echo multi-band resting-state fMRI scan and self-report measures of trait resilience and emotion-related symptomology (e.g., depressive symptoms). Resting-state data were submitted to an independent component analysis (ICA) to identify core neurocognitive networks (salience and emotion network [SEN], default mode network [DMN], central executive network [CEN]). We tested for links among trait resilience and dynamic (i.e., time-varying) as well as conventional static (i.e., averaged across the entire session) resting-state functional connectivity (rsFC) of core neurocognitive networks. Results: Youth with higher trait resilience spent a lower fraction of time in a particular dynamic rsFC state, characterized by heightened rsFC between the anterior DMN and right CEN. Within this state, trait resilience was associated with lower rsFC of the SEN with the right CEN and anterior DMN. There were no associations among trait resilience and conventional static rsFC. Importantly, although more resilient youth reported lower depressive symptoms, the effects of resilience on rsFC were independent of depressive symptoms and adversity exposure. Conclusions: The present study is the first to report on the neural correlates of trait resilience in youth, and offers initial insight into potential adaptive patterns of brain organization in the context of environmental stressors. Understanding the neural dynamics underlying positive adaptation to early adversity will aid in the development of interventions that focus on strengthening resilience rather than mitigating already-present psychological problems.

Behavioral activation sensitivity and default mode network-subgenual cingulate cortex connectivity in youth.

Increased resting-state functional connectivity (rsFC) between the default mode network (DMN) and subgenual anterior cingulate cortex (sgACC) is consistently reported in adults and youth with psychopathologies related to affect dysregulation (e.g. depression, posttraumatic stress disorder). This pattern of increased rsFC is thought to underlie ruminative thought patterns through integration of negative affect (via sgACC) into self-referential operations supported by the DMN. Neurobiological studies in adults show that behavioral activation system (BAS) sensitivity is a potential protective factor against the development of psychopathology, particularly in the context of stress and trauma exposure. However, whether BAS sensitivity is associated with variation in DMN-sgACC stress-vulnerability circuitry in youth, particularly those at risk for affect dysregulation, has not yet been studied. This association was tested in a sample of ninety-eight children and adolescents (ages 6-17) at high sociodemographic risk for psychopathology (i.e., urban, lower income, high frequency of violence and abuse exposure). Participants underwent a six-minute resting-state functional magnetic resonance imaging scan. Using a targeted, small-volume corrected approach, we found that youth with higher BAS sensitivity demonstrated lower DMN-sgACC rsFC, suggesting a potential link between the purported protective effects of BAS sensitivity and stress-vulnerability circuitry. This work suggests that interventions that augment BAS sensitivity, such as behavioral activation therapy, may protect against the development of stress-related psychopathology by modifying a critical rumination circuitry in the brain. Such interventions may be especially important for bolstering resiliency in at-risk urban youth, who are disproportionately burdened by early stress and associated psychopathology.