Daniela Rabellino

The neurobiology of emotion regulation in posttraumatic stress disorder: Amygdala downregulation via real‐time fMRI neurofeedback

Amygdala dysregulation has been shown to be central to the pathophysiology of posttraumatic stress disorder (PTSD) representing a critical treatment target. Here, amygdala downregulation was targeted using real‐time fMRI neurofeedback (rt‐fMRI‐nf) in patients with PTSD, allowing us to examine further the regulation of emotional states during symptom provocation. Patients (n = 10) completed three sessions of rt‐fMRI‐nf with the instruction to downregulate activation in the amygdala, while viewing personalized trauma words. Amygdala downregulation was assessed by contrasting (a) regulate trials, with (b) viewing trauma words and not attempting to regulate. Training was followed by one transfer run not involving neurofeedback. Generalized psychophysiological interaction (gPPI) and dynamic causal modeling (DCM) analyses were also computed to explore task‐based functional connectivity and causal structure, respectively. It was found that PTSD patients were able to successfully downregulate both right and left amygdala activation, showing sustained effects within the transfer run. Increased activation in the dorsolateral and ventrolateral prefrontal cortex (PFC), regions related to emotion regulation, was observed during regulate as compared with view conditions. Importantly, activation in the PFC, rostral anterior cingulate cortex, and the insula, were negatively correlated to PTSD dissociative symptoms in the transfer run. Increased functional connectivity between the amygdala‐ and both the dorsolateral and dorsomedial PFC was found during regulate, as compared with view conditions during neurofeedback training. Finally, our DCM analysis exploring directional structure suggested that amygdala downregulation involves both top‐down and bottom‐up information flow with regard to observed PFC‐amygdala connectivity. This is the first demonstration of successful downregulation of the amygdala using rt‐fMRI‐nf in PTSD, which was critically sustained in a subsequent transfer run without neurofeedback, and corresponded to increased connectivity with prefrontal regions involved in emotion regulation during the intervention. Hum Brain Mapp 38:541–560, 2017.

fMRI functional connectivity of the periaqueductal gray in PTSD and its dissociative subtype

Posttraumatic stress disorder (PTSD) is associated with hyperarousal and active fight or flight defensive responses. By contrast, the dissociative subtype of PTSD, characterized by depersonalization and derealization symptoms, is frequently accompanied by additional passive or submissive defensive responses associated with autonomic blunting. Here, the periaqueductal gray (PAG) plays a central role in defensive responses, where the dorsolateral (DL‐PAG) and ventrolateral PAG (VL‐PAG) are thought to mediate active and passive defensive responses, respectively.

The innate alarm system in PTSD: conscious and subconscious processing of threat

The innate alarm system (IAS), comprised of functionally connected brain regions including the brainstem, amygdala, pulvinar, and frontotemporal cortex, is a fast subcortical brain network facilitating rapid responses to threat. Post-traumatic stress disorder (PTSD) features subconscious and conscious threat detection, together contributing to hyperarousal symptoms. Emerging literature identifies aberrant threat-related neurocircuitry involved in subconscious and conscious threat processing in PTSD. We review this literature, focusing on subconscious threat processing and its relation to the IAS. Available evidence indicates increased neural activity and functional connectivity between IAS brain regions (e.g. locus coeruleus, superior colliculus, amygdala, and prefrontal cortex). These alterations are observed during both subconscious threat processing and at rest, suggesting increased defensive posturing, maintained in the absence of overt threat.

Group Membership Modulates the Neural Circuitry Underlying Third Party Punishment

This research aims to explore the neural correlates involved in altruistic punishment, parochial altruism and anti-social punishment, using the Third-Party Punishment (TPP) game. In particular, this study considered these punishment behaviors in in-group vs. out-group game settings, to compare how people behave with members of their own national group and with members of another national group. The results showed that participants act altruistically to protect in-group members. This study indicates that norm violation in in-group (but not in out-group) settings results in increased activity in the medial prefrontal cortex and temporo-parietal junction, brain regions involved in the mentalizing network, as the third-party attempts to understand or justify in-group members’ behavior. Finally, exploratory analysis during anti-social punishment behavior showed brain activation recruitment of the ventromedial prefrontal cortex, an area associated with altered regulation of emotions.

Aberrant Functional Connectivity of the Amygdala Complexes in PTSD during Conscious and Subconscious Processing of Trauma-Related Stimuli

Post-traumatic stress disorder (PTSD) is characterized by altered functional connectivity of the amygdala complexes at rest. However, amygdala complex connectivity during conscious and subconscious threat processing remains to be elucidated. Here, we investigate specific connectivity of the centromedial amygdala (CMA) and basolateral amygdala (BLA) during conscious and subconscious processing of trauma-related words among individuals with PTSD (n = 26) as compared to non-trauma-exposed controls (n = 20). Psycho-physiological interaction analyses were performed using the right and left amygdala complexes as regions of interest during conscious and subconscious trauma word processing. These analyses revealed a differential, context-dependent responses by each amygdala seed during trauma processing in PTSD. Specifically, relative to controls, during subconscious processing, individuals with PTSD demonstrated increased connectivity of the CMA with the superior frontal gyrus, accompanied by a pattern of decreased connectivity between the BLA and the superior colliculus. During conscious processing, relative to controls, individuals with PTSD showed increased connectivity between the CMA and the pulvinar. These findings demonstrate alterations in amygdala subregion functional connectivity in PTSD and highlight the disruption of the innate alarm network during both conscious and subconscious trauma processing in this disorder.

“I can't tell whether it's my hand”: a pilot study of the neurophenomenology of body representation during the rubber hand illusion in trauma-related disorders

Background Early traumatic experiences are thought to be causal factors in the development of trauma-related dissociative experiences, including depersonalization and derealization. The rubber hand illusion (RHI), a well-known paradigm that measures multi-sensorial integration of a rubber hand into ones own body representation, has been used to investigate alterations in the experience of body ownership and of body representation. Critically, however, it has never been studied in individuals with trauma-related disorders. Objective To investigate body representation distortions occurring in trauma-related disorders in response to the RHI. Method The RHI was administered to three individuals with the dissociative subtype of posttraumatic stress disorder (PTSD), and subjective, behavioral, cardiovascular and skin conductance responses were recorded. Results Participants’ subjective experiences of the RHI were differentiated and complex. The illusion was induced following both synchronous and asynchronous brushing and variably evoked subjective distress, depersonalization and derealization experiences, tonic immobility, increased physiological arousal and flashbacks. Conclusions The present findings point towards the RHI as a strong provocation stimulus that elicits individual patterns of symptom presentation, including experiences of distress and dissociation, in individuals with trauma-related disorders, including the dissociative subtype of PTSD. Highlights of the article The rubber hand illusion (RHI) elicits distress, tonic immobility, depersonalization and derealization, and autonomic responses in individuals with trauma-related disorders, including the dissociative subtype of posttraumatic stress disorder (PTSD). RHI effects related to body misrepresentation may trigger altered experiences related to body ownership. The RHI represents a promising paradigm for studying the neurophenomenology of body distortion in individuals experiencing trauma-related altered states of consciousness (TRASC).

The cerebellum after trauma: Resting-state functional connectivity of the cerebellum in posttraumatic stress disorder and its dissociative subtype

The cerebellum plays a key role not only in motor function but also in affect and cognition. Although several psychopathological disorders have been associated with overall cerebellar dysfunction, it remains unclear whether different regions of the cerebellum contribute uniquely to psychopathology. Accordingly, we compared seed‐based resting‐state functional connectivity of the anterior cerebellum (lobule IV–V), of the posterior cerebellum (Crus I), and of the anterior vermis across posttraumatic stress disorder (PTSD; n = 65), its dissociative subtype (PTSD + DS; n = 37), and non‐trauma‐exposed healthy controls (HC; n = 47). Here, we observed decreased functional connectivity of the anterior cerebellum and anterior vermis with brain regions involved in somatosensory processing, multisensory integration, and bodily self‐consciousness (temporo‐parietal junction, postcentral gyrus, and superior parietal lobule) in PTSD + DS as compared to PTSD and HC. Moreover, the PTSD + DS group showed increased functional connectivity of the posterior cerebellum with cortical areas related to emotion regulation (ventromedial prefrontal and orbito‐frontal cortex, subgenual anterior cingulum) as compared to PTSD. By contrast, PTSD showed increased functional connectivity of the anterior cerebellum with cortical areas associated with visual processing (fusiform gyrus), interoceptive awareness (posterior insula), memory retrieval, and contextual processing (hippocampus) as compared to HC. Finally, we observed decreased functional connectivity between the posterior cerebellum and prefrontal regions involved in emotion regulation, in PTSD as compared to HC. These findings not only highlight the crucial role of each cerebellar region examined in the psychopathology of PTSD but also reveal unique alterations in functional connectivity distinguishing the dissociative subtype of PTSD versus PTSD.

Resting-state functional connectivity of the bed nucleus of the stria terminalis in post-traumatic stress disorder and its dissociative subtype

The bed nucleus of the stria terminals (BNST) is a subcortical structure involved in anticipatory and sustained reactivity to threat and is thus essential to the understanding of anxiety and stress responses. Although chronic stress and anxiety represent a hallmark of post‐traumatic stress disorder (PTSD), to date, few studies have examined the functional connectivity of the BNST in PTSD. Here, we used resting state functional Magnetic Resonance Imaging (fMRI) to investigate the functional connectivity of the BNST in PTSD (n = 70), its dissociative subtype (PTSD + DS) (n = 41), and healthy controls (n = 50). In comparison to controls, PTSD showed increased functional connectivity of the BNST with regions of the reward system (ventral and dorsal striatum), possibly underlying stress‐induced reward‐seeking behaviors in PTSD. By contrast, comparing PTSD + DS to controls, we observed increased functional connectivity of the BNST with the claustrum, a brain region implicated in consciousness and a primary site of kappa‐opioid receptors, which are critical to the dynorphin‐mediated dysphoric stress response. Moreover, PTSD + DS showed increased functional connectivity of the BNST with brain regions involved in attention and salience detection (anterior insula and caudate nucleus) as compared to PTSD and controls. Finally, BNST functional connectivity positively correlated with default‐mode network regions as a function of state identity dissociation, suggesting a role of BNST networks in the disruption of self‐relevant processing characterizing the dissociative subtype. These findings represent an important first step in elucidating the role of the BNST in aberrant functional networks underlying PTSD and its dissociative subtype.

Altered Sense of Body Ownership and Agency in Posttraumatic Stress Disorder and Its Dissociative Subtype: A Rubber Hand Illusion Study

Traumatic experiences have been linked to the development of altered states of consciousness affecting bodily perception, including alterations in body ownership and in sense of agency, the conscious experience of the body as ones own and under voluntary control. Severe psychological trauma and prolonged distress may lead to posttraumatic stress disorder (PTSD). Together, symptoms of derealization and, related specifically to the sense of body ownership and agency, of depersonalization (where parts of the body or the entire body itself is perceived as detached and out of control), constitute the dissociative subtype (PTSD+DS). In this study, we explored the Rubber Hand Illusion, an experimental paradigm utilized to manipulate sense of body ownership in PTSD (n = 4) and PTSD+DS (n = 6) as compared to healthy controls (n = 7). Perceived finger location and self-report questionnaires were used as behavioral and subjective measures of the illusion, respectively. In addition, the correlation between the illusions effect and sense of agency as a continuous feeling of controlling ones own body movements was explored. Here, a lower illusion effect was observed in the PTSD as compared to the control group after synchronous stimulation for both the proprioceptive drift and subjectively perceived illusion. Moreover, by both proprioceptive drift and by subjective ratings, the PTSD+DS group showed a response characterized by high variance, ranging from a very strong to a very weak effect of the illusion. Finally, sense of agency showed a trend toward a negative correlation with the strength of the illusion as subjectively perceived by participants with PTSD and PTSD+DS. These findings suggest individuals with PTSD may, at times, maintain a rigid representation of the body as an avoidance strategy, with top-down cognitive processes weakening the impact of manipulation of body ownership. By contrast, the response elicited in PTSD+DS appeared to be driven by either an increased vulnerability to manipulation of embodiment or by a dominant top-down cognitive representation of the body, with disruption of multisensory integration processes likely in both cases. Taken together, these findings further our understanding of bodily consciousness in PTSD and its dissociative subtype and highlight the supportive role played by sense of agency for the maintenance of body ownership.

Neuroimaging the traumatized self: fMRI reveals altered response in cortical midline structures and occipital cortex during visual and verbal self- and other-referential processing in women with PTSD

ABSTRACT Background: Changes to the diagnostic criteria for PTSD in DSM-5 reflect an increased emphasis on negative cognition referring to self and other, including self-blame, and related pervasive negative affective states including for self-conscious emotions such as guilt and shame. Objective: Investigate the neural correlates of valenced self-referential processing (SRP) and other-referential processing (ORP) in persons with PTSD. Method: We compared response to the Visual-Verbal Self-Other Referential Processing Task in an fMRI study of women with (n = 20) versus without (n = 24) PTSD primarily relating to childhood and interpersonal trauma histories using statistical parametric mapping and group independent component analysis. Results: As compared to women without PTSD, women with PTSD endorsed negative words as more descriptive both of themselves and others, whereas positive words were endorsed as less descriptive both of themselves and others. Women with PTSD also reported a greater experience of negative affect and a lesser experience of positive affect during SRP specifically. Significant differences between groups were observed within independent components defined by ventral- and middle-medial prefrontal corte x, mediolateral parietal cortex, and visual cortex, depending on experimental conditions. Conclusions: This study reveals brain-based disturbances during SRP and ORP in women with PTSD related to interpersonal and developmental trauma. Psychological assessment and treatment should address altered sense of self and affective response to others in PTSD.