The Hijacked Self: Midbrain and Default Mode Network Functional Patterns in PTSD

In post-traumatic stress disorder (PTSD), self-related processing disturbances are demonstrated commonly and have been linked to the default mode network (DMN), a large-scale, neural network altered significantly after trauma. However, emerging evidence suggests the midbrain may be underlying self-related processing disturbances as well, yet midbrain systems remain poorly characterized in PTSD. Here, we evaluated midbrain activity and functional connectivity during subliminal, trauma-related stimulus processing (Chapters 2–4), as well as during moral injury-related (MI) memory recall (Chapter 5) in participants with PTSD as compared to healthy controls. Initially, during subliminal, trauma-related stimulus processing, we revealed stronger midbrain periaqueductal gray (PAG) activity among participants with PTSD as compared to healthy controls (Chapter 2). Afterward, we evaluated the functional connectivity exhibited by the PAG, where we revealed stronger functional connectivity between the PAG and the medial prefrontal cortex (mPFC), as well as between the PAG and the precuneus (PCN) among participants with PTSD as compared to healthy controls (Chapter 3). Critically, the mPFC and the PCN are both DMN hubs, which we did not expect to covary functionally with the PAG. Next, we evaluated directionality, where we revealed stronger excitatory functional connectivity directed by the PAG toward the mPFC and toward the PCN among participants with PTSD as compared to healthy controls (Chapter 4). Lastly, during script-driven, MI-related memory recall, we revealed convergent evidence to the above using an independent component analysis (ICA) across participants with civilian-related PTSD, participants with military- or public safety-related PTSD, and MI-exposed, healthy controls. Here, we evaluated the functional network connectivity across the IC correlated most strongly to the DMN. In PTSD, we revealed stronger functional network connectivity exhibited by the PAG across the DMN IC as compared to MI-exposed, healthy controls (Chapter 5). Taken together, these findings suggest the midbrain may be related functionally to the DMN. In PTSD, critically, the DMN appears to be recruited during trauma- and MI-related memory processing, which assists to explain the clinical significance trauma has toward self-related processing and self-identity more generally. Lastly, these findings highlight the importance the midbrain has toward large-scale, neural networks, a long-overlooked dynamic in psychopathology

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

Back to the Basics: Resting State Functional Connectivity of the Reticular Activation System in PTSD and its Dissociative Subtype.

BACKGROUND: Brainstem and midbrain neuronal circuits that control innate, reflexive responses and arousal are increasingly recognized as central to the neurobiological framework of post-traumatic stress disorder (PTSD). The reticular activation system represents a fundamental neuronal circuit that plays a critical role not only in generating arousal but also in coordinating innate, reflexive responding. Accordingly, the present investigation aims to characterize the resting state functional connectivity of the reticular activation system in PTSD and its dissociative subtype. METHODS: We investigated patterns of resting state functional connectivity of a central node of the reticular activation system, namely, the pedunculopontine nuclei, among individuals with PTSD (n = 77), its dissociative subtype (PTSD+DS; n = 48), and healthy controls (n = 51). RESULTS: Participants with PTSD and PTSD+DS were characterized by within-group pedunculopontine nuclei resting state functional connectivity to brain regions involved in innate threat processing and arousal modulation (i.e., midbrain, amygdala, ventromedial prefrontal cortex). Critically, this pattern was most pronounced in individuals with PTSD+DS, as compared to both control and PTSD groups. As compared to participants with PTSD and controls, individuals with PTSD+DS showed enhanced pedunculopontine nuclei resting state functional connectivity to the amygdala and the parahippocampal gyrus as well as to the anterior cingulate and the ventromedial prefrontal cortex. No group differences emerged between PTSD and control groups. In individuals with PTSD+DS, state derealization/depersonalization was associated with reduced resting state functional connectivity between the left pedunculopontine nuclei and the anterior nucleus of the thalamus. Altered connectivity in these regions may restrict the thalamo-cortical transmission necessary to integrate internal and external signals at a cortical level and underlie, in part, experiences of depersonalization and derealization. CONCLUSIONS: The present findings extend the current neurobiological model of PTSD and provide emerging evidence for the need to incorporate brainstem structures, including the reticular activation system, into current conceptualizations of PTSD and its dissociative subtype

The hijacked self: Disrupted functional connectivity between the periaqueductal gray and the default mode network in posttraumatic stress disorder using dynamic causal modeling.

Self-related processes define assorted self-relevant or social-cognitive functions that allow us to gather insight and to draw inferences related to our own mental conditions. Self-related processes are mediated by the default mode network (DMN), which, critically, shows altered functionality in individuals with posttraumatic stress disorder (PTSD). In PTSD, the midbrain periaqueductal gray (PAG) demonstrates stronger functional connectivity with the DMN [i.e., precuneus (PCN), medial prefrontal cortex (mPFC)] as compared to healthy individuals during subliminal, trauma-related stimulus processing. Here, we analyzed the directed functional connectivity between the PAG and the PCN, as well as between the PAG and the mPFC to more explicitly characterize the functional connectivity we have observed previously on the corresponding sample and paradigm. We evaluated three models varying with regard to context-dependent modulatory directions (i.e., bi-directional, bottom-up, top-down) among individuals with PTSD (n = 26) and healthy participants (n = 20), where Bayesian model selection was used to identify the most optimal model for each group. We then compared the effective connectivity strength for each parameter across the models and between our groups using Bayesian model averaging. Bi-directional models were found to be favoured across both groups. In PTSD, we revealed the PAG to show stronger excitatory effective connectivity to the PCN, as well as to the mPFC as compared to controls. In PTSD, we further demonstrated that PAG-mediated effective connectivity to the PCN, as well as to the mPFC were modulated more strongly during subliminal, trauma-related stimulus conditions as compared to controls. Clinical disturbances towards self-related processes are reported widely by participants with PTSD during trauma-related stimulus processing, where altered functional connectivity directed by the PAG to the DMN may elucidate experiential links between self- and trauma-related processing in traumatized individuals

The Threatful Self: Midbrain Functional Connectivity to Cortical Midline and Parietal Regions During Subliminal Trauma-Related Processing in PTSD.

BACKGROUND: The innate alarm system consists of a subcortical network of interconnected midbrain, lower brainstem, and thalamic nuclei, which together mediate the detection of evolutionarily-relevant stimuli. The periaqueductal gray is a midbrain structure innervated by the innate alarm system that coordinates the expression of defensive states following threat detection. In participants with post-traumatic stress disorder, the periaqueductal gray displays overactivation during the subliminal presentation of trauma-related stimuli as well as altered resting-state functional connectivity. Aberrant functional connectivity is also reported in post-traumatic stress disorder for the default-mode network, a large-scale brain network recruited during self-referential processing and autobiographical memory. Here, research lacks investigation on the extent to which functional interactions are displayed between the midbrain and the large-scale cortical networks in post-traumatic stress disorder. METHODS: Using a subliminal threat presentation paradigm, we investigated psycho-physiological interactions during functional neuroimaging in participants with post-traumatic stress disorder (n = 26) and healthy control subjects (n = 20). Functional connectivity of the periaqueductal gray was investigated across the whole-brain of each participant during subliminal exposure to trauma-related and neutral word stimuli. RESULTS: As compared to controls during subliminal threat presentation, the post-traumatic stress disorder group showed significantly greater periaqueductal gray functional connectivity with regions of the default-mode network (i.e., angular gyrus, precuneus, superior frontal gyrus). Moreover, multiple regression analyses revealed that the functional connectivity between the periaqueductal gray and the regions of the default-mode network correlated positively to symptoms of avoidance and state dissociation in post-traumatic stress disorder. CONCLUSION: Given that the periaqueductal gray engages the expression of defensive states, stronger midbrain functional coupling with the default-mode network may have clinical implications to self-referential and trauma-related processing in participants with post-traumatic stress disorder

Large-scale functional hyperconnectivity patterns in trauma-related dissociation: an rs-fMRI study of PTSD and its dissociative subtype

The dissociative subtype of post-traumatic stress disorder (PTSD) is a distinct PTSD phenotype characterized by trauma-related dissociation, alongside unique patterns of functional connectivity. However, disparate findings across multiple scales of investigation have highlighted the need for a cohesive understanding of dissociative neurobiology. We took a step towards this goal by conducting one of the broadest region of interest (ROI)-to-ROI analyses performed on a PTSD population to date. In this retrospective study, we investigated resting-state functional MRI data collected from a total of 192 participants, 134 of whom were diagnosed with PTSD. Small functional connectivity differences (maximum effect size 0.27) were found between participants with PTSD and controls in the temporal regions and the right frontoparietal network. Participants with the dissociative subtype showed a markedly different pattern of widespread functional hyperconnectivity compared with controls (maximum effect size 0.46), spanning subcortical regions, sensorimotor and other intrinsic connectivity networks. Furthermore, analysis of latent dimensions underlying both ROI-to-ROI brain results and a range of behavioral and clinical measures identified three clinically relevant latent dimensions—two linked to dissociation and one linked to PTSD symptoms. These results advance our understanding of dissociative neurobiology, characterizing it as a divergence from normative small-world organization. These patterns of hyperconnectivity are thought to serve a compensatory function to preserve global brain functioning in participants experiencing trauma-related dissociation

Moral wounds run deep: exaggerated midbrain functional network connectivity across the default mode network in posttraumatic stress disorder

Background: A moral injury occurs when a deeply held moral code has been violated, and it can lead to the development of symptoms of posttraumatic stress disorder (PTSD). However, the neural correlates that differentiate moral injury and PTSD remain largely unknown. Intrinsic connectivity networks such as the default mode network (DMN) appear to be altered in people with PTSD who have experienced moral injury. However, brainstem, midbrain and cerebellar systems are rarely integrated into the intrinsic connectivity networks; this is a critical oversight, because these systems display marked differences in people with PTSD and are thought to underlie strong moral emotions such as shame, guilt and betrayal. Methods: We conducted an independent component analysis on data generated during script-driven memory recall of moral injury in participants with military-or law enforcement–related PTSD (n = 28), participants with civilian-related PTSD (n = 28) and healthy controls exposed to a potentially morally injurious event (n = 18). We conducted group-wise comparisons of functional network connectivity differences across a DMN-correlated independent component, with a particular focus on brainstem, midbrain and cerebellar systems. Results: We found stronger functional network connectivity in the midbrain periaqueductal grey (t71 = 4.95, pFDR = 0.028, k = 39) and cerebellar lobule IX (t71 = 4.44, pFDR = 0.046, k = 49) in participants with civilian-related PTSD as compared to healthy controls. We also found a trend toward stronger functional network connectivity in the midbrain periaqueductal grey (t71 = 4.22, pFDR = 0.076, k = 60) in participants with military-or law enforcement–related PTSD as compared to healthy controls. Limitations: The significant clusters were large, but resolution is generally lower for subcortical structures. Conclusion: In PTSD, the DMN appears to be biased toward lower-level, midbrain systems, which may drive toxic shame and related moral emotions that are common in PTSD, highlighting the depth at which moral injuries are represented neurobiologically

Spectral decomposition of EEG microstates in post-traumatic stress disorder

Microstates offer a promising framework to study fast-scale brain dynamics in the resting-state electroencephalogram (EEG). However, microstate dynamics have yet to be investigated in post-traumatic stress disorder (PTSD), despite research demonstrating resting-state alterations in PTSD. We performed microstate-based segmentation of resting-state EEG in a clinical population of participants with PTSD (N = 61) and a non-traumatized, healthy control group (N = 61). Microstate-based measures (i.e., occurrence, mean duration, time coverage) were compared group-wise using broadband (1–30 Hz) and frequency-specific (i.e., delta, theta, alpha, beta bands) decompositions. In the broadband comparisons, the centro-posterior maximum microstate (map E) occurred significantly less frequently (d = -0.64, pFWE = 0.03) and had a significantly shorter mean duration in participants with PTSD as compared to controls (d = -0.71, pFWE \u3c 0.01). These differences were reflected in the narrow frequency bands as well, with lower frequency bands like delta (d = -0.78, pFWE \u3c 0.01), theta (d = -0.74, pFWE = 0.01), and alpha (d = -0.65, pFWE = 0.02) repeating these group-level trends, only with larger effect sizes. Interestingly, a support vector machine classification analysis comparing broadband and frequency-specific measures revealed that models containing only alpha band features significantly out-perform broadband models. When classifying PTSD, the classification accuracy was 76 % and 65 % for the alpha band and the broadband model, respectively (p = 0.03). Taken together, we provide original evidence supporting the clinical utility of microstates as diagnostic markers of PTSD and demonstrate that filtering EEG into distinct frequency bands significantly improves microstate-based classification of a psychiatric disorder

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

Large-Scale Functional Hyperconnectivity Patterns Characterizing Trauma-Related Dissociation: A rs-fMRI Study of PTSD and its Dissociative Subtype

Background: In 2012, a dissociative subtype of post-traumatic stress disorder (PTSD) was introduced into the DSM based on emerging clinical and neurobiological evidence of a distinct PTSD phenotype characterized by trauma-related dissociation. Ten years later, considerable research has demonstrated unique small-scale (i.e., node-based) and large-scale (i.e., network-related) functional connectivity patterns, specific to the dissociative subtype. However, the field has yet to arrive at a neurobiological framework able to account for the disparate findings across these various scales of investigation. Methods: We conducted the largest region of interest (ROI)-to-ROI analysis performed on a PTSD population to date, with a total of 132 ROIs and 197 participants, 134 of whom were diagnosed with PTSD. We implemented a whole-brain approach, comparing patterns of intra- and inter-network functional connectivity between participants with PTSD, its dissociative subtype, and non-traumatized, healthy controls. We also performed a joint factor analysis between the discovered patterns of functional connectivity and a battery of behavioural, demographic, and clinical scores. Results: Whereas participants with PTSD showed only modest differences to that of controls in temporal regions and the right frontoparietal network, participants with the dissociative subtype demonstrated widespread small-scale and large-scale functional hyperconnectivity, compared to controls. Three major joint factors were also identified, characterizing two dissociative and one PTSD symptom-linked factor. Conclusion: In the dissociative subtype, we found evidence of a general pattern of hyperconnectivity, especially among subcortical regions, sensory- and motor-related networks, and intrinsic connectivity networks, diverging from what we would expect based on a small-world organization of the brain