Altered Amygdala Resting-State Functional Connectivity in Post-Traumatic Stress Disorder

Post-traumatic stress disorder (PTSD) is often characterized by aberrant amygdala activation and functional abnormalities in corticolimbic circuitry, as elucidated by functional neuroimaging. These “activation” studies have primarily relied on tasks designed to induce region-specific, and task-dependent brain responses in limbic (e.g., amygdala) and paralimbic brain areas through the use of aversive evocative probes. It remains unknown if these corticolimbic circuit abnormalities exist at baseline or “at rest,” in the absence of fear/anxiety-related provocation and outside the context of task demands. Therefore the primary aim of the present experiment was to investigate aberrant amygdala functional connectivity patterns in combat-related PTSD patients during resting-state. Seventeen Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans with combat-related PTSD (PTSD group) and 17 combat-exposed OEF/OIF veterans without PTSD [combat-exposed control (CEC) group] underwent an 8-min resting-state functional magnetic resonance imaging scan. Using an anatomically derived amygdala “seed” region we observed stronger functional coupling between the amygdala and insula in the PTSD group compared to the CEC group, but did not find group differences in amygdala–prefrontal connectivity. These findings suggest that the aberrant amygdala and insula activation to fear-evocative probes previously characterized in PTSD may be driven by an underlying enhanced connectivity between the amygdala, a region known for perceiving threat and generating fear responses, and the insula, a region known for processing the meaning and prediction of aversive bodily states. This enhanced amygdala–insula connectivity may reflect an exaggerated, pervasive state of arousal that exists outside the presence of an overt actual threat/danger. Studying amygdala functional connectivity “at rest” extends our understanding of the pathophysiology of PTSD

Focal And Aberrant Prefrontal Engagement During Emotion Regulation In Veterans With Posttraumatic Stress Disorder

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109312/1/da22243.pd

Individual differences in cognitive reappraisal use and emotion regulatory brain function in combat‐exposed veterans with and without PTSD

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135971/1/da22551.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135971/2/da22551_am.pd

Study protocol of an investigation of attention and prediction error as mechanisms of action for latent inhibition of dental fear in humans

Background Evidence suggests that dental anxiety and phobia are frequently the result of direct associative fear conditioning but that pre-exposure to dental stimuli prior to conditioning results in latent inhibition of fear learning. The mechanisms underlying the pre-exposure effect in humans, however, are poorly understood. Moreover, pain sensitivity has been linked to dental fear conditioning in correlational investigations and theory suggests it may moderate the latent inhibition effect, but this hypothesis has not been directly tested. These gaps in our understanding are a barrier to the development of evidence-based dental phobia prevention efforts. Methods Healthy volunteers between the ages of 6 and 35 years will be enrolled across two sites. Participants will complete a conditioning task in a novel virtual reality environment, allowing for control over pre-exposure and the examination of behaviour. A dental startle (a brief, pressurized puff of air to a tooth) will serve as the unconditioned stimulus. Using a within-subjects experimental design, participants will experience a pre-exposed to-be conditioned stimulus, a non-pre-exposed to-be conditioned stimulus, and a neutral control stimulus. Two hypothesized mechanisms, changes in prediction errors and attention, are expected to mediate the association between stimulus condition and fear acquisition, recall, and retention. To ascertain the involvement of pain sensitivity, this construct will be measured through self-report and the cold pressor task. Discussion Dental phobia negatively affects the dental health and overall health of individuals. This study aims to determine the mechanisms through which pre-exposure retards conditioned dental fear acquisition, recall, and retention. A randomized control trial will be used to identify these mechanisms so that they can be precisely targeted and maximally engaged in preventative efforts

Specialization of amygdala subregions in emotion processing

The amygdala is important for human fear processing. However, recent research has failed to reveal specificity, with evidence that the amygdala also responds to other emotions. A more nuanced understanding of the amygdala's role in emotion processing, particularly relating to fear, is needed given the importance of effective emotional functioning for everyday function and mental health. We studied 86 healthy participants (44 females), aged 18–49 (mean 26.12 ± 6.6) years, who underwent multiband functional magnetic resonance imaging. We specifically examined the reactivity of four amygdala subregions (using regions of interest analysis) and related brain connectivity networks (using generalized psycho-physiological interaction) to fear, angry, and happy facial stimuli using an emotional face-matching task. All amygdala subregions responded to all stimuli (p-FDR <.05), with this reactivity strongly driven by the superficial and centromedial amygdala (p-FDR <.001). Yet amygdala subregions selectively showed strong functional connectivity with other occipitotemporal and inferior frontal brain regions with particular sensitivity to fear recognition and strongly driven by the basolateral amygdala (p-FDR <.05). These findings suggest that amygdala specialization to fear may not be reflected in its local activity but in its connectivity with other brain regions within a specific face-processing network

The Associative Representation of Fear Memories Mediated by the Amygdala.

This dissertation investigates how memories for emotional events are represented within the brain. The amygdala is a region of the brain that has been identified as playing a major role in emotional memory. The amygdala contains two subregions, the basolateral complex and the central nucleus, which have been found to be important in the acquisition and expression of emotional memories, respectively. For example, damage to either brain area in rats or humans prevents the acquisition of Pavlovian fear conditioning, a form of emotional learning in which neutral stimuli that do not provoke fear come to do some after being paired with an aversive event. However, rats with damage to the basolateral amygdala can acquire fear if given sufficient experience (e.g., many conditioning trials) and it appears that the central nucleus acquires fear memories under these conditions. These findings suggest that either the nature of the memories acquired during limited or extensive training are different, which therefore recruits different brain areas, or the amygdala subregions serve similar roles in fear learning. To address this, the author first examined whether the nature of fear memories formed after limited and extensive training are in fact different. Previous work has suggested that early in conditioning the ability of a conditioned stimulus to produce learned responses is based on retrieving a memory of the aversive outcome, but that after extensive training the conditioned stimulus directly retrieves the learned response. The author therefore manipulated the animals’ representation of the aversive outcome after fear conditioning to assess whether fear memories depend on an expectation of an aversive event. Even after extensive training fear memories were dependent on the expectation of an aversive event, suggesting that the nature of learned fear associations does not change as a function of training. Next, the author investigated whether the nature of learned fear associations mediated by the basolateral complex and central nucleus are similar. Using either permanent or temporary lesions of the amygdala, it was found that both basolateral and central nucleus-dependent memories are affected by post-conditioning changes in the value of the aversive outcome, suggesting that they depend on thePh.D.PsychologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/62330/1/rabinak_1.pd

Associative Structure of Fear Memory After Basolateral Amygdala Lesions in Rats

The authors have recently demonstrated that rats with basolateral amygdala (BLA) lesions acquire Pavlovian fear conditioning after overtraining. However, it is not known whether the associative basis of Pavlovian fear memory acquired by rats with BLA lesions is similar to that of intact rats. Associations are typically formed between the conditional (CS) and unconditional (US) stimuli (stimulus–stimulus; S-S), although it is possible for stimuli to enter into association with the responses they produce (stimulus–response; S-R). Indeed, the central nucleus of the amygdala, which is essential for fear conditioning in rats with BLA lesions, may mediate S-R associations in some Pavlovian tasks. The authors therefore used a postconditioning US inflation procedure (i.e., exposure to intense footshock USs) to assess the contribution of S-S associations to fear conditioning after overtraining in rats with BLA lesions. In Experiment 1, intact rats that were overtrained and later inflated displayed elevated freezing levels when tested, indicating that S-S associations contribute to overtrained fear memories. Interestingly, neither neurotoxic BLA lesions nor temporary inactivation of the BLA during overtraining prevented the inflation effect (Experiment 2 and 3, respectively). These results reveal that S-S associa- tions support Pavlovian fear memories after overtraining in both intact rats and rats with BLA lesions, and imply that the central nucleus of the amygdala encodes CS-US associations during fear conditioning.NIH (RO1MH073655)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83229/1/rabinakBN08.pd

Pontine stimulation overcomes developmental limitations in the neural mechanisms of eyeblink conditioning

Pontine neuronal activation during auditory stimuli increases ontogenetically between postnatal days (P) P17 and P24 in rats. Pontine neurons are an essential component of the conditioned stimulus (CS) pathway for eyeblink conditioning, providing mossy fiber input to the cerebellum. Here we examined whether the developmental limitation in pontine responsiveness to a CS in P17 rats could be overcome by direct stimulation of the CS pathway. Eyeblink conditioning was established in infant rats on P17-P18 and P24-P25 using pontine stimulation as a CS. There were no significant age-related differences in the rate or level of conditioning. Eyeblink conditioned responses established with the stimulation CS were abolished by inactivation of the ipsilateral cerebellar nuclei and overlying cortex in both age groups. The findings suggest that developmental changes in the CS pathway play an important role in the ontogeny of eyeblink conditioning

Targeting the Endocannabinoid System in the Treatment of Posttraumatic Stress Disorder : A Promising Case of Preclinical-Clinical Translation?

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 and thereby influences an organisms ability to cope with threats and stressful experiences. Animal studies show that CB1 receptor activation within the amygdala is essential for extinction of fear memories. Failure to extinguish traumatic memories is a core symptom of posttraumatic stress disorder, suggesting that potentiating eCB signaling may have a therapeutic potential in this condition. However, it has 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 receptor activation, using Delta(9)-tetrahydrocannabinol or its synthetic analogs; or indirect potentiation, through inhibition of eCB-degrading enzymes, the anandamide-degrading enzyme fatty acid amide hydrolase; or the 2-AG (2-arachidonoyl glycerol)-degrading enzyme monoacylglycerol lipase. We then review recent human data on direct CB1 receptor activation via Delta(9)-tetrahydrocannabinol and anandamide potentiation through fatty acid amide hydrolase 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.Funding Agencies|Swedish Research CouncilSwedish Research CouncilEuropean Commission [2013-07434, 2019-01138]; Brain &amp; Behavior Research FoundationNARSAD [27094]; National Institute of Mental HealthUnited States Department of Health &amp; Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [R33MH111935, R01MH122867]</p