Fear Neurocircuitry Research Articles

Aberrant functional connectivity of amygdala subregions in temporal lobe epilepsy with ictal panic.

The amygdala joins the model of fear neurocircuitry for its subregional roles in processing and mediating panic. This study aims to explore the underlying neuromechanisms of temporal lobe epilepsy (TLE) patients with ictal panic (IP) by investigating the amygdala subregions functional connectivity (FC) alteration. 18 TLE patients with IP (TLE-IP group), 23 TLE patients without IP (TLE-none-IP group) and 22 age- and sex- matched healthy controls (HC) were enrolled and required to take resting-state functional magnetic resonance imaging (rs-fMRI) scanning. The basolateral (BLA), centromedial (CMA), and superficial(SFA) amygdala subregions were extracted from Juelich histological atlas. The amygdala subregions-based FC was computed and compared among three groups. The TLE-IP group demonstrated stronger FC between the left BLA and right middle frontal gyrus (MFG) than the TLE-none-IP group and HC. Compared with the TLE-none-IP group and HC, the TLE-IP group showed increased FC between the right BLA and right postcentral gyrus. The FC between the left BLA/SFA and the orbital part of right MFG increased in the TLE-IP group. Furthermore, the TLE-IP group exhibited decreased FC between the left CMA and pons. Further analysis indicated altered FC between the amygdala subregions and the pons, precuneus and thalamus in the left-sided TLE-IP group, but the MFG, inferior parietal gyrus, supplementary motor area and cerebellum in the right-sided TLE-IP group. The present study revealed aberrant amygdala subregions-based FC in TLE patients with IP. These findings offer unique insights into the understanding of fear neurocircuitry in TLE patients with IP.

Inflammation as a Neurobiological Mechanism of Cognitive Impairment in Psychological Stress.

The feeling of emotional tension, restlessness, pressure, and inability to relax is referred to as psychological stress. Although it is unclear how psychological stress affects neurobiological processes, several factors are thought to be involved, including central and peripheral neuroinflammation, structural degeneration in the prefrontal cortex and hippocampus, alterations in fear neurocircuitry, and neuroplasticity. Aside from data relating cognitive impairment to chronic low-grade inflammatory stress, there is growing evidence linking mental stress, oxidative stress, and systemic inflammation to the development of psychological disorders. After chronic and acute illnesses, insomnia, depression, anxiety, posttraumatic stress disorder, and cognitive impairment were reported. Cognitive impairment is exacerbated by systemic and central inflammatory processes. There is uncertainty about the potential mechanisms causing these symptoms, although they are likely complex, with systemic inflammation playing a significant role. Therefore, this review aims to investigate the role of inflammation in stress-induced cognitive impairment. Depicting the inflammatory mechanisms of cognitive impairment is critical for understanding and treating illnesses, such as chronic stress exposure and anxiety disorders.

Childhood Maltreatment in Females Is Associated with Enhanced Fear Acquisition and an Overgeneralization of Fear.

Childhood maltreatment may alter fear neurocircuitry, which results in pathological anxiety and depression. One alteration of fear-related behaviors that has been observed in several psychiatric populations is an overgeneralization of fear. Thus, we examined the association between childhood maltreatment and fear generalization in a non-clinical sample of young adults. Two hundred and ninety-one participants underwent differential fear conditioning in a fear-potentiated startle paradigm. One visual stimulus (CS+), but not another (CS-), was associated with an aversive airblast to the throat (US) during acquisition. The next day, participants were tested for their fear responses to the CS+, CS-, and several generalization stimuli (GS) without the presence of the US. Participants also completed questionnaires that assessed symptoms of childhood maltreatment, anxiety, depression, and post-traumatic stress disorder (PTSD). Participants reporting high childhood maltreatment (n = 71; 23 males, 48 females) exhibited significantly greater anxiety, depression, and symptoms of PTSD than participants reporting low childhood maltreatment (n = 220; 133 males, 87 females). Females reporting high childhood maltreatment demonstrated significantly enhanced fear learning and greater fear generalization, based on their fear-potentiated startle responses. Our findings suggest that childhood maltreatment may sex-dependently influence the development of fear neurocircuitry and result in greater fear generalization in maltreated females.

Neurochemical Alterations in Social Anxiety Disorder (SAD): A Systematic Review of Proton Magnetic Resonance Spectroscopic Studies.

(1) Objective: Considering that current knowledge of mechanisms involved in the molecular pathogenesis of Social Anxiety Disorder (SAD) is limited, we conducted a systematic review to evaluate cumulative data obtained by Proton Magnetic Resonance Spectroscopic (1H MRS) studies. (2) Methods: A computer-based literature search of Medline, EMBASE, PsycInfo, and ProQuest was performed. Only cross-sectional studies using 1H MRS techniques in participants with SAD and healthy controls (HCs) were selected. (3) Results: The search generated eight studies. The results indicated regional abnormalities in the ‘fear neurocircuitry’ in patients with SAD. The implicated regions included the anterior cingulate cortex (ACC), dorsomedial prefrontal cortex (dmPFC), dorsolateral prefrontal cortex (dlPFC), insula, occipital cortex (OC), as well as the subcortical regions, including the thalamus, caudate, and the putamen. (4) Conclusions: The evidence derived from eight studies suggests that possible pathophysiological mechanisms of SAD include impairments in the integrity and function of neurons and glial cells, including disturbances in energy metabolism, maintenance of phospholipid membranes, dysregulations of second messenger systems, and excitatory/inhibitory neurocircuitry. Conducting more cross-sectional studies with larger sample sizes is warranted given the limited evidence in this area of research.

Neurobiological mechanisms underlying delayed expression of posttraumatic stress disorder: A scoping review.

BACKGROUNDThe capacity of posttraumatic stress disorder (PTSD) to occur with delayed onset has been documented in several systematic reviews and meta-analyses. Neurobiological models of PTSD may provide insight into the mechanisms underlying the progressive increase in PTSD symptoms over time as well as into occasional occurrences of long-delayed PTSD with few prodromal symptoms. AIMTo obtain an overview of key concepts explaining and types of evidence supporting neurobiological underpinnings of delayed PTSD.METHODSA scoping review of studies reporting neurobiological findings relevant to delayed PTSD was performed, which included 38 studies in the qualitative synthesis. RESULTSNeurobiological mechanisms underlying PTSD symptoms, onset, and course involve several interconnected systems. Neural mechanisms involve the neurocircuitry of fear, comprising several structures, such as the hippocampus, amygdala, and prefrontal cortex, that are amenable to time-dependent increases in activity through sensitization and kindling. Neural network models explain generalization of the fear response. Neuroendocrine mechanisms consist of autonomic nervous system and hypothalamic-pituitary-adrenocortical axis responses, both of which may be involved in sensitization to stress. Neuroinflammatory mechanisms are characterized by immune activation, which is sometimes due to the effects of traumatic brain injury. Finally, neurobehavioral/contextual mechanisms involve the effects of intervening stressors and mental and physical disorder comorbidities, and these may be particularly relevant in cases of long-delayed PTSD. CONCLUSIONThus, delayed PTSD may result from multiple underlying neurobiological mechanisms that may influence the likelihood of developing prodromal symptoms preceding the onset of full-blown PTSD.

Apical intercalated cell cluster: A distinct sensory regulator in the amygdala.

GABAergic neurons regulate different aspects of information processing in the amygdala. Among these are clusters of intercalated cells (ITCs), which have been implicated in fear-related behaviors. Although a few of the ITC clusters have been studied, the functional role of apical ITCs (apITCs) is unknown. Here, we combine monosynaptic rabies tracing with optogenetics and demonstrate that apITCs receive synaptic input from medial geniculate nucleus (MGm), posterior intralaminar nucleus (PIN), and medial dorsal nucleus of the thalamus and from a diverse range of cortical areas including temporal association, entorhinal, insular, piriform, and somatosensory cortex. Upon fear learning, PIN/MGm inputs are strengthened, indicative of their involvement in fear behaviors. 3-D reconstruction of apITCs reveals local arborization and innervation of the dorsal striatum and lateral amygdala. We further show that apITCs provide sensory feedforward inhibition to LA principal cells, a putative mechanism for controlling plasticity during fear learning.

Altered Anxiety Neural Circuit in Combat Veterans With PTSD

Post-traumatic stress disorder (PTSD) affects more than 30% of Veterans returning from modern wars. Unfortunately, PTSD is often resistant to current treatments, such as SSRIs and exposure therapy, that target fear neurocircuitry. One possible explanation is that the neurobiology of PTSD extends beyond fear neurocircuitry and includes alterations in neural circuits that underlie anxiety. In this study, we investigated the bed nucleus of the stria terminalis (BNST), a brain region implicated in the anxiety, hypervigilance and threat anticipation response that is characteristic of PTSD.

Common and dissociable effects of oxytocin and lorazepam on the neurocircuitry of fear

Benzodiazepines (BZDs) represent the gold standard of anxiolytic pharmacotherapy; however, their clinical benefit is limited by side effects and addictive potential. Consequently, there is an urgent need to develop novel and safe anxiolytics. The peptide hormone oxytocin (OXT) exhibits anxiolytic-like properties in animals and humans, but whether OXT and BZDs share similar effects on the neural circuitry of fear is unclear. Therefore, the rationale of this ultra-high-field functional MRI (fMRI) study was to test OXT against the clinical comparator lorazepam (LZP) with regard to their neuromodulatory effects on local and network responses to fear-related stimuli. One hundred twenty-eight healthy male participants volunteered in this randomized double-blind, placebo-controlled, between-group study. Before scanning using an emotional face-matching paradigm, participants were randomly administered a single dose of OXT (24 IU), LZP (1 mg), or placebo. On the behavioral level, LZP, but not OXT, caused mild sedation, as evidenced by a 19% increase in reaction times. On the neural level, both OXT and LZP inhibited responses to fearful faces vs. neutral faces within the centromedial amygdala (cmA). In contrast, they had different effects on intra-amygdalar connectivity; OXT strengthened the coupling between the cmA and basolateral amygdala, whereas LZP increased the interplay between the cmA and superficial amygdala. Furthermore, OXT, but not LZP, enhanced the coupling between the cmA and the precuneus and dorsomedial prefrontal cortex. These data implicate inhibition of the cmA as a common denominator of anxiolytic action, with only OXT inducing large-scale connectivity changes of potential therapeutic relevance.

Increased activation of the fear neurocircuitry in children exposed to violence.

Most studies investigating the effect of childhood trauma on the brain are retrospective and mainly focus on maltreatment, whereas different types of trauma exposure such as growing up in a violent neighborhood, as well as developmental stage, could have differential effects on brain structure and function. The current magnetic resonance imaging study assessed the effect of trauma exposure broadly and violence exposure more specifically, as well as developmental stage on the fear neurocircuitry in 8- to 14-year-old children and adolescents (N = 69). We observed reduced hippocampal and increased amygdala volume with increasing levels of trauma exposure. Second, higher levels of violence exposure were associated with increased activation in the amygdala, hippocampus, and ventromedial prefrontal cortex during emotional response inhibition. This association was specifically observed in children younger than 10 years. Finally, increased functional connectivity between the amygdala and brainstem was associated with higher levels of violence exposure. Based on the current findings, it could be hypothesized that trauma exposure during childhood results in structural changes that are associated with later risk for psychiatric disorders. At the same time, it could be postulated that growing up in an unsafe environment leads the brain to functionally adapt to this situation in a way that promotes survival, where the long-term costs or consequences of these adaptations are largely unknown and an area for future investigations.

Efficacy of rTMS in a mouse model of posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is associated with brain changes that commonly involve the fear network including the prefrontal cortex (PFC), hippocampus and amygdala. Neurostimulation can been recommended as an adjunct to psychotherapy in order to facilitate extinction of fear in PTSD. Repetitive transcranial magnetic stimulation (rTMS) can thus target the PFC to provide promising treatment responses. However, preclinical rodent-based studies need to be performed to enhance the comprehension and empirical-driven efficacy of rTMS. We used a focal 40-mm coil to apply a high frequency/intensity rTMS pattern (5 daily sessions) to the ventromedial PFC (vmPFC) in a mouse model of PTSD. This procedure was assessed against fluoxetine (SSRI treatment). Through spatially precise stereotaxic framing, one session of rTMS (750 pulses) was able to focally increase c-Fos functional maps in the vmPFC immediately after stimulation. When used as a chronic treatment (5 daily sessions for 3750 pulses) in a foot-shock PTSD model, rTMS counteracted PTSD-related behavioural deficit in the object recognition task 6 days after the last treatment session and enhanced extinction dynamics in a reexposure task (4 days afterward) compared to sham treatment. Reexposure-associated c-Fos activity was found increased in the infralimbic cortex, the basolateral amygdala and the CA1 of ventral hippocampus of mice exposed to the trauma and treated with rTMS. In conclusion, chronic rTMS treatment reversed PTSD-induced impairments by acting on distributed networks of fear neurocircuitry that self-sustained 10 days post-treatment in the infralimbic cortex, the basolateral amygdala and the ventral CA1.

Exposure to an obesogenic diet during adolescence leads to abnormal maturation of neural and behavioral substrates underpinning fear and anxiety

BackgroundPost-traumatic stress disorder (PTSD) and obesity are highly prevalent in adolescents. Emerging findings from our laboratory and others are consistent with the novel hypothesis that obese individuals may be predisposed to developing PTSD. Given that aberrant fear responses are pivotal in the pathogenesis of PTSD, the objective of this study was to determine the impact of an obesogenic Western-like high-fat diet (WD) on neural substrates associated with fear. MethodsAdolescent Lewis rats (n = 72) were fed with either the experimental WD (41.4% kcal from fat) or the control diet. The fear-potentiated startle paradigm was used to determine sustained and phasic fear responses. Diffusion tensor imaging metrics and T2 relaxation times were used to determine the structural integrity of the fear circuitry including the medial prefrontal cortex (mPFC) and the basolateral complex of the amygdala (BLA). ResultsThe rats that consumed the WD exhibited attenuated fear learning and fear extinction. These behavioral impairments were associated with oversaturation of the fear circuitry and astrogliosis. The BLA T2 relaxation times were significantly decreased in the WD rats relative to the controls. We found elevated fractional anisotropy in the mPFC of the rats that consumed the WD. We show that consumption of a WD may lead to long-lasting damage to components of the fear circuitry. ConclusionsOur findings demonstrate that consumption of an obesogenic diet during adolescence has a profound impact in the maturation of the fear neurocircuitry. The implications of this research are significant as they identify potential biomarkers of risk for psychopathology in the growing obese population.

Can anxiety damage the brain?

Stress exacerbates mental illnesses such as depression but also appears to increase risk of dementia, suggesting a common mechanism for development of stress-induced affective and cognitive impairment. The purpose of this review is to address the question of whether anxiety 'damages' the brain, and to identify potential mechanisms for the link between stress and neuropsychiatric illness. Anxiety disorders are associated with alterations in fear neurocircuitry such that 'bottom-up' processes in the amygdala which respond to threat are exaggerated, and regulation of these processes by the prefrontal cortex (PFC) and hippocampus is impaired. Chronic stress exposure similarly alters fear neurocircuitry by enhancing amygdalar functioning while causing structural degeneration in the PFC and hippocampus thereby inhibiting PFC/hippocampus control over the stress response. Pharmacological (e.g., antidepressant medications) and nonpharmacological interventions (cognitive-behavioral therapy, exercise) may reverse stress-induced damage in the brain. Pathological anxiety and chronic stress lead to structural degeneration and impaired functioning of the hippocampus and the PFC, which may account for the increased risk of developing neuropsychiatric disorders, including depression and dementia. Longitudinal studies are needed to determine whether reversal of stress-induced brain changes by interventions such as cognitive-behavioral therapy can reduce risk of neuropsychiatric illness.

Lifelong disturbance of serotonin transporter functioning results in fear learning deficits: Reversal by blockade of CRF1 receptors

The inability to associate aversive events with relevant cues (i.e. fear learning) may lead to maladaptive anxiety. To further study the role of the serotonin transporter (SERT) in fear learning, classical fear conditioning was studied in SERT knockout rats (SERT−/−) using fear potentiation of the startle reflex. Next, fear acquisition and concomitant development of contextual conditioned fear were monitored during training. To differentiate between developmental and direct effects of reduced SERT functioning, effects of acute and chronic SSRI treatment were studied in adult rats. Considering the known interactions between serotonin and corticotropin-releasing factor (CRF), we studied the effect of the CRFR1 antagonist CP154,526 on behavioral changes observed and determined CRF1 receptor levels in SERT−/− rats. SERT−/− showed blunted fear potentiation and enhanced contextual fear, which resulted from a deficit in fear acquisition. Paroxetine treatment did not affect acquisition or expression of fear-potentiated startle, suggesting that disturbed fear learning in SERT−/− results from developmental changes and not from reduced SERT functioning. Although CRF1 receptor levels did not differ significantly between genotypes, CP154,526 treatment normalized both cue- and contextual fear in SERT−/− during acquisition, but not expression of fear-potentiated startle. The disrupted fear acquisition and concomitant increase in contextual conditioned fear-potentiated startle fear in SERT−/− resembles the associative learning deficit seen in patients with panic disorder and suggests that normal SERT functioning is crucial for the development of an adequate fear neuro-circuitry. Moreover, the normalization of fear acquisition by CP154,526 suggests a role for central CRF signaling in the generalization of fear.

Fear extinction, persistent disruptive behavior and psychopathic traits: fMRI in late adolescence.

Children diagnosed with a Disruptive Behavior Disorder (DBD, i.e. Oppositional Defiant Disorder or Conduct Disorder), especially those with psychopathic traits, are at risk of developing persistent and severe antisocial behavior. Reduced fear conditioning has been proposed to underlie persistent antisocial development. However, we have recently shown that both DBD persisters and desisters are characterized by increased fear conditioning compared with healthy controls (HCs). In this study, we investigated whether brain function during fear extinction is associated with DBD subgroup-membership and psychopathic traits. Adolescents from a childhood arrestee cohort (mean age 17.6 years, s.d. 1.4) who met criteria for a DBD diagnosis during previous assessments were re-assessed and categorized as persistent DBD (n = 25) or desistent DBD (n = 25). Functional MRI during the extinction phase of a classical fear-conditioning task was used to compare regional brain function between these subgroups and 25 matched controls. Both DBD persisters and desisters showed hyperreactivity during fear extinction, when compared with HCs. Impulsive-irresponsible psychopathic traits were positively associated with responses in the fear neurocircuitry and mediated the association between neural activation and group membership. These results suggest that fear acquisition and fear extinction deficits may provide an endophenotype for an emotionally hyperreactive subtype of antisocial development.

Transcranial Direct Current Stimulation (tDCS) for Panic Disorder: A Case Study

Background: Panic disorder (PD) is characterized primarily by the presence of recurrent and unexpected panic attacks, followed by at least one month of persistent concern about other attacks, the possible consequences of attacks and a significant behavioral change related to the attacks. The neurocircuitry of fear includes two pathways for processing of sensory information. Transcranial direct current stimulation (tDCS) use has not been reported for PD. Objective: To report the results of an experimental tDCS protocol for ameliorating anxiety symptoms in a patient with panic disorder. Method: The current report is based on a single case study. We used an experimental tDCS intervention protocol as to inhibit the right dorsolateralprefrontal cortex during a period of two weeks. Symptoms were assessed by adequate clinical scales. Results: We hereby describe a 44-year-old woman with PD who successfully underwent a tDCS intervention, with important ameliorating of her symptoms. Discussion and Conclusion: To the best of our knowledge, this it is the first report using tDCS for PD. Some study limitations, however, should be addressed. Our findings are based on a case study, thus having limited generalizability. Nonetheless, these encouraging results should be seen as hypothesis-driving for further controlled, randomized trials exploring the impact of tDCS in the treatment of PD and maybe other anxiety disorders.

Development of fear acquisition and extinction in children: Effects of age and anxiety

Development of anxiety disorders is associated with neurobiological changes in areas that are a critical part of the fear neurocircuitry. Fear conditioning paradigms can offer insight into the mechanisms underlying the neurobiological ontogeny of anxiety. A small number of studies have focused on the effects of age and anxiety separately in school age children. The present study aimed to investigate these effects in 8–13year old children with higher and lower trait anxiety. We examined differential fear conditioning and extinction using skin conductance responses and fear-potentiated startle in 60 children recruited from a low-income urban population. The results indicated that children under 10years of age show poor discrimination of conditioned stimuli, and that anxiety increases fear responses during fear acquisition. After controlling for age and trauma exposure, fear-potentiated startle to the safety cue predicted child anxiety levels suggesting that impaired safety signal learning may be a risk factor for anxiety disorders in adulthood. Identifying risk phenotypes in children may provide opportunities for early intervention and prevention of illness.

Opposite effects of noradrenergic arousal on amygdala processing of fearful faces in men and women

Fear-related disorders are significantly more prevalent in women than in men. Stress may modulate the neurocircuitry of fear and is a critical factor in the pathogenesis of fear-related disorders. Therefore, we tested in the present experiment the hypothesis that noradrenaline and glucocorticoids, two major stress mediators, have differential effects on fear processing in men and women. In a placebo-controlled, double-blind between-subject design, 80 healthy men and women were administered orally the α2-adrenoceptor antagonist yohimbine and/or the synthetic glucocorticoid hydrocortisone before they rated images of neutral and fearful faces with respect to the degree of fearfulness of the facial expression. During presentation of facial expressions, functional magnetic resonance images were collected. Yohimbine increased subjective ratings of the fearfulness of the faces in women but reduced fearfulness ratings in men. Neuroimaging data showed that yohimbine increased amygdala activity in response to fearful faces in women, whereas it attenuated amygdala responsivity to fearful faces in men. Moreover, yohimbine decreased orbitofrontal activity while viewing fearful faces in women. Hydrocortisone did not affect fear processing, neither in men nor in women. Our findings suggest that noradrenergic arousal may have opposite effects on fear processing in men and women. These sex differences may represent a biological mechanism that contributes to the differential prevalence of fear-related disorders in men and women.

Neural substrates of childhood anxiety disorders: a review of neuroimaging findings.

The development of fear is a normative process, and significant progress has been made in identifying fear neurocircuitry. The normal development of fear goes awry in children who develop anxiety disorders, and dysfunction in fear circuitry is likely. In this article, the authors present current knowledge about the neural basis of normal fear development and reviews findings from structural and functional neuroimaging studies of childhood anxiety disorders.

Anterior Cingulate Cortex: Unique Role in Cognition and Emotion

Anterior Cingulate Cortex: Unique Role in Cognition and Emotion

The Neurocircuitry of Fear, Stress, and Anxiety Disorders

Anxiety disorders are a significant problem in the community, and recent neuroimaging research has focused on determining the brain circuits that underlie them. Research on the neurocircuitry of anxiety disorders has its roots in the study of fear circuits in animal models and the study of brain responses to emotional stimuli in healthy humans. We review this research, as well as neuroimaging studies of anxiety disorders. In general, these studies have reported relatively heightened amygdala activation in response to disorder-relevant stimuli in post-traumatic stress disorder, social phobia, and specific phobia. Activation in the insular cortex appears to be heightened in many of the anxiety disorders. Unlike other anxiety disorders, post-traumatic stress disorder is associated with diminished responsivity in the rostral anterior cingulate cortex and adjacent ventral medial prefrontal cortex. Additional research will be needed to (1) clarify the exact role of each component of the fear circuitry in the anxiety disorders, (2) determine whether functional abnormalities identified in the anxiety disorders represent acquired signs of the disorders or vulnerability factors that increase the risk of developing them, (3) link the findings of functional neuroimaging studies with those of neurochemistry studies, and (4) use functional neuroimaging to predict treatment response and assess treatment-related changes in brain function. (Reprinted with permission from Neuropsychopharmacology Reviews 2010; 35:169–191)