The functional and structural alterations in brain regions related to the fear network model in panic disorder: A resting-state fMRI and T1-weighted imaging study.

Abnormal functional connectivity (FC) within the fear network model (FNM) has been identified in panic disorder (PD) patients, but the specific local structural and functional properties, as well as effective connectivity (EC), remain poorly understood in PD. The purpose of this study was to investigate the structural and functional patterns of the FNM in PD. Magnetic resonance imaging data were collected from 33 PD patients and 35 healthy controls (HCs). Gray matter volume (GMV), degree centrality (DC), regional homogeneity (ReHo), and amplitude of low-frequency fluctuation (ALFF) were used to identify the structural and functional characteristics of brain regions within the FNM in PD. Subsequently, FC and EC of abnormal regions, based on local structural and functional features, and their correlation with clinical features were further examined. PD patients exhibited preserved GMV, ReHo, and ALFF in the brain regions of the FNM compared with HCs. However, increased DC in the bilateral amygdala was observed in PD patients. The amygdala and its subnuclei exhibited altered EC with rolandic operculum, insula, medial superior frontal gyrus, supramarginal gyrus, opercular part of inferior frontal gyrus, and superior temporal gyrus. Additionally, Hamilton Anxiety Scale score was positively correlated with EC from left lateral nuclei (dorsal portion) of amygdala to right rolandic operculum and left superior temporal gyrus. Our findings revealed a reorganized functional network in PD involving brain regions regulating exteroceptive-interoceptive signals, mood, and somatic symptoms. These results enhance our understanding of the neurobiological underpinnings of PD, suggesting potential biomarkers for diagnosis and targets for therapeutic intervention.

Impact of childhood trauma on the abnormal functional connectivity of brain regions in the fear network model of panic disorder.

BACKGROUND: People who have suffered childhood trauma may be more susceptible to panic disorder (PD). Existing evidence indicates that childhood trauma can significantly impact brain function. Meanwhile, the brain regions involved in the fear network model (FNM) of PD highly overlap with the brain regions affected by childhood trauma. However, it remains unclear whether functional connections between brain regions associated with the FNM in patients with PD are affected by childhood trauma. This study aimed to investigate the effects of childhood trauma on the functional connectivity (FC) of brain regions associated with the FNM in patients with PD. METHOD: This study recruited 62 patients with PD, including 21 with a high level of childhood trauma (PD_HCT), 41 with a low level of childhood trauma (PD_LCT), and 40 healthy controls (HCs). The patients underwent magnetic resonance imaging resting-state scanning. The amygdala, anterior cingulate, thalamus, and hippocampus were chosen as regions of interest (ROIs) to examine group differences in ROIs and whole-brain resting-state FC (rsFC). RESULTS: Compared with PD_HCT patients, PD_LCT patients exhibited significantly increased rsFC in the right thalamus, right temporo-occipital middle temporal gyrus, left thalamus, and right temporo-occipital middle temporal gyrus. Compared with HCs, PD_LCT patients had increased rsFC between the right thalamus and the right temporo-occipital middle temporal gyrus. CONCLUSION: Patients with PD who had suffered high and low levels of childhood trauma were found to exhibit different pathological rsFC alterations in the FNM, suggesting that childhood trauma may be an important risk factor for the development of PD symptoms.

Functional interplay between central and autonomic nervous systems in human fear conditioning.

Historically, studies on the neural basis of fear conditioning have emphasized the role of the central nervous system. However, there is growing evidence for the role of the autonomic nervous system in human fear conditioning. Here, we provide an overview of the sophisticated anatomical-functional interplay between the prefrontal cortex and heart-related dynamics in human fear conditioning and propose a theoretical model to conceptualize these psychophysiological processes, the neurovisceral integration model of fear (NVI-f). A richer understanding of the neurovisceral concomitants of this functional interplay will have both theoretical and clinical implications.

Abnormal functional connectivity of brain regions associated with fear network model in panic disorder.

Background: Patients with panic disorder (PD) have an abnormal function in brain regions related to fear network is well recognised. However, the traditional fear network model (FNM) which was based on animals' horrible behaviours has been found that it's not enough to explain the pathological mechanism of PD. This study aims to explore brain regions' abnormalities in the new advanced FNM, and estimate whether it can better explain PD.Methods: Magnetic resonance imaging resting-state scans were acquired in 40 patients with PD (35 drug-naïve and 5 drug-free) and 40 healthy controls (HCs). Twelve brain regions in the advanced FNM were chosen as regions of interest (ROIs) to examine the group difference in the ROIs and whole-brain resting-state functional connectivity (rsFC).Results: We found significantly increased thalamic rsFC with the insula, compared with HCs. And it was significantly correlated with HAMA-somatic score. We also found increased thalamic rsFC with occipital gyrus, temporal gyrus, and frontal gyrus when compared with HCs.Conclusions: Taken together, PD patients exhibit abnormal rsFC alterations within the advanced FNM, especially the increased rsFC within thalamus-insula loop, suggesting that excessive sensitivity to external information plays an important role in PD. The advanced FNM may provide a fuller explanation about PD.

Multimodal MRI of fear network in panic disorder / 中华行为医学与脑科学杂志

The etiology and pathological mechanism of panic disorder (PD) are still unclear, which hinders the development of clinical diagnosis and treatment. In order to clarify the pathogenesis, biological diagnostic markers, curative effect prediction of PD, and ultimately provide a basis for individualized treatment, this article reviews the magnetic resonance imaging (MRI) research on PD in the past 5 years in conjunction with the hypothesis of the " fear network model" . It is found that the brain function and structural abnormalities of PD patients are not limited to the classic " fear network model" , but also a wider range of brain areas such as the cingulate gyrus, fronto-temporal cortex, insula, striatum, thalamus, sensorimotor related brain regions and cerebellum, together with classic brain regions such as the amygdala, form an expanded fear network. Among them, the amygdala, insula, medial prefrontal lobe, somato-motor network (SMN) and cerebellum are specific brain areas that differentiate PD from other anxiety disorders. The changes in the activity of the frontal lobe-limbic loop included in the fear network model can predict the treatment outcome of different methods for PD. This article improved the fear network hypothesis of PD, and more accurately identifies the biological indicators that can be used for accurate diagnosis and efficacy prediction of PD, which lays the foundation for the ultimate realization of personalized diagnosis and treatment of PD.

Take my breath away: Neural activation at breath-hold differentiates individuals with panic disorder from healthy controls.

There is neuroanatomical evidence of an "extended fear network" of brain structures involved in the etiology of panic disorder (PD). Although ventilatory distrubance is a primary symptom of PD these sensations may also trigger onset of a panic attack (PA). Here, a voluntary breath-holding paradigm was used to mimic the hypercapnia state in order to compare blood oxygen level-dependent (BOLD) response, at the peak of a series of 18 s breath-holds, of 21 individuals with PD to 21 low anxiety matched controls. Compared to the rest condition, BOLD activity at the peak (12 - 18 s) of the breath-hold was greater for PD versus controls within a number of structures implicated in the extended fear network, including hippocampus, thalamus, and brainstem. Activation was also observed in cortical structures that are shown to be involved in interoceptive and self-referential processing, such as right insula, middle frontal gyrus, and precuneus/posterior cingulate. In lieu of amygdala activation, our findings show elevated activity throughout an extended network of cortical and subcortical structures involved in contextual, interoceptive and self-referential processing when individuals with PD engage in voluntary breath-holding.

Altered functional connectivity in the fear network of firefighters with repeated traumatic stress.

BACKGROUND: Firefighters are routinely exposed to various traumatic events and often experience a range of trauma-related symptoms. Although these repeated traumatic exposures rarely progress to the development of post-traumatic stress disorder, firefighters are still considered to be a vulnerable population with regard to trauma.AimsTo investigate how the human brain responds to or compensates for the repeated experience of traumatic stress. METHOD: We included 98 healthy firefighters with repeated traumatic experiences but without any diagnosis of mental illness and 98 non-firefighter healthy individuals without any history of trauma. Functional connectivity within the fear circuitry, which consists of the dorsal anterior cingulate cortex, insula, amygdala, hippocampus and ventromedial prefrontal cortex (vmPFC), was examined using resting-state functional magnetic resonance imaging. Trauma-related symptoms were evaluated using the Impact of Event Scale - Revised. RESULTS: The firefighter group had greater functional connectivity between the insula and several regions of the fear circuitry including the bilateral amygdalae, bilateral hippocampi and vmPFC as compared with healthy individuals. In the firefighter group, stronger insula-amygdala connectivity was associated with greater severity of trauma-related symptoms (ß = 0.36, P = 0.005), whereas higher insula-vmPFC connectivity was related to milder symptoms in response to repeated trauma (ß = -0.28, P = 0.01). CONCLUSIONS: The current findings suggest an active involvement of insular functional connectivity in response to repeated traumatic stress. Functional connectivity of the insula in relation to the amygdala and vmPFC may be potential pathways that underlie the risk for and resilience to repeated traumatic stress, respectively.Declaration of interestNone.

Fear Network Model in Panic Disorder: The Past and the Future.

The core concept for pathophysiology in panic disorder (PD) is the fear network model (FNM). The alterations in FNM might be linked with disturbances in the autonomic nervous system (ANS), which is a common phenomenon in PD. The traditional FNM included the frontal and limbic regions, which were dysregulated in the feedback mechanism for cognitive control of frontal lobe over the primitive response of limbic system. The exaggerated responses of limbic system are also associated with dysregulation in the neurotransmitter system. The neuroimaging studies also corresponded to FNM concept. However, more extended areas of FNM have been discovered in recent imaging studies, such as sensory regions of occipital, parietal cortex and temporal cortex and insula. The insula might integrate the filtered sensory information via thalamus from the visuospatial and other sensory modalities related to occipital, parietal and temporal lobes. In this review article, the traditional and advanced FNM would be discussed. I would also focus on the current evidences of insula, temporal, parietal and occipital lobes in the pathophysiology. In addition, the white matter and functional connectome studies would be reviewed to support the concept of advanced FNM. An emerging dysregulation model of fronto-limbic-insula and temporooccipito-parietal areas might be revealed according to the combined results of recent neuroimaging studies. The future delineation of advanced FNM model can be beneficial from more extensive and advanced studies focusing on the additional sensory regions of occipital, parietal and temporal cortex to confirm the role of advanced FNM in the pathophysiology of PD.

Fear Network Model in Panic Disorder: The Past and the Future

The core concept for pathophysiology in panic disorder (PD) is the fear network model (FNM). The alterations in FNM might be linked with disturbances in the autonomic nervous system (ANS), which is a common phenomenon in PD. The traditional FNM included the frontal and limbic regions, which were dysregulated in the feedback mechanism for cognitive control of frontal lobe over the primitive response of limbic system. The exaggerated responses of limbic system are also associated with dysregulation in the neurotransmitter system. The neuroimaging studies also corresponded to FNM concept. However, more extended areas of FNM have been discovered in recent imaging studies, such as sensory regions of occipital, parietal cortex and temporal cortex and insula. The insula might integrate the filtered sensory information via thalamus from the visuospatial and other sensory modalities related to occipital, parietal and temporal lobes. In this review article, the traditional and advanced FNM would be discussed. I would also focus on the current evidences of insula, temporal, parietal and occipital lobes in the pathophysiology. In addition, the white matter and functional connectome studies would be reviewed to support the concept of advanced FNM. An emerging dysregulation model of fronto-limbic-insula and temporooccipito-parietal areas might be revealed according to the combined results of recent neuroimaging studies. The future delineation of advanced FNM model can be beneficial from more extensive and advanced studies focusing on the additional sensory regions of occipital, parietal and temporal cortex to confirm the role of advanced FNM in the pathophysiology of PD.

Pain-Related Fear-Dissociable Neural Sources of Different Fear Constructs.

Fear of pain demonstrates significant prognostic value regarding the development of persistent musculoskeletal pain and disability. Its assessment often relies on self-report measures of pain-related fear by a variety of questionnaires. However, based either on "fear of movement/(re)injury/kinesiophobia," "fear avoidance beliefs," or "pain anxiety," pain-related fear constructs plausibly differ while it is unclear how specific the questionnaires are in assessing these different constructs. Furthermore, the relationship of pain-related fear to other anxiety measures such as state or trait anxiety remains ambiguous. Advances in neuroimaging such as machine learning on brain activity patterns recorded by functional magnetic resonance imaging might help to dissect commonalities or differences across pain-related fear constructs. We applied a pattern regression approach in 20 human patients with nonspecific chronic low back pain to reveal predictive relationships between fear-related neural pattern information and different pain-related fear questionnaires. More specifically, the applied multiple kernel learning approach allowed the generation of models to predict the questionnaire scores based on a hierarchical ranking of fear-related neural patterns induced by viewing videos of activities potentially harmful for the back. We sought to find evidence for or against overlapping pain-related fear constructs by comparing the questionnaire prediction models according to their predictive abilities and associated neural contributors. By demonstrating evidence of nonoverlapping neural predictors within fear-processing regions, the results underpin the diversity of pain-related fear constructs. This neuroscientific approach might ultimately help to further understand and dissect psychological pain-related fear constructs.

Directed threat imagery in generalized anxiety disorder.

BACKGROUND: Worrying has been suggested to prevent emotional and elaborative processing of fears. In cognitive-behavioral therapy (CBT), generalized anxiety disorder (GAD) patients are exposed to their fears during the method of directed threat imagery by inducing emotional reactivity. However, studies investigating neural correlates of directed threat imagery and emotional reactivity in GAD patients are lacking. The present functional magnetic resonance imaging (fMRI) study aimed at delineating neural correlates of directed threat imagery in GAD patients. METHOD: Nineteen GAD patients and 19 healthy controls (HC) were exposed to narrative scripts of either disorder-related or neutral content and were encouraged to imagine it as vividly as possible. RESULTS: Rating results showed that GAD patients experienced disorder-related scripts as more anxiety inducing and arousing than HC. These results were also reflected in fMRI data: Disorder-related v. neutral scripts elicited elevated activity in the amygdala, dorsomedial prefrontal cortex, ventrolateral prefrontal cortex and the thalamus as well as reduced activity in the ventromedial prefrontal cortex/subgenual anterior cingulate cortex in GAD patients relative to HC. CONCLUSION: The present study presents the first behavioral and neural evidence for emotional reactivity during directed threat imagery in GAD. The brain activity pattern suggests an involvement of a fear processing network as a neural correlate of initial exposure during directed imagery in CBT in GAD.

Neuroimaging in patients with panic disorder / 上海交通大学学报（医学版）

Panic disorder (PD) is characterized by recurrent unexpected panic attacks and fear of dying or losing control, which negatively influences the social functioning and life quality of the patients. The neurobiological mechanisms underlying PD have not been clearly understood. Previous opinion held that hyperactivity of the fear network which included amygdala, hypothalamus, hippocampus, brain stem and so on and dysfunction of prefrontal cortex underlay PD. Summarizing recent advances on magnetic resonance imaging studies in PD, this review focuses on the functional, structural and metabolic neuroanatomical alterations in the specific population. There is evidence to show that the hyperactivity of fear network, prefrontal and occipital cortex may be involved in the pathophysiology of PD and it is necessary to revise models of anxiety disorder.

Neuroimaging in patients with panic disorder / 上海交通大学学报（医学版）

Panic disorder (PD) is characterized by recurrent unexpected panic attacks and fear of dying or losing control,which negatively influences the social functioning and life quality of the patients.The neurobiological mechanisms underlying PD have not been clearly understood.Previous opinion held that hyperactivity of the fear network which included amygdala,hypothalamus,hippocampus,brain stem and so on and dysfunction of prefrontal cortex underlay PD.Summarizing recent advances on magnetic resonance imaging studies in PD,this review focuses on the functional,structural and metabolic neuroanatomical alterations in the specific population.There is evidence to show that the hyperactivity of fear network,prefrontal and occipital cortex may be involved in the pathophysiology of PD and it is necessary to revise models of anxiety disorder.

Individual Differences in Anticipatory Somatosensory Cortex Activity for Shock is Positively Related with Trait Anxiety and Multisensory Integration.

Anxiety is associated with an exaggerated expectancy of harm, including overestimation of how likely a conditioned stimulus (CS+) predicts a harmful unconditioned stimulus (US). In the current study we tested whether anxiety-associated expectancy of harm increases primary sensory cortex (S1) activity on non-reinforced (i.e., no shock) CS+ trials. Twenty healthy volunteers completed a differential-tone trace conditioning task while undergoing fMRI, with shock delivered to the left hand. We found a positive correlation between trait anxiety and activity in right, but not left, S1 during CS+ versus CS- conditions. Right S1 activity also correlated with individual differences in both primary auditory cortices (A1) and amygdala activity. Lastly, a seed-based functional connectivity analysis demonstrated that trial-wise S1 activity was positively correlated with regions of dorsolateral prefrontal cortex (dlPFC), suggesting that higher-order cognitive processes contribute to the anticipatory sensory reactivity. Our findings indicate that individual differences in trait anxiety relate to anticipatory reactivity for the US during associative learning. This anticipatory reactivity is also integrated along with emotion-related sensory signals into a brain network implicated in fear-conditioned responding.

SPIDER OR NO SPIDER? NEURAL CORRELATES OF SUSTAINED AND PHASIC FEAR IN SPIDER PHOBIA.

BACKGROUND: Processes of phasic fear responses to threatening stimuli are thought to be distinct from sustained, anticipatory anxiety toward an unpredicted, potential threat. There is evidence for dissociable neural correlates of phasic fear and sustained anxiety. Whereas increased amygdala activity has been associated with phasic fear, sustained anxiety has been linked with activation of the bed nucleus of stria terminalis (BNST), anterior cingulate cortex (ACC), and the insula. So far, only a few studies have focused on the dissociation of neural processes related to both phasic and sustained fear in specific phobia. We suggested that first, conditions of phasic and sustained fear would involve different neural networks and, second, that overall neural activity would be enhanced in a sample of phobic compared to nonphobic participants. METHODS: Pictures of spiders and neutral stimuli under conditions of either predicted (phasic) or unpredicted (sustained) fear were presented to 28 subjects with spider phobia and 28 nonphobic control subjects during functional magnetic resonance imaging (fMRI) scanning. RESULTS: Phobic patients revealed significantly higher amygdala activation than controls under conditions of phasic fear. Sustained fear processing was significantly related to activation in the insula and ACC, and phobic patients showed a stronger activation than controls of the BNST and the right ACC under conditions of sustained fear. Functional connectivity analysis revealed enhanced connectivity of the BNST and the amygdala in phobic subjects. CONCLUSIONS: Our findings support the idea of distinct neural correlates of phasic and sustained fear processes. Increased neural activity and functional connectivity in these networks might be crucial for the development and maintenance of anxiety disorders.