Emotional Reactivity in Posttraumatic Stress Disorder: Behavioural and Neurobiological Correlates of Underlying Mechanisms and the Role of Emotional Memory Modification

The symptom pattern of posttraumatic stress disorder (PTSD) comprises four clusters: “involuntary distressing memories”, “persistent avoidance of stimuli related to the traumatic event”, “negative alterations in cognition and mood”, and “in arousal and reactivity” (DSM 5, American Psychological Association). Increasing evidence points towards enhanced emotional reactivity as an underlying mechanism of the latter mentioned symptom pattern in individuals with PTSD. From a process oriented perspective, enhanced emotional reactivity has been linked to aberrant fear conditioning processes: Classical fear conditioning paradigms comprise the association of a neutral cue with an aversive event (danger cue) while another cue (safety cue) is never followed by an aversive event. Although the picture is not clear yet, complex alterations in the context of fear processing have been observed in PTSD: While overall enhanced reactivity to both cues has been found, also difficulties in the ability to differentiate between the conditioned danger and safety cue was examined. Additionally, studies point to slower and/ or reduced fear extinction. It is important to note that the diagnostic criteria of PTSD state that emotional responses in PTSD tend to spread to a variety of stimuli, resembling the traumatic event, which is referred to as overgeneralization. However, as mentioned before, classical fear conditioning paradigms are restricted to two conditioned cues and thus, cannot investigate the transfer of emotional responses to other cues. Therefore, extending the classic paradigms by including a range of cues is important to ensure a better understanding of the respective pathomechanism. On a neurobiological level, enhanced emotional reactivity has been associated with elevated cardiovascular activity and decreased neuronal activity in prefrontal regions, while simultaneously activity of limbic regions has been found to be increased. This pattern is referred to as decreased top-down regulation. Thus, aberrant neurobiological emotional processing in PTSD points to difficulties in regulating emotional states and thus, alterations in emotional reactivity. Importantly, heart rate variability (HRV) is stated to be a biomarker of emotion regulation, since a high HRV has been associated with one’s regulatory capacity. Importantly, HRV has been found to be lower in PTSD. Yet, the relation between HRV and the neuronal response pattern associated with autonomic functioning has not been studied in PTSD. Investigating both parameters simultaneously is hypothesized to help gain a better understanding of PTSD patients’ capacity to regulate emotional responses. Altogether, emotion overreactivity is a key facet of PTSD. Therefore, one aim of therapeutical attempts is to attenuate strong emotional memory. Interestingly, upcoming evidence from experimental research points to a promising technique, which might provide the opportunity to modify consolidated memory permanently and thus, may be beneficial with respect to therapy. That is, upon retrieval of consolidated memories, these memories must once again stabilize, in order to persist. This process of re-stabilization is known as reconsolidation. Herein, pharmacological, as well as behavioral intervention protocols have been shown to successfully attenuate prior learned emotional responses, when applied during reconsolidation. However, studies are sparse in testing whether therapeutical interventions in combination with reconsolidation provide a beneficial effect on emotional memories. Altogether, the present thesis investigated underlying mechanisms of heightened emotional reactivity in PTSD. Moreover, an experimental approach aiming at attenuating a newly formed aversive emotional memory was tested, to provide further insights into processes that may contribute to overcome strong negative emotional states. In the first study, alterations in the acquisition and generalization of fear were examined. A recently introduced fear conditioning and generalization paradigm was studied in 30 PTSD individuals, 30 healthy trauma exposed and 30 non-trauma exposed healthy control participants. The paradigm covers a range of stimuli parametrically varying in their similarity and thus, forming a continuum between the danger and safety cue. This allows the testing of fear transfer to stimuli that resemble the danger cue. Hints towards altered emotional reactivity, here, alterations in generalization was found with respect to reaction times while evaluating the risk of an aversive event associated with generalization stimuli in PTSD: PTSD patients were slower in judging the risk related to stimuli of moderate similarity to the danger cue. Additionally, PTSD subjects overall subjectively expected more risk irrespective of the stimulus type across all experimental phases. Importantly, while explicit risk perception was linked to PTSD, implicit measures of overgeneralization were related to traumatization per se. In a second study, neurophysiological underpinnings of emotion regulation have been addressed. Specifically, the combination of HRV and its’ neuronal response pattern (central autonomic network, CAN) was assessed in 57 PTSD individuals and 41 healthy control subjects during resting state functional magnetic resonance imaging (fMRI). PTSD patients were characterized by lower HRV compared to controls. Moreover, PTSD subjects exhibited a widespread connectivity pattern between key nodes of the CAN and multiple cortical and subcortical areas compared to controls. Importantly, while CAN connectivity was related to HRV in controls, this association was not found to be significant in PTSD. These data were interpreted in the frame of increased emotional reactivity and a decoupling of central and autonomic functioning in PTSD. In a third study, we investigated whether pharmacological and behavioral interventions applied during memory reconsolidation can attenuate a prior acquired fear memory. A differential fear conditioning paradigm was studied in 80 female healthy individuals: Two stimuli (CS+) were associated with an aversive event, while one (CS-) was never followed by an aversive event. Pharmacological (propranolol) and behavioural (reappraisal, multimodal sensory stimulation) intervention protocols were applied upon memory reactivation of one of the two CS+ (reconsolidation disruption) and contrasted to a placebo control condition. Effects on memory were tested during extinction and reinstatement testing. Differential effects regarding the reactivated and non-reactivated CS+ have only been observed in the propranolol condition. Specifically, fear memory was stronger in response to the non-reactivated CS+ compared to the placebo group. None of the behavioural interventions did attenuate fear memory. Yet, an increasing number of studies point towards difficulties in triggering reconsolidation processes. Findings are discussed with respect to boundary conditions. In sum, the first two studies extended prior investigations on emotional reactivity in PTSD. Results showed that PTSD individuals exhibited altered emotional reactivity to safe stimuli resembling the danger cue, as indexed by alterations in the generalization of fear with respect to the certainty of stimulus evaluation. Together with increased subjective risk perception and alterations in baseline responding and fear learning, these findings provide further evidence for a correlate of altered emotional reactivity in PTSD. Moreover, study II hints towards a psychophysiological-neuronal profile, contributing to emotion regulation difficulties in PTSD. Thus, while PTSD individuals exhibited lower resting HRV, the latter was not associated with the central autonomic network, pointing to a desynchronized pattern. Both studies implicate the importance of emotional (over-) reactivity in PTSD in contributing to the defined symptom pattern of PTSD. However, an attempt to experimentally target emotional memories did not show a beneficial effect by combining reconsolidation with either a pharmacological agent (propranolol) or behavioural therapeutical techniques on a prior established fear memory. Future research should focus on the combination of the mentioned investigation on emotion reactivity and regulation in PTSD. This would provide a broader picture of the complex interplay between both concepts and their associated behavioural und psychobiological profile. Possible implications for PTSD psychotherapy include strategies that reduce uncertainty in save situations. Although more fundamental research is needed to investigate boundary conditions for reconsolidation to occur, a better understanding of the respective mechanism may help to improve therapeutical strategies

Emotional Reactivity in Posttraumatic Stress Disorder: Behavioural and Neurobiological Correlates of Underlying Mechanisms and the Role of Emotional Memory Modification

The symptom pattern of posttraumatic stress disorder (PTSD) comprises four clusters: “involuntary distressing memories”, “persistent avoidance of stimuli related to the traumatic event”, “negative alterations in cognition and mood”, and “in arousal and reactivity” (DSM 5, American Psychological Association). Increasing evidence points towards enhanced emotional reactivity as an underlying mechanism of the latter mentioned symptom pattern in individuals with PTSD. From a process oriented perspective, enhanced emotional reactivity has been linked to aberrant fear conditioning processes: Classical fear conditioning paradigms comprise the association of a neutral cue with an aversive event (danger cue) while another cue (safety cue) is never followed by an aversive event. Although the picture is not clear yet, complex alterations in the context of fear processing have been observed in PTSD: While overall enhanced reactivity to both cues has been found, also difficulties in the ability to differentiate between the conditioned danger and safety cue was examined. Additionally, studies point to slower and/ or reduced fear extinction. It is important to note that the diagnostic criteria of PTSD state that emotional responses in PTSD tend to spread to a variety of stimuli, resembling the traumatic event, which is referred to as overgeneralization. However, as mentioned before, classical fear conditioning paradigms are restricted to two conditioned cues and thus, cannot investigate the transfer of emotional responses to other cues. Therefore, extending the classic paradigms by including a range of cues is important to ensure a better understanding of the respective pathomechanism. On a neurobiological level, enhanced emotional reactivity has been associated with elevated cardiovascular activity and decreased neuronal activity in prefrontal regions, while simultaneously activity of limbic regions has been found to be increased. This pattern is referred to as decreased top-down regulation. Thus, aberrant neurobiological emotional processing in PTSD points to difficulties in regulating emotional states and thus, alterations in emotional reactivity. Importantly, heart rate variability (HRV) is stated to be a biomarker of emotion regulation, since a high HRV has been associated with one’s regulatory capacity. Importantly, HRV has been found to be lower in PTSD. Yet, the relation between HRV and the neuronal response pattern associated with autonomic functioning has not been studied in PTSD. Investigating both parameters simultaneously is hypothesized to help gain a better understanding of PTSD patients’ capacity to regulate emotional responses. Altogether, emotion overreactivity is a key facet of PTSD. Therefore, one aim of therapeutical attempts is to attenuate strong emotional memory. Interestingly, upcoming evidence from experimental research points to a promising technique, which might provide the opportunity to modify consolidated memory permanently and thus, may be beneficial with respect to therapy. That is, upon retrieval of consolidated memories, these memories must once again stabilize, in order to persist. This process of re-stabilization is known as reconsolidation. Herein, pharmacological, as well as behavioral intervention protocols have been shown to successfully attenuate prior learned emotional responses, when applied during reconsolidation. However, studies are sparse in testing whether therapeutical interventions in combination with reconsolidation provide a beneficial effect on emotional memories. Altogether, the present thesis investigated underlying mechanisms of heightened emotional reactivity in PTSD. Moreover, an experimental approach aiming at attenuating a newly formed aversive emotional memory was tested, to provide further insights into processes that may contribute to overcome strong negative emotional states. In the first study, alterations in the acquisition and generalization of fear were examined. A recently introduced fear conditioning and generalization paradigm was studied in 30 PTSD individuals, 30 healthy trauma exposed and 30 non-trauma exposed healthy control participants. The paradigm covers a range of stimuli parametrically varying in their similarity and thus, forming a continuum between the danger and safety cue. This allows the testing of fear transfer to stimuli that resemble the danger cue. Hints towards altered emotional reactivity, here, alterations in generalization was found with respect to reaction times while evaluating the risk of an aversive event associated with generalization stimuli in PTSD: PTSD patients were slower in judging the risk related to stimuli of moderate similarity to the danger cue. Additionally, PTSD subjects overall subjectively expected more risk irrespective of the stimulus type across all experimental phases. Importantly, while explicit risk perception was linked to PTSD, implicit measures of overgeneralization were related to traumatization per se. In a second study, neurophysiological underpinnings of emotion regulation have been addressed. Specifically, the combination of HRV and its’ neuronal response pattern (central autonomic network, CAN) was assessed in 57 PTSD individuals and 41 healthy control subjects during resting state functional magnetic resonance imaging (fMRI). PTSD patients were characterized by lower HRV compared to controls. Moreover, PTSD subjects exhibited a widespread connectivity pattern between key nodes of the CAN and multiple cortical and subcortical areas compared to controls. Importantly, while CAN connectivity was related to HRV in controls, this association was not found to be significant in PTSD. These data were interpreted in the frame of increased emotional reactivity and a decoupling of central and autonomic functioning in PTSD. In a third study, we investigated whether pharmacological and behavioral interventions applied during memory reconsolidation can attenuate a prior acquired fear memory. A differential fear conditioning paradigm was studied in 80 female healthy individuals: Two stimuli (CS+) were associated with an aversive event, while one (CS-) was never followed by an aversive event. Pharmacological (propranolol) and behavioural (reappraisal, multimodal sensory stimulation) intervention protocols were applied upon memory reactivation of one of the two CS+ (reconsolidation disruption) and contrasted to a placebo control condition. Effects on memory were tested during extinction and reinstatement testing. Differential effects regarding the reactivated and non-reactivated CS+ have only been observed in the propranolol condition. Specifically, fear memory was stronger in response to the non-reactivated CS+ compared to the placebo group. None of the behavioural interventions did attenuate fear memory. Yet, an increasing number of studies point towards difficulties in triggering reconsolidation processes. Findings are discussed with respect to boundary conditions. In sum, the first two studies extended prior investigations on emotional reactivity in PTSD. Results showed that PTSD individuals exhibited altered emotional reactivity to safe stimuli resembling the danger cue, as indexed by alterations in the generalization of fear with respect to the certainty of stimulus evaluation. Together with increased subjective risk perception and alterations in baseline responding and fear learning, these findings provide further evidence for a correlate of altered emotional reactivity in PTSD. Moreover, study II hints towards a psychophysiological-neuronal profile, contributing to emotion regulation difficulties in PTSD. Thus, while PTSD individuals exhibited lower resting HRV, the latter was not associated with the central autonomic network, pointing to a desynchronized pattern. Both studies implicate the importance of emotional (over-) reactivity in PTSD in contributing to the defined symptom pattern of PTSD. However, an attempt to experimentally target emotional memories did not show a beneficial effect by combining reconsolidation with either a pharmacological agent (propranolol) or behavioural therapeutical techniques on a prior established fear memory. Future research should focus on the combination of the mentioned investigation on emotion reactivity and regulation in PTSD. This would provide a broader picture of the complex interplay between both concepts and their associated behavioural und psychobiological profile. Possible implications for PTSD psychotherapy include strategies that reduce uncertainty in save situations. Although more fundamental research is needed to investigate boundary conditions for reconsolidation to occur, a better understanding of the respective mechanism may help to improve therapeutical strategies

The Vestibulocerebellum and the Shattered Self: a Resting-State Functional Connectivity Study in Posttraumatic Stress Disorder and Its Dissociative Subtype

The flocculus is a region of the vestibulocerebellum dedicated to the coordination of neck, head, and eye movements for optimal posture, balance, and orienting responses. Despite growing evidence of vestibular and oculomotor impairments in the aftermath of traumatic stress, little is known about the effects of chronic psychological trauma on vestibulocerebellar functioning. Here, we investigated alterations in functional connectivity of the flocculus at rest among individuals with post-traumatic stress disorder (PTSD) and its dissociative subtype (PTSD + DS) as compared to healthy controls. Forty-four healthy controls, 57 PTSD, and 32 PTSD + DS underwent 6-min resting-state MRI scans. Seed-based functional connectivity analyses using the right and left flocculi as seeds were performed. These analyses revealed that, as compared to controls, PTSD and PTSD + DS showed decreased resting-state functional connectivity of the left flocculus with cortical regions involved in bodily self-consciousness, including the temporo-parietal junction, the supramarginal and angular gyri, and the superior parietal lobule. Moreover, as compared to controls, the PTSD + DS group showed decreased functional connectivity of the left flocculus with the medial prefrontal cortex, the precuneus, and the mid/posterior cingulum, key regions of the default mode network. Critically, when comparing PTSD + DS to PTSD, we observed increased functional connectivity of the right flocculus with the right anterior hippocampus, a region affected frequently by early life trauma. Taken together, our findings point toward the crucial role of the flocculus in the neurocircuitry underlying a coherent and embodied self, which can be compromised in PTSD and PTSD + DS

Contrasting Associations Between Heart Rate Variability and Brainstem-Limbic Connectivity in Posttraumatic Stress Disorder and Its Dissociative Subtype: A Pilot Study

Background: Increasing evidence points toward the need to extend the neurobiological conceptualization of posttraumatic stress disorder (PTSD) to include evolutionarily conserved neurocircuitries centered on the brainstem and the midbrain. The reticular activating system (RAS) helps to shape the arousal state of the brain, acting as a bridge between brain and body. To modulate arousal, the RAS is closely tied to the autonomic nervous system (ANS). Individuals with PTSD often reveal altered arousal patterns, ranging from hyper- to blunted arousal states, as well as altered functional connectivity profiles of key arousal-related brain structures that receive direct projections from the RAS. Accordingly, the present study aims to explore resting state functional connectivity of the RAS and its interaction with the ANS in participants with PTSD and its dissociative subtype. Methods: Individuals with PTSD (n = 57), its dissociative subtype (PTSD + DS, n = 32) and healthy controls (n = 40) underwent a 6-min resting functional magnetic resonance imaging and pulse data recording. Resting state functional connectivity (rsFC) of a central node of the RAS – the pedunculopontine nuclei (PPN) – was investigated along with its relation to ANS functioning as indexed by heart rate variability (HRV). HRV is a prominent marker indexing the flexibility of an organism to react adaptively to environmental needs, with higher HRV representing greater effective adaptation. Results: Both PTSD and PTSD + DS demonstrated reduced HRV as compared to controls. HRV measures were then correlated with rsFC of the PPN. Critically, participants with PTSD and participants with PTSD + DS displayed inverse correlations between HRV and rsFC between the PPN and key limbic structures, including the amygdala. Whereas participants with PTSD displayed a positive relationship between HRV and PPN rsFC with the amygdala, participants with PTSD + DS demonstrated a negative relationship between HRV and PPN rsFC with the amygdala. Conclusion: The present exploratory investigation reveals contrasting patterns of arousal-related circuitry among participants with PTSD and PTSD + DS, providing a neurobiological lens to interpret hyper- and more blunted arousal states in PTSD and PTSD + DS, respectively

Comparing Discounting of Potentially Real Rewards and Losses by Means of Functional Magnetic Resonance Imaging

AimDelay discounting (DD) has often been investigated in the context of decision making whereby individuals attribute decreasing value to rewards in the distant future. Less is known about DD in the context of negative consequences. The aim of this pilot study was to identify commonalities and differences between reward and loss discounting on the behavioral as well as the neural level by means of computational modeling and functional Magnetic Resonance Imaging (fMRI). We furthermore compared the neural activation between anticipation of rewards and losses.MethodWe conducted a study combining an intertemporal choice task for potentially real rewards and losses (decision-making) with a monetary incentive/loss delay task (reward/loss anticipation). Thirty healthy participants (age 18-35, 14 female) completed the study. In each trial, participants had to choose between a smaller immediate loss/win and a larger loss/win at a fixed delay of two weeks. Task-related brain activation was measured with fMRI.ResultsHyperbolic discounting parameters of loss and reward conditions were correlated (r = 0.56). During decision-making, BOLD activation was observed in the parietal and prefrontal cortex, with no differences between reward and loss conditions. During reward and loss anticipation, dissociable activation was observed in the striatum, the anterior insula and the anterior cingulate cortex.ConclusionWe observed behavior concurrent with DD in both the reward and loss condition, with evidence for similar behavioral and neural patterns in the two conditions. Intertemporal decision-making recruited the fronto-parietal network, whilst reward and loss anticipation were related to activation in the salience network. The interpretation of these findings may be limited to short delays and small monetary outcomes

Modification of Fear Memory by Pharmacological and Behavioural Interventions during Reconsolidation.

Dysfunctional fear responses play a central role in many mental disorders. New insights in learning and memory suggest that pharmacological and behavioural interventions during the reconsolidation of reactivated fear memories may increase the efficacy of therapeutic interventions. It has been proposed that interventions applied during reconsolidation may modify the original fear memory, and thus prevent the spontaneous recovery and reinstatement of the fear response.We investigated whether pharmacological (propranolol) and behavioural (reappraisal, multisensory stimulation) interventions reduce fear memory, and prevent reinstatement of fear in comparison to a placebo control group. Eighty healthy female subjects underwent a differential fear conditioning procedure with three stimuli (CS). Two of these (CS+) were paired with an electric shock on day 1. On day 2, 20 subjects were pseudo-randomly assigned to either the propranolol or placebo condition, or underwent one of the two behavioural interventions after one of the two CS+ was reactivated. On day 3, all subjects underwent an extinction phase, followed by a reinstatement test. Dependent variables were US expectancy ratings, fear-potentiated startle, and skin conductance response.Differential fear responses to the reactivated and non-reactivated CS+ were observed only in the propranolol condition. Here, the non-reactivated CS+ evoked stronger fear-potentiated startle-responses compared to the placebo group. None of the interventions prevented the return of the extinguished fear response after re-exposure to the unconditioned stimulus.Our data are in line with an increasing body of research stating that the occurrence of reconsolidation may be constrained by boundary conditions such as subtle differences in experimental manipulations and instructions. In conclusion, our findings do not support a beneficial effect in using reconsolidation processes to enhance effects of psychotherapeutic interventions. This implies that more research is required before therapeutic interventions may benefit from a combination with reconsolidation processes

Modification of fear memory by pharmacological and behavioural interventions during reconsolidation

Dysfunctional fear responses play a central role in many mental disorders. New insights in learning and memory suggest that pharmacological and behavioural interventions during the reconsolidation of reactivated fear memories may increase the efficacy of therapeutic interventions. It has been proposed that interventions applied during reconsolidation may modify the original fear memory, and thus prevent the spontaneous recovery and reinstatement of the fear response.We investigated whether pharmacological (propranolol) and behavioural (reappraisal, multisensory stimulation) interventions reduce fear memory, and prevent reinstatement of fear in comparison to a placebo control group. Eighty healthy female subjects underwent a differential fear conditioning procedure with three stimuli (CS). Two of these (CS+) were paired with an electric shock on day 1. On day 2, 20 subjects were pseudo-randomly assigned to either the propranolol or placebo condition, or underwent one of the two behavioural interventions after one of the two CS+ was reactivated. On day 3, all subjects underwent an extinction phase, followed by a reinstatement test. Dependent variables were US expectancy ratings, fear-potentiated startle, and skin conductance response.Differential fear responses to the reactivated and non-reactivated CS+ were observed only in the propranolol condition. Here, the non-reactivated CS+ evoked stronger fear-potentiated startle-responses compared to the placebo group. None of the interventions prevented the return of the extinguished fear response after re-exposure to the unconditioned stimulus.Our data are in line with an increasing body of research stating that the occurrence of reconsolidation may be constrained by boundary conditions such as subtle differences in experimental manipulations and instructions. In conclusion, our findings do not support a beneficial effect in using reconsolidation processes to enhance effects of psychotherapeutic interventions. This implies that more research is required before therapeutic interventions may benefit from a combination with reconsolidation processes

The Innate Alarm System and Subliminal Threat Presentation in Posttraumatic Stress Disorder: Neuroimaging of the Midbrain and Cerebellum

Background The innate alarm system, a network of interconnected midbrain, other brainstem, and thalamic structures, serves to rapidly detect stimuli in the environment prior to the onset of conscious awareness. This system is sensitive to threatening stimuli and has evolved to process these stimuli subliminally for hastened responding. Despite the conscious unawareness, the presentation of subliminal threat stimuli generates increased activation of limbic structures, including the amygdala and insula, as well as emotionally evaluative structures, including the cerebellum and orbitofrontal cortex. Posttraumatic stress disorder (PTSD) is associated with an increased startle response and decreased extinction learning to conditioned threat. The role of the innate alarm system in the clinical presentation of PTSD, however, remains poorly understood. Methods Here, we compare midbrain, brainstem, and cerebellar activation in persons with PTSD (n = 26) and matched controls (n = 20) during subliminal threat presentation. Subjects were presented with masked trauma-related and neutral stimuli below conscious threshold. Contrasts of subliminal brain activation for the presentation of neutral stimuli were subtracted from trauma-related brain activation. Group differences in activation, as well as correlations between clinical scores and PTSD activation, were examined. Imaging data were preprocessed utilizing the spatially unbiased infratentorial template toolbox within SPM12. Results Analyses revealed increased midbrain activation in PTSD as compared to controls in the superior colliculus, periaqueductal gray, and midbrain reticular formation during subliminal threat as compared to neutral stimulus presentation. Controls showed increased activation in the right cerebellar lobule V during subliminal threat presentation as compared to PTSD. Finally, a negative correlation emerged between PTSD patient scores on the Multiscale Dissociation Inventory for the Depersonalization/Derealization subscale and activation in the right lobule V of the cerebellum during the presentation of subliminal threat as compared to neutral stimuli. Conclusion We interpret these findings as evidence of innate alarm system overactivation in PTSD and of the prominent role of the cerebellum in the undermodulation of emotion observed in PTSD