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This review examines recent functional neuroimaging research of resting-state regional connectivity between brain regions in anxiety disorders. Studies compiled in the PubMed–National Center for Biotechnology Information database targeting resting-state functional connectivity in anxiety disorders were reviewed. Diagnoses included posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), obsessive–compulsive disorder (OCD), panic disorder (PD), and specific phobia (SP). Alterations to network connectivity were demonstrated in PTSD, GAD, SAD, OCD, and PD in several resting-state investigations. Differences from control subjects were primarily observed in the default mode network within PTSD, SAD, and OCD. Alterations within the salience network were observed primarily in PTSD, GAD, and SAD. Alterations in corticostriatal networks were uniquely observed in OCD. Finally, alterations within somatosensory networks were observed in SAD and PD investigations. Resting-state studies involving SPs as a primary diagnosis (with or without comorbidities) were not generated during the literature search. The emerging use of resting-state paradigms may be an effective method for understanding associations between anxiety disorders. Targeted studies of PD and SPs, meta-analyses of the studies conducted to date, and studies of the impact of specific comorbid presentations, are recommended future research directions.

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.

Interpretable latent variable models that probabilistically link behavioral observations to an underlying latent process have increasingly been used to draw inferences on cognition from observed behavior. The latent process usually connects experimental variables to cognitive computation. While such models provide important insights into the latent processes generating behavior, one important aspect has often been overlooked. They may also be used to generate precise and falsifiable behavioral predictions as a function of the modeled experimental variables. In doing so, they pinpoint how experimental conditions must be designed to elicit desired behavior and generate adaptive experiments. These ideas are exemplified on the process of delay discounting (DD). After inferring DD models from behavior on a typical DD task, the models are leveraged to generate a second adaptive DD task. Experimental trials in this task are designed to elicit 9 graded behavioral discounting probabilities across participants. Models are then validated and contrasted to competing models in the field by assessing the ouf-of-sample prediction error. The proposed framework induces discounting probabilities on nine levels. In contrast to several alternative models, the applied model exhibits high validity as indicated by a comparably low prediction error. We also report evidence for inter-individual differences with respect to the most suitable models underlying behavior. Finally, we outline how to adapt the proposed method to the investigation of other cognitive processes including reinforcement learning. Inducing graded behavioral frequencies with the proposed framework may help to highly resolve the underlying cognitive construct and associated neuronal substrates.

A neurocircuitry model of post-traumatic stress disorder (PTSD) suggests increased amygdala responses to emotional stimuli, coupled with hypoactivation of prefrontal regions associated with cognitive control. However, results are heterogenous across different subsamples of PTSD as well as different paradigms. We investigated cognitive control in a classic and emotional Stroop task in 28 female patients with complex PTSD (cPTSD), 28 female trauma-exposed healthy controls (TCs) and 28 female non-trauma-exposed healthy controls (HCs) using functional neuroimaging. Afterwards, we assessed memory function in a spontaneous free recall and recognition task. Patients with cPTSD displayed significantly greater Stroop interference with trauma-related words (as reflected in slower reaction times and increased errors) compared to the other conditions and compared to the TC and HC groups. Moreover, patients with cPTSD showed increased activation in the context of trauma-related words in brain regions associated with cognitive control (dlPFC, vmPFC, dACC) compared to both control groups, and a trend for increased activation in the insula compared to the HC group. Increased recruitment of regions contributing to cognitive control in patients with cPTSD, together with a lack of amygdala response may point to efforts to compensate for emotional distraction caused by the trauma-related words.

Background: Increasing evidence points towards 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 connectivity profiles of key arousal-related 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 six-minute 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 adaption. 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. Conclusions: 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.

Background Impairments in the domain of interpersonal functioning such as the feeling of loneliness and fear of abandonment have been associated with a negative bias during processing of social cues in Borderline Personality Disorder (BPD). Since these symptoms show low rates of remission, high rates of recurrence and are relatively resistant to treatment, in the present study we investigated whether a negative bias during social cognitive processing exists in BPD even after symptomatic remission. We focused on facial emotion recognition since it is one of the basal social-cognitive processes required for successful social interactions and building relationships. Methods Ninety-eight female participants (46 symptom-remitted BPD [r-BPD]), 52 healthy controls [HC]) rated the intensity of anger and happiness in ambiguous (anger/happiness blends) and unambiguous (emotion/neutral blends) emotional facial expressions. Additionally, participants assessed the confidence they experienced in their own judgments. Results R-BPD participants assessed ambiguous expressions as less happy and as more angry when the faces displayed predominantly happiness. Confidence in these judgments did not differ between groups, but confidence in judging happiness in predominantly happy faces was lower in BPD patients with a higher level of BPD psychopathology. Conclusions Evaluating social cues that signal the willingness to affiliate is characterized by a negative bias that seems to be a trait-like feature of social cognition in BPD. In contrast, confidence in judging positive social signals seems to be a state-like feature of emotion recognition in BPD that improves with attenuation in the level of acute BPD symptoms.

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.

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.

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.

Emerging studies corroborate the importance of neuroimaging biomarkers and machine learning to improve diagnostic classification of amyotrophic lateral sclerosis (ALS). While most studies focus on structural data, recent studies assessing functional connectivity between brain regions by linear methods highlight the role of brain function. These studies have yet to be combined with brain structure and nonlinear functional features. We investigate the role of linear and nonlinear functional brain features, and the benefit of combining brain structure and function for ALS classification. ALS patients (N = 97) and healthy controls (N = 59) underwent structural and functional resting state magnetic resonance imaging. Based on key hubs of resting state networks, we defined three feature sets comprising brain volume, resting state functional connectivity (rsFC), as well as (nonlinear) resting state dynamics assessed via recurrent neural networks. Unimodal and multimodal random forest classifiers were built to classify ALS. Out‐of‐sample prediction errors were assessed via five‐fold cross‐validation. Unimodal classifiers achieved a classification accuracy of 56.35–61.66%. Multimodal classifiers outperformed unimodal classifiers achieving accuracies of 62.85–66.82%. Evaluating the ranking of individual features' importance scores across all classifiers revealed that rsFC features were most dominant in classification. While univariate analyses revealed reduced rsFC in ALS patients, functional features more generally indicated deficits in information integration across resting state brain networks in ALS. The present work undermines that combining brain structure and function provides an additional benefit to diagnostic classification, as indicated by multimodal classifiers, while emphasizing the importance of capturing both linear and nonlinear functional brain properties to identify discriminative biomarkers of ALS. The current study aims at identifying neuroimaging biomarkers for diagnostic classification of amyotrophic lateral sclerosis (ALS). We investigate the potential of combining brain structure and function for the classification of ALS and examine a novel feature set capturing nonlinear functional features from network dynamics based on recurrent neural networks. We demonstrate that combining different modalities improves classification, and that both linear and nonlinear functional brain features indeed deliver discriminative biomarkers of the disease.