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Individuals with posttraumatic stress disorder (PTSD) are at increased risk for the development of various forms of dementia. Nevertheless, the neuropathological link between PTSD and neurodegeneration remains unclear. Degeneration of the human basal forebrain constitutes a pathological hallmark of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. In this seed‐based resting‐state (rs‐)fMRI study identifying as outcome measure the temporal BOLD signal fluctuation magnitude, a seed‐to‐voxel analyses assessed temporal correlations between the average BOLD signal within a bilateral whole basal forebrain region‐of‐interest and each whole‐brain voxel among individuals with PTSD (n = 65), its dissociative subtype (PTSD+DS) (n = 38) and healthy controls (n = 46). We found that compared both with the PTSD and healthy controls groups, the PTSD+DS group exhibited increased BOLD signal variability within two nuclei of the seed region, specifically in its extended amygdaloid region: the nucleus accumbens and the sublenticular extended amygdala. This finding is provocative, because it mimics staging models of neurodegenerative diseases reporting allocation of neuropathology in early disease stages circumscribed to the basal forebrain. Here, underlying candidate etiopathogenetic mechanisms are neurovascular uncoupling, decreased connectivity in local‐ and large‐scale neural networks, or disrupted mesolimbic dopaminergic circuitry, acting indirectly upon the basal forebrain cholinergic pathways. These abnormalities may underpin reward‐related deficits representing a putative link between persistent traumatic memory in PTSD and anterograde memory deficits in neurodegeneration. Observed alterations of the basal forebrain in the dissociative subtype of PTSD point towards the urgent need for further exploration of this region as a potential candidate vulnerability mechanism for neurodegeneration in PTSD., In this seed‐based resting‐state (rs‐)fMRI study we investigated the role of the human basal forebrain in PTSD, as a putative neuroimaging marker of PTSD‐related neurodegeneration. We observed an increased hemodynamic BOLD signal variability within the basal forebrain of PTSD subtype dissociative group, which mimics previous reports of dysfunction and degeneration of the basal forebrain in early phases of neurodegenerative diseases such as Alzheimer's disease. Observed alterations of the basal forebrain in the dissociative subtype of PTSD point toward the urgent need for further exploration of this region as a potential candidate vulnerability mechanism for neurodegeneration in PTSD.

Posttraumatic stress disorder (PTSD) has been associated with a disturbance in neural intrinsic connectivity networks (ICN), including the central executive network (CEN), default mode network (DMN), and salience network (SN). Here, we conducted a preliminary investigation examining potential changes in ICN recruitment as a function of real-time fMRI neurofeedback (rt-fMRI-NFB) during symptom provocation where we targeted the downregulation of neural response within the amygdala-a key region-of-interest in PTSD neuropathophysiology. Patients with PTSD (n = 14) completed three sessions of rt-fMRI-NFB with the following conditions: (a) regulate: decrease activation in the amygdala while processing personalized trauma words; (b) view: process trauma words while not attempting to regulate the amygdala; and (c) neutral: process neutral words. We found that recruitment of the left CEN increased over neurofeedback runs during the regulate condition, a finding supported by increased dlPFC activation during the regulate as compared to the view condition. In contrast, DMN task-negative recruitment was stable during neurofeedback runs, albeit was the highest during view conditions and increased (normalized) during rest periods. Critically, SN recruitment was high for both the regulate and the view conditions, a finding potentially indicative of CEN modality switching, adaptive learning, and increasing threat/defense processing in PTSD. In conclusion, this study provides provocative, preliminary evidence that downregulation of the amygdala using rt-fMRI-NFB in PTSD is associated with dynamic changes in ICN, an effect similar to those observed using EEG modalities of neurofeedback.

Objectives The innate alarm system (IAS) models the neurocircuitry involved in threat processing in posttraumatic stress disorder (PTSD). Here, we investigate a primary subcortical structure of the IAS model, the superior colliculus (SC), where the SC is thought to contribute to the mechanisms underlying threat-detection in PTSD. Critically, the functional connectivity between the SC and other nodes of the IAS remains unexplored. Experimental design We conducted a resting-state fMRI study to investigate the functional architecture of the IAS, focusing on connectivity of the SC in PTSD (n = 67), its dissociative subtype (n = 41), and healthy controls (n = 50) using region-of-interest seed-based analysis. Principal observations We observed group-specific resting state functional connectivity between the SC for both PTSD and its dissociative subtype, indicative of dedicated IAS collicular pathways in each group of patients. When comparing PTSD to its dissociative subtype, we observed increased resting state functional connectivity between the left SC and the right dorsolateral prefrontal cortex (DLPFC) in PTSD. The DLPFC is involved in modulation of emotional processes associated with active defensive responses characterising PTSD. Moreover, when comparing PTSD to its dissociative subtype, increased resting state functional connectivity was observed between the right SC and the right temporoparietal junction in the dissociative subtype. The temporoparietal junction is involved in depersonalization responses associated with passive defensive responses typical of the dissociative subtype. Conclusions Our findings suggest that unique resting state functional connectivity of the SC parallels the unique symptom profile and defensive responses observed in PTSD and its dissociative subtype. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc.

Objective Posttraumatic stress disorder (PTSD) is associated with decreased top-down emotion modulation from medial prefrontal cortex (mPFC) regions, a pathophysiology accompanied by hyperarousal and hyperactivation of the amygdala. By contrast, PTSD patients with the dissociative subtype (PTSD + DS) often exhibit increased mPFC top-down modulation and decreased amygdala activation associated with emotional detachment and hypoarousal. Crucially, PTSD and PTSD + DS display distinct functional connectivity within the PFC, amygdala complexes, and the periaqueductal gray (PAG), a region related to defensive responses/emotional coping. However, differences in directed connectivity between these regions have not been established in PTSD, PTSD + DS, or controls. Methods To examine directed (effective) connectivity among these nodes, as well as group differences, we conducted resting-state stochastic dynamic causal modeling (sDCM) pairwise analyses of coupling between the ventromedial (vm)PFC, the bilateral basolateral and centromedial (CMA) amygdala complexes, and the PAG, in 155 participants (PTSD [n = 62]; PTSD + DS [n = 41]; age-matched healthy trauma-unexposed controls [n = 52]). Results PTSD was characterized by a pattern of predominant bottom-up connectivity from the amygdala to the vmPFC and from the PAG to the vmPFC and amygdala. Conversely, PTSD + DS exhibited predominant top-down connectivity between all node pairs (from the vmPFC to the amygdala and PAG, and from the amygdala to the PAG). Interestingly, the PTSD + DS group displayed the strongest intrinsic inhibitory connections within the vmPFC. Conclusions These results suggest the contrasting symptom profiles of PTSD and its dissociative subtype (hyper- vs. hypo-emotionality, respectively) may be driven by complementary changes in directed connectivity corresponding to bottom-up defensive fear processing versus enhanced top-down regulation. Hum Brain Mapp 38:5551-5561, 2017. © 2017 Wiley Periodicals, Inc.

Background Posttraumatic stress disorder (PTSD) is characterized by dysregulated arousal and altered cardiac autonomic response as evidenced by decreased high-frequency heart rate variability (HF-HRV), an indirect measure of parasympathetic modulation of the heart. Indeed, subtle threatening cues can cause autonomic dysregulation, even without explicit awareness of the triggering stimulus. Accordingly, examining the neural underpinnings associated with HF-HRV during both sub- and supraliminal exposure to trauma-related cues is critical to an enhanced understanding of autonomic nervous system dysfunction in PTSD. Methods We compared neural activity in brain regions associated with HF-HRV in PTSD (n = 18) and healthy controls (n = 18) during exposure to sub- and supraliminal processing of personalized trauma-related words. Results As compared to controls, PTSD exhibited decreased HF-HRV reactivity in response to sub- and supraliminal cues. Notably, during subliminal processing of trauma-related versus neutral words, as compared to controls, PTSD showed decreased neural response associated with HF-HRV within the left dorsal anterior insula. By contrast, during supraliminal processing of trauma-related versus neutral words, decreased neural activity associated with HF-HRV within the posterior insula/superior temporal cortex, and increased neural activity associated with HF-HRV within the left centromedial amygdala was observed in PTSD as compared to controls. Conclusions Impaired parasympathetic modulation of autonomic arousal in PTSD appears related to altered activation of cortical and subcortical regions involved in the central autonomic network. Interestingly, both sub- and supraliminal trauma-related cues appear to elicit dysregulated arousal and may contribute to the maintenance of hyperarousal in PTSD. Hum Brain Mapp 38:4898–4907, 2017. © 2017 Wiley Periodicals, Inc.

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. © 2016 Wiley Periodicals, Inc.

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.

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.

Objective Posttraumatic stress disorder (PTSD) is associated with decreased top–down emotion modulation from medial prefrontal cortex (mPFC) regions, a pathophysiology accompanied by hyperarousal and hyperactivation of the amygdala. By contrast, PTSD patients with the dissociative subtype (PTSD + DS) often exhibit increased mPFC top–down modulation and decreased amygdala activation associated with emotional detachment and hypoarousal. Crucially, PTSD and PTSD + DS display distinct functional connectivity within the PFC, amygdala complexes, and the periaqueductal gray (PAG), a region related to defensive responses/emotional coping. However, differences in directed connectivity between these regions have not been established in PTSD, PTSD + DS, or controls. Methods: To examine directed (effective) connectivity among these nodes, as well as group differences, we conducted resting‐state stochastic dynamic causal modeling (sDCM) pairwise analyses of coupling between the ventromedial (vm)PFC, the bilateral basolateral and centromedial (CMA) amygdala complexes, and the PAG, in 155 participants (PTSD [n = 62]; PTSD + DS [n = 41]; age‐matched healthy trauma‐unexposed controls [n = 52]). Results: PTSD was characterized by a pattern of predominant bottom–up connectivity from the amygdala to the vmPFC and from the PAG to the vmPFC and amygdala. Conversely, PTSD + DS exhibited predominant top–down connectivity between all node pairs (from the vmPFC to the amygdala and PAG, and from the amygdala to the PAG). Interestingly, the PTSD + DS group displayed the strongest intrinsic inhibitory connections within the vmPFC. Conclusions: These results suggest the contrasting symptom profiles of PTSD and its dissociative subtype (hyper‐ vs. hypo‐emotionality, respectively) may be driven by complementary changes in directed connectivity corresponding to bottom–up defensive fear processing versus enhanced top–down regulation. Hum Brain Mapp 38:5551–5561, 2017. © 2017 Wiley Periodicals, Inc.

Objectives Although dysfunctional emotion regulatory capacities are increasingly recognized as contributing to posttraumatic stress disorder (PTSD), little work has sought to identify biological markers of this vulnerability. Heart rate variability (HRV) is a promising biomarker that, together with neuroimaging, may assist in gaining a deeper understanding of emotion dysregulation in PTSD. The objective of the present study was, therefore, to characterize autonomic response patterns, and their related neuronal patterns in individuals with PTSD at rest. Methods PTSD patients (N = 57) and healthy controls (N = 41) underwent resting-state fMRI. Connectivity patterns of key regions within the central autonomic network (CAN)—including the ventromedial prefrontal cortex (vmPFC), amygdala, and periaqueductal gray (PAG)—were examined using a seed-based approach. Observed connectivity patterns were then correlated to resting HRV. Results In contrast to controls, individuals with PTSD exhibited lower HRV. In addition, whereas controls engaged a localized connectivity pattern of CAN-related brain regions, in PTSD, key CAN regions were associated with widespread connectivity patterns in regions related to emotional reactivity (vmPFC and amygdala to insular cortex and lentiform nucleus; PAG to insula) and motor readiness (vmPFC and amygdala to precentral gyrus; PAG to precentral gyrus and cerebellum). Critically, whereas CAN connectivity in controls was strongly related to higher HRV (insula, mPFC, superior frontal cortex, thalamus), HRV covariation was absent in PTSD subjects. Conclusions This study provides the first evidence for a specific psychophysiological–neuronal profile in PTSD individuals characterized by lower resting HRV and a lack of HRV covariation with CAN-related brain connectivity. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc.