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Avoidance behavior in panic disorder: the moderating influence of perceived control.

The relations among anxiety sensitivity, perceived control, and agoraphobia were examined in 239 patients diagnosed with panic disorder (PD). Most patients exhibited agoraphobia accompanying their PD (98% situational avoidance; 90% experiential avoidance; and 80% endorsed interoceptive fear and avoidance). Anxiety sensitivity and perceived emotional control were associated with agoraphobia, and perceived threat control was found to moderate the relationship between anxiety sensitivity and agoraphobia. Lower levels of perceived control were associated with a stronger relationship between anxiety sensitivity and agoraphobia. Results were consistent for self-reported and clinician-rated agoraphobia. Implications for the role of perceived control in agoraphobia development and treatment are discussed.

Adolescent↗

Voluntary hyperventilation in the treatment of panic disorder--functions of hyperventilation, their implications for breathing training, and recommendations for standardization.

Hyperventilation has numerous theoretical and empirical links to anxiety and panic. Voluntary hyperventilation (VH) tests have been applied experimentally to understand psychological and physiological mechanisms that produce and maintain anxiety, and therapeutically in the treatment of anxiety disorders. From the theoretical perspective of hyperventilation theories of anxiety, VH is useful diagnostically to the clinician and educationally to the patient. From the theoretical perspective of cognitive-behavior therapy, VH is a way to expose patients with panic disorder to sensations associated with panic and to activate catastrophic cognitions that need restructuring. Here we review panic disorder treatment studies using breathing training that have included VH. We differentiate the roles of VH in diagnosis, education about symptoms, training of breathing strategies, interoceptive exposure, and outcome measurement--discussing methodological issues specific to these roles and VH test reliability and validity. We propose how VH procedures might be standardized in future studies.

Anxiety Disorders↗

Emotional exposure in the treatment of substance use disorders: conceptual model, evidence, and future directions.

In this article, we review research on the nature and treatment of panic disorder, and apply these findings to a discussion of the role of internal cue exposure in the treatment of substance use disorders (SUDs). Two features of panic treatment were used as a model for interventions for SUDs: exposure to internal (interoceptive) cues rather than reliance on external (environmental) exposure alone, and use of cue exposure to try to inoculate individuals against future maladaptive patterns. Specifically, we emphasized the role of exposure to internal, largely emotional cues, as a way to enhance resilience to cues for relapse in individuals with SUDs. Hypothesized moderators and mediators of this treatment approach were discussed, as were similarities between this research agenda and an increasing focus on the role of emotional acceptance/tolerance in cognitive-behavioral treatments.

Cognitive Behavioral Therapy↗

Eating disorders and personality: a methodological and empirical review.

Methodological approaches utilized to evaluate models of the relationship between personality and eating disorders, as well as empirical support for each model, are reviewed. Limited prospective research suggests that negative emotionality, perfectionism, drive for thinness, poor interoceptive awareness, ineffectiveness, and obsessive-compulsive personality traits are likely predisposing factors. Limited family study research suggests that obsessive-compulsive personality disorder (OCPD) and anorexia nervosa share a common familial liability. Potential pathoplastic personality factors include Cluster B personality disorders and OCPD, which predict a poorer course and/or outcome, and histrionic personality traits and self-directedness, which predict a more favorable course and/or outcome. Future research should focus upon sophisticated prospective and family study research in order to best evaluate competing models of the eating disorder-personality relationship.

Anorexia Nervosa↗

The effects of acceptance versus control contexts on avoidance of panic-related symptoms.

The present study compared the effects of creating an acceptance versus a control treatment context on the avoidance of aversive interoceptive stimulation. Sixty high anxiety sensitive females were exposed to two 10-min periods of 10% carbon dioxide enriched air, an anxiogenic stimulus. Before each inhalation period, participants underwent a training procedure aimed at encouraging them either to mindfully observe (acceptance context) or to control symptoms via diaphragmatic breathing (control context). A third group was given no particular training or instructions. We hypothesized that an acceptance rather than control context would be more useful in the reduction of anxious avoidance. Compared to control context and no-instruction participants, acceptance context participants were less avoidant behaviorally and reported less intense fear and cognitive symptoms and fewer catastrophic thoughts during the CO(2) inhalations. We discuss the implications of our findings for an acceptance-focused vs. control-focused context when conducting clinical interventions for panic and other anxiety disorders.

Analysis of Variance↗

Elevated pain threshold in eating disorders: physiological and psychological factors.

Several studies have found decreased pain sensitivity in patients with eating disorders but it is unclear what physiological and psychological factors are associated with this abnormality. In the present investigation, thermal pain threshold latency, somatoform dissociation, body image disturbance and physiological indices of autonomic neural system activity were measured in 39 female patients with eating disorders (21 with anorexia nervosa and 18 with bulimia nervosa) and 17 healthy women. Pain threshold was elevated in patients with eating disorders, especially those with binge-purging symptomatology. A regression analysis indicated that increased pain threshold is moderately associated with decreased peripheral skin temperature and weakly associated with lack of familiarity with one's own body. However, the between group differences in pain perception remained significant after controlling for peripheral skin temperature. Hence, elevation of pain threshold in eating disorders is a replicable finding, which is not explicable by peripheral indices of autonomic system activity or by somatoform dissociation. In future research it may be evaluated as a potential marker of broader phenotype of decreased interoceptive awareness, which may be associated with vulnerability to the development of eating disorders.

Adult↗

Does regional brain perfusion correlate with eating disorder symptoms in anorexia and bulimia nervosa patients?

OBJECTIVE: Using single photon emission computed tomography (SPECT), we sought brain perfusion correlates of eating disorder symptoms in anorexia and bulimia nervosa patients. METHOD: We investigated 67 female eating disordered (ED) patients. Eating disorder symptoms were measured by the Eating Disorders Inventory (EDI). Determination of brain areas in which regional perfusion co-varied with drive for thinness, bulimia, body dissatisfaction, ineffectiveness, perfectionism, interpersonal distrust, interoceptive awareness and maturity fears was done by open explorative correlation analysis using Statistical Parametrical Mapping (SPM). RESULTS: A significant positive correlation between scores on body dissatisfaction and ineffectiveness, and brain perfusion in the prefrontal and parietal cortex was demonstrated. There were no correlations between other eating disorder symptoms and brain perfusion. CONCLUSION: Based on the finding of an association between regional brain flow and body dissatisfaction and ineffectiveness, we argue that neurobiological findings in ED patients may not only reflect emotional and behavioural factors but cognitive-evaluative features as well.

Adult↗

Suffocation and respiratory responses to carbon dioxide and breath holding challenges in individuals with panic disorder.

OBJECTIVE: Findings showing that individuals with panic disorder (PD) are prone to experience panic attacks when inhaling CO2-enriched air have given rise to the hypothesis that physiological systems underlying the experience of suffocation may be important in the etiology of PD. In this study, we tested several predictions stemming from this view. METHODS: Forty individuals with PD and 32 controls underwent both a breath-holding challenge and a CO2 rebreathing challenge. A wide array of physiological and psychological responses, including continuous measurements of subjective suffocation, was recorded. RESULTS: Individuals with PD experienced elevated physiological reactivity to both challenges and greater levels of suffocation sensations during the rebreathing challenge. Furthermore, PD individuals who experienced a panic attack in response to the rebreathing challenge exhibited faster but shallower breathing during the challenge than did other PD individuals. CONCLUSION: Findings are consistent with theories linking PD to hypersensitive brain systems underlying the experience of suffocation. The possibility that subjective suffocation was in part mediated by peripheral interoceptive disturbances (vs. brainstem dysregulation) is discussed.

Adult↗

Neural correlates of internally-generated disgust via autobiographical recall: a functional magnetic resonance imaging investigation.

Converging lines of evidence suggest the involvement of the insula and basal ganglia in the processing of disgust, an important primary emotion that guides the avoidance of potential physical contamination and disease. Prior human lesion and functional brain imaging studies have employed exteroceptive sensory stimuli such as facial expressions of disgust, and disgust-eliciting pictures. Thus, the neural substrates underlying the internal experience of disgust remain unknown. The present fMRI study examined the neural correlates of self-induced disgust aided by the recall and re-experience of personally salient life events. Subjects were scanned while they recalled and re-experienced either a recent situation that evoked intense disgust or a time-matched, equally vivid neutral/non-emotional event. Relative to the emotionally neutral condition, self-induced disgust was associated with activation of the insula, hippocampus, anterior and posterior cingulate cortex, basal ganglia, thalamus, and primary visual cortex. These findings suggest that areas previously associated with the perception of disgust (e.g., insula, basal ganglia) are also involved interoceptive experience of disgust.

Adult↗

Eyes open and eyes closed as rest conditions: impact on brain activation patterns.

The patterns of associated brain activations during eyes-open and eyes-closed states in complete darkness considerably differ in fMRI. An "interoceptive" state with the eyes closed is characterized by visual cortex activation, while an "exteroceptive" state with the eyes open is characterized by ocular motor system activity. The impact of the chosen rest condition (eyes open or eyes closed in complete darkness) on the pattern of brain activations during visual stimulation was evaluated in 14 healthy volunteers. During fixation or dim light room illumination, the activation of the visual cortex was larger with the eyes-open rest condition than with the eyes-closed rest condition; however, activation of the lateral geniculate nucleus was smaller. Activations that can be attributed to ocular motor structures, such as the prefrontal cortex, parietal and frontal eye fields, cerebellar vermis, the thalamus, and basal ganglia were larger with the eyes-closed rest condition than with the eyes-open rest condition. BOLD signal decreases of cortical areas that represent visual, somatosensory, auditory, and vestibular functions were seen in the comparison fixation of light emitting diode (LED) minus eyes closed. Thus, the choice of rest condition (either eyes closed or eyes open) is critical for stimulus-induced brain activation patterns. Activity of the ocular motor system as well as deactivation of sensory cortical areas may go undetected with eyes open as rest condition.

Adolescent↗

Activity in ventromedial prefrontal cortex covaries with sympathetic skin conductance level: a physiological account of a "default mode" of brain function.

We examined neural activity related to modulation of skin conductance level (SCL), an index of sympathetic tone, using functional magnetic resonance imaging (fMRI) while subjects performed biofeedback arousal and relaxation tasks. Neural activity within the ventromedial prefrontal cortex (VMPFC) and the orbitofrontal cortex (OFC) covaried with skin conductance level (SCL), irrespective of task. Activity within striate and extrastriate cortices, anterior cingulate and insular cortices, thalamus, hypothalamus and lateral regions of prefrontal cortex reflected the rate of change in electrodermal activity, highlighting areas supporting transient skin conductance responses (SCRs). Successful performance of either biofeedback task (where SCL changed in the intended direction) was associated with enhanced activity in mid-OFC. The findings point to a dissociation between neural systems controlling basal sympathetic tone (SCL) and transient skin conductance responses (SCRs). The level of activity in VMPFC has been related to a default mode of brain function and our findings provide a physiological account of this state, indicating that activity within VMPFC and OFC reflects a dynamic between exteroceptive and interoceptive deployment of attention.

Adult↗

Eye closure in darkness animates olfactory and gustatory cortical areas.

In two previous fMRI studies, it was reported that eyes-open and eyes-closed conditions in darkness had differential effects on brain activity, and typical patterns of cortical activity were identified. Without external stimulation, ocular motor and attentional systems were activated when the eyes were open. On the contrary, the visual, somatosensory, vestibular, and auditory systems were activated when the eyes were closed. In this study, we investigated whether cortical areas related to the olfactory and gustatory system are also animated by eye closure without any other external stimulation. In a first fMRI experiment (n = 22), we identified cortical areas including the piriform cortex activated by olfactory stimulation. In a second experiment (n = 12) subjects lying in darkness in the MRI scanner alternately opened and closed their eyes. In accordance to previous studies, we found activation clusters bilaterally in visual, somatosensory, vestibular and auditory cortical areas for the contrast eyes-closed vs. eyes-open. In addition, we were able to show that cortical areas related to the olfactory and gustatory system were also animated by eye closure. These results support the hypothesis that there are two different states of mental activity: with the eyes closed, an "interoceptive" state characterized by imagination and multisensory activity and with the eyes open, an "exteroceptive" state characterized by attention and ocular motor activity. Our study also suggests that the chosen baseline condition may have a considerable impact on activation patterns and on the interpretation of brain activation studies. This needs to be considered for studies of the olfactory and gustatory system.

Attention↗

Empathy for positive and negative emotions in the gustatory cortex.

Anterior insula and adjacent frontal operculum (hereafter referred to as IFO) are active during exposure to tastants/odorants (particularly disgusting ones), and during the viewing of disgusted facial expressions. Together with lesion data, the IFO has thus been proposed to be crucial in processing disgust-related stimuli. Here, we examined IFO involvement in the processing of other people's gustatory emotions more generally by exposing participants to food-related disgusted, pleased and neutral facial expressions during functional magnetic resonance imaging (fMRI). We then exposed participants to pleasant, unpleasant and neutral tastants for the purpose of mapping their gustatory IFO. Finally, we associated participants' self reported empathy (measured using the Interpersonal Reactivity Index, IRI) with their IFO activation during the witnessing of others' gustatory emotions. We show that participants' empathy scores were predictive of their gustatory IFO activation while witnessing both the pleased and disgusted facial expression of others. While the IFO has been implicated in the processing of negative emotions of others and empathy for negative experiences like pain, our finding extends this concept to empathy for intense positive feelings, and provides empirical support for the view that the IFO contributes to empathy by mapping the bodily feelings of others onto the internal bodily states of the observer, in agreement with the putative interoceptive function of the IFO.

Emotions↗

Cortical processing of visceral and somatic stimulation: differentiating pain intensity from unpleasantness.

Visceral and somatic pain perception differs in several aspects: poor localization of visceral pain and the ability of visceral pain to be referred to somatic structures. The perception of pain intensity and affect in visceral and somatic pain syndromes is often different, with visceral pain reported as more unpleasant. To determine whether these behavioral differences are due to differences in the central processing of visceral and somatic pain, non-invasive imaging tools are required to examine the neural correlates of visceral and somatic events when the behavior has been isolated and matched for either unpleasantness or pain intensity. In this study we matched the unpleasantness of somatic and visceral sensations and imaged the neural representation of this perception using functional magnetic resonance imaging in 10 healthy right-handed subjects. Each subject received noxious thermal stimuli to the left foot and midline lower back and balloon distension of the rectum while being scanned. Stimuli were matched to the same unpleasantness rating, producing mild-moderate pain intensity for somatic stimuli but an intensity below the pain threshold for the visceral stimuli. Visceral stimuli induced deactivation of the perigenual cingulate bilaterally with a relatively greater activation of the right anterior insula-i.e. regions encoding affect. Somatic pain induced left dorso-lateral pre-frontal cortex and bilateral inferior parietal cortex activation i.e. regions encoding spatial orientation and assessing perceptual valence of the stimulus. We believe that the observed patterns of activation represent the differences in cortical process of interoceptive (visceral) and exteroceptive (somatic) stimuli when matched for unpleasantness.

Adult↗

Expression of melanocortin-4 receptor by rat parabrachial neurons responsive to immune and aversive stimuli.

The pontine parabrachial nucleus is a major relay area for visceral and other interoceptive information, and has been implicated in mechanisms underlying anorexia and food aversion during disease. Thus, physiological studies have shown that peripheral immune stimuli, as well as the administration of aversive substances such as lithium chloride, evoke a prominent Fos-expression in the lateral parabrachial nucleus and behavioral experiments have demonstrated that this structure is critical for the acquisition of conditioned taste aversion. The present study examined in rats the relationship between parabrachial neurons activated by systemic administration of bacterial cell-wall lipopolysaccharide or lithium chloride and the melanocortin system, a major regulator of feeding and energy homeostasis that also has been implicated in aversive behavior. Dual-labeling in situ hybridization showed melanocortin-4 receptor expression on neurons in the external lateral parabrachial subnucleus that displayed lipopolysaccharide- or lithium chloride-induced expression of c-fos mRNA. Melanocortin-4 receptor mRNA was also co-expressed with mRNA for calcitonin gene-related peptide in this subnucleus. Taken together with previous observations showing that calcitonin gene-related peptide expressing neurons in the external lateral parabrachial subnucleus are activated by peripheral immune challenge, that lipopolysaccharide-activated external lateral parabrachial subnucleus neurons project to the amygdala, and that the amygdala-projecting neurons in the external lateral parabrachial subnucleus are calcitonin gene-related peptide-positive, the present findings suggest the presence of a melanocortin-regulated calcitonin gene-related peptide-positive pathway from the external lateral parabrachial subnucleus to the amygdala that relays information of importance to forebrain responses to certain aspects of sickness behavior. These observations may thus help explain how melanocortins can reduce feeding and influence conditioned taste aversion during inflammation and other disease conditions.

Animals↗

Stimulant-induced adaptations in neostriatal matrix and striosome systems: transiting from instrumental responding to habitual behavior in drug addiction.

Converging evidence indicates that repeated exposure to motor stimulants such as cocaine and amphetamine produces marked alterations in network responsiveness of striatal neurons to subsequent challenge with the same stimulant drug. Such alterations, which correlate with persistent patterns of repetitive behavior, associate with distinct compartmental changes in the neostriatum. Striatal matrix system neurons undergo "silencing" following repeated drug challenges, allowing striosome system neurons to exhibit preferential activation. Matrix neurons are innervated by sensory and motor areas of neocortex and are activated in the course of on-going, adaptive behavior. Inactivation of matrix neurons by chronic stimulant exposure may therefore constrain sensorimotor and cognitive processing. In turn, the striosomes are anatomically connected through re-entrant loops with limbic prefrontal and allocortical structures, such as anterior cingulate cortex, orbital frontal cortex, and basolateral amygdala, all of which play a part in stimulant-induced reinforcement and relapse to drug-taking. Moreover, functional evidence links striosome system neurons, which are responsible for providing inhibitory regulatory feedback to midbrain dopamine neurons, with reinforcement-based processes. In considering such evidence, we postulate that recurrent matrix inactivation and recruitment of striosome-based pathways by chronic stimulant exposure represent neural end-points of the transit from action-outcome associative behavior to conditioned habitual responding. Within this theoretical framework, habitual behavior can be elicited by both interoceptive cues and exteroceptive conditioned stimuli to promote the automatic execution of learned responses.

Amphetamine↗

Cortical effects of anticipation and endogenous modulation of visceral pain assessed by functional brain MRI in irritable bowel syndrome patients and healthy controls.

Visceral pain processing is abnormal in a majority of irritable bowel syndrome (IBS) patients. Aberrant endogenous nociceptive modulation and anticipation are possible underlying mechanisms investigated in the current study. Twelve IBS patients and 12 matched healthy controls underwent brain fMRI scanning during the following randomised stimuli: sham and painful rectal distensions by barostat without and with simultaneous activation of endogenous descending nociceptive inhibition using ice water immersion of the foot for heterotopic stimulation. Heterotopic stimulation decreased rectal pain scores from 3.7+/-0.2 to 3.1+/-0.3 (mean+/-SE, scale 0-5) in controls (p<0.01), but not significantly in IBS. Controls differed from IBS patients in showing significantly greater activation bilaterally in the anterior insula, SII and putamen during rectal stimulation alone compared to rectal plus heterotopic stimulation. Greater activation during rectal plus heterotopic versus rectal stimulation was seen bilaterally in SI and the right superior temporal gyrus in controls and in the right inferior lobule and bilaterally in the superior temporal gyrus in IBS. Rectal pain scores were similarly low during sham stimulation in both groups, but brain activation patterns differed. In conclusion, IBS patients showed dysfunctional endogenous inhibition of pain and concomitant aberrant activation of brain areas involved in pain processing and integration. Anticipation of rectal pain was associated with different brain activation patterns in IBS involving multiple interoceptive, homeostatic, associative and emotional areas, even though pain scores were similar during sham distension. The aberrant activation of endogenous pain inhibition appears to involve circuitry relating to anticipation as well as pain processing itself.

Adult↗

Hallucinogen-like actions of 5-methoxy-N,N-diisopropyltryptamine in mice and rats.

Few studies have examined the effects of 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) in vivo. In these studies, 5-MeO-DIPT was tested in a drug-elicited head twitch assay in mice where it was compared to the structurally similar hallucinogen N,N-dimethyltryptamine (N,N-DMT) and challenged with the selective serotonin (5-HT)2A antagonist M100907, and in a lysergic acid diethylamide (LSD) discrimination assay in rats where its subjective effects were challenged with M100907 or the 5-HT 1A selective antagonist WAY-100635. Finally, the affinity of 5-MeO-DIPT for three distinct 5-HT receptors was determined in rat brain. 5-MeO-DIPT, but not N,N-DMT, induced the head twitch responses in the mouse, and this effect was potently antagonized by prior administration of M100907. In rats trained with LSD as a discriminative stimulus, there was an intermediate degree (75%) of generalization to 5-MeO-DIPT and a dose-dependent suppression of response rates. These interoceptive effects were abolished by M100907, but were not significantly attenuated by WAY-100635. Finally, 5-MeO-DIPT had micromolar affinity for 5-HT 2A and 5-HT 2C receptors, but much higher affinity for 5-HT 1A receptors. 5-MeO-DIPT is thus effective in two rodent models of 5-HT2 agonist activity, and has affinity at receptors relevant to hallucinogen effects. The effectiveness with which M100907 antagonizes the behavioral actions of this compound, coupled with the lack of significant antagonist effects of WAY-100635, strongly suggests that the 5-HT 2A receptor is an important site of action for 5-MeO-DIPT, despite its apparent in vitro selectivity for the 5-HT 1A receptor.

5-Methoxytryptamine↗