Initial white matter connectivity differences between remitters and non-remitters of patients with panic disorder after 6 months of pharmacotherapy.

Panic disorder (PD) is a harmful mental condition that causes relapsed and persistent impairment. In the treatment of PD, the prognosis for PD should be considered. However, the relationship between pharmacotherapy and biomarkers, for predicting a better response through neuroimaging, is a little known. The purpose of the present study was to examine whether there would be the initial white matter (WM) regions associated with the remission in 6 months. A total of 104 patients with PD were investigated in the study. After six months, there were 17 remission patients with PD and 81 non-remission patients. The Panic Disorder Severity Scale, Albany Panic and Phobia Questionnaire, Anxiety Sensitivity Inventory-Revised, Beck Anxiety Inventory, and Beck Depression Inventory were assessed for all patients at baseline. We compared the diffusion indices between remission and non-remission group at 6 months using Tract-Based Spatial Statistics. The results showed that the fractional anisotropy (FA) values were significantly higher in the non-remitter group compared with those in the remitter group in the WM regions, such as the posterior corona radiata and superior longitudinal fasciculus, at the 6 month evaluation. The logistic regression analysis with clinical symptom severity and FA values of the WM regions as covariates showed that FA values in those regions and the Beck Depression Inventory-II predicted poor remission. This study suggests that posterior corona radiata and superior longitudinal fasciculus are related to potential predictive factors of 6-month remission in patients with PD. WM regions associated with the long-term remission should be verified with further investigations.

In vivo investigation on bio-markers of perimenopausal panic disorder and catgut embedding acupoints mechanism.

BACKGROUND: Panic disorder (PD), defined by repeated and unexpected panic attacks, severely affects patients' living quality and social function. Perimenopausal women are high-risk group of PD and suffer greatly from it. Modern medicine therapies for this disorder have many side reactions and poor effects, so nonpharmacological modality is an urgent need. Although acupoint catgut embedding is widely used in clinical practice, there is no persuasive evidence of its effect for perimenopausal PD. The aim of this study is to investigate the effectiveness and safety of acupoint catgut embedding for perimenopausal PD and to elucidate the correlations among brain neural activation, bio-markers (amino acids) and clinical outcomes with radiographic evidence, thus to explore its neural mechanism. METHODS: The parallel designed, exploratory randomized controlled trial will include 70 outpatients with perimenopausal PD recruited from two hospitals of Chinese Medicine. These subjects will be randomly allocated to an intervention group (Group Embedding) and a control group (Group Medication) in a 1:1 ratio. The subjects in the intervention group will receive acupoint catgut embedding treatment two weeks a time in the following predefined acupuncture points: Shenshu (BL23), Sanyinjiao (SP6), Guanyuan (RN4), Ganshu (BL18), Zusanli (ST36) and Pishu (BL20). The included women of the control group will take 0.4 mg Alprazolam tablet orally, 1 tablet a time, 3 times a day. There is a study period of 3 months and a follow-up period of 1 month for each group. The primary outcomes will be the following therapeutic indexes: the frequency of panic attack, Panic Disorder Severity Score (PDSS), and Panic-associated Symptoms Score (PASS) during the observation period and follow-up period. The changes in Hamilton Anxiety Scale (HAMA) Score and Symptom Checklist 90 (SCL-90) Score will also be compared between these two groups. Additionally, functional magnetic resonance imaging (fMRI) and proton magnetic resonance spectroscopy (1H-MRS) scans will be done before and after the observation period to show cranial neuroimaging changes. DISCUSSION: We present a study design and rationale to explore the effectiveness and neural mechanism of acupoint catgut embedding for perimenopausal PD. There are still several factors restrict our research such as no unified standard of diagnostic criteria and curative effect evaluation. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-INR-16009724, registered in November 2016.

Further Exploration of Treatment Response in Latinos with Comorbid Asthma and Panic Disorder: A Brief Report of HRV and ETCO2 as Potential Mediators of Treatment Response.

Heart rate variability (HRV) and end tidal CO2 (ETCO2) in relation to treatment response have not been studied in Latino populations or in comorbid asthma and panic disorder (PD). An extension of previously published research, the current study explored psychophysiological variables as possible mediators of treatment response. Latino treatment completers (N = 32) in the Bronx with asthma-PD received either Cognitive-Behavioral Psychophysiological Therapy (CBPT) or Music Relaxation Therapy (MRT). CBPT included HRV-biofeedback (HRVB); in-the-moment heart rate data to help an individual learn to influence his/her own heart rate. The sample was primarily female (93.8%) and Puerto Rican (81.25%). Treatment groups did not differ on demographics, except for less education in CBPT. The Panic Disorder Severity Scale (PDSS) and Asthma Control Questionnaire (ACQ) assessed changes in symptoms. HRV and ETCO2 were measured at four of eight therapy sessions. Baseline ETCO2 and changes in HRV from first to last of psychophysiology sessions were investigated as mediators of change on ACQ and PDSS. Mixed model analyses indicated in the CPBT group, changes in both asthma control and PD severity were not mediated by changes in HRV. In the CBPT and MRT groups combined, changes in PD severity were not mediated by baseline ETCO2. These findings may be due to the brevity of HRVB in CBPT, multiple treatment components, ETCO2 not directly targeted, and/or unique physiological pathways in Latinos with asthma-PD.

P50, N100, and P200 Sensory Gating in Panic Disorder.

Panic disorder (PD) has been linked to abnormalities in information processing. However, only little evidence has been published for sensory gating in PD. Sensory gating describes the brain's ability to exclude stimuli of low relevance from higher level information processing, thereby sustaining efficient cognitive processing. Deficits in sensory gating have been associated with various psychiatric conditions, most prominently schizophrenia. In this case-control event-related potential study, we tested 32 patients with PD and 39 healthy controls in a double click paradigm. Both groups were compared with regard to pre-attentive (P50), early-attentive (N100), and late-attentive (P200) sensory gating indices. Contrary to a hypothesized deficit, PD patients and healthy controls showed no differences in P50, N100 and P200 values. These results suggest that sensory gating seems to be functional across the pre-attentive, early-attentive, and late-attentive time span in this clinical population. Given this consistency across auditory sensory gating indices, further research aiming to clarify information processing deficits in PD should focus on other neurophysiological markers to investigate information processing deficits in PD (eg, P300, error-related negativity or mismatch negativity).

Abnormal frontal generator during auditory sensory gating in panic disorder: An MEG study.

Patients with panic disorder (PD) exhibit abnormalities in early-stage information processing, even for the nonthreatening stimuli. A previous event-related potential study reported that PD patients show a deficit in sensory gating (SG), a protective mechanism of the brain to filter out irrelevant sensory inputs. However, there is no clear understanding about the neural correlates of SG deficits in PD. Moreover, whether SG deficits, if any, are associated with clinical manifestations remain unknown. In this study, 18 patients with PD and 20 age- and gender-matched healthy controls were recruited to perform auditory paired-stimulus paradigm using magnetoencephalographic (MEG) recordings. Results showed that PD patients demonstrated significantly higher M50 SG ratios in the right inferior frontal gyrus (RIFG) and higher M100 SG ratios in both RIFG and right superior temporal gyrus (RSTG) than those of the control group. It was important to note that in the RIFG, the M50 SG ratios correlated significantly with the scores of Body Sensation Questionnaire (BSQ) and Distractibility scale of Sensory Gating Inventory among patients with PD. In conclusion, this study suggests that PD patients exhibited a deficient ability to filter out irrelevant information, and such a defect might lead to cognitive misinterpretation of somatic sensations and distractibility.

Heightened sensitivity to panic-related sounds with reduced sensitivity to neutral sounds in preattentive processing among panic patients.

BACKGROUND: Hypervigilance to panic-related stimuli is believed to play a critical role in the pathogenesis of panic disorder. The current event-related potential study explored whether this hyperresponsivity occurred in the absence of focused attention. METHODS: Mismatch negativity (MMN) responses to panic-related vs. neutral deviants were assessed in 15 medication-free panic patients without agoraphobia and 16 healthy controls using a reverse-standard-deviant paradigm. RESULTS: Panic patients relative to healthy controls exhibited an enhanced MMN in response to panic-related sounds but a reduced MMN in response to neutral sounds. Furthermore, MMN responses were delayed in panic patients compared to healthy controls, irrespective of stimulus type. LIMITATION: The sample size is relatively small. CONCLUSIONS: Our data provide evidence that panic disorder was associated with an increased sensitivity to panic-related changes, accompanied by a reduced sensitivity to other acoustic changes as well as a general slow-down of cognitive processing during the preattentive processing stage.

Brain activation during disorder-related script-driven imagery in panic disorder: a pilot study.

Despite considerable effort, the neural correlates of altered threat-related processing in panic disorder (PD) remain inconclusive. Mental imagery of disorder-specific situations proved to be a powerful tool to investigate dysfunctional threat processing in anxiety disorders. The current functional magnetic resonance imaging (fMRI) study aimed at investigating brain activation in PD patients during disorder-related script-driven imagery. Seventeen PD patients and seventeen healthy controls (HC) were exposed to newly developed disorder-related and neutral narrative scripts while brain activation was measured with fMRI. Participants were encouraged to imagine the narrative scripts as vividly as possible and they rated their script-induced emotional states after the scanning session. PD patients rated disorder-related scripts as more arousing, unpleasant and anxiety-inducing as compared to HC. Patients relative to HC showed elevated activity in the right amygdala and the brainstem as well as decreased activity in the rostral anterior cingulate cortex, and the medial and lateral prefrontal cortex to disorder-related vs. neutral scripts. The results suggest altered amygdala/ brainstem and prefrontal cortex engagement and point towards the recruitment of brain networks with opposed activation patterns in PD patients during script-driven imagery.

Recovery of Percent Vital Capacity by Breathing Training in Patients With Panic Disorder and Impaired Diaphragmatic Breathing.

Slow diaphragmatic breathing is one of the therapeutic methods used in behavioral therapy for panic disorder. In practice, we have noticed that some of these patients could not perform diaphragmatic breathing and their percent vital capacity was initially reduced but could be recovered through breathing training. We conducted a comparative study with healthy controls to investigate the relationship between diaphragmatic breathing ability and percent vital capacity in patients with panic disorder. Our findings suggest that percent vital capacity in patients with impaired diaphragmatic breathing was significantly reduced compared with those with normal diaphragmatic breathing and that diaphragmatic breathing could be restored by breathing training. Percent vital capacity of the healthy controls was equivalent to that of the patients who had completed breathing training. This article provides preliminary findings regarding reduced vital capacity in relation to abnormal respiratory movements found in patients with panic disorder, potentially offering alternative perspectives for verifying the significance of breathing training for panic disorder.

A Multisite Benchmarking Trial of Capnometry Guided Respiratory Intervention for Panic Disorder in Naturalistic Treatment Settings.

Panic disorder (PD) is associated with hyperventilation. The efficacy of a brief respiratory feedback program for PD has been established. The aim of the present study was to expand these results by testing a similar program with more clinically representative patients and settings. Sixty-nine adults with PD received 4 weeks of Capnometry Guided Respiratory Intervention (CGRI) using Freespira, which provides feedback of end-tidal CO2 (PETCO2) and respiration rate (RR), in four non-academic clinical settings. This intervention is delivered via home use following initial training by a clinician and provides remote monitoring of client adherence and progress by the clinician. Outcomes were assessed post-treatment and at 2- and 12-month follow-up. CGRI was associated with an intent-to-treat response rate of 83% and a remission rate of 54%, and large decreases in panic severity. Similar decreases were found in functional impairment and in global illness severity. Gains were largely sustained at follow-up. PETCO2 moved from the slightly hypocapnic range to the normocapnic range. Benchmarking analyses against a previously-published controlled trial showed very similar outcomes, despite substantial differences in sample composition and treatment settings. The present study confirms prior clinical results and lends further support to the viability of CGRI in the treatment of PD.

Effect of Zuogui Pill () on monoamine neurotransmitters and sex hormones in climacteric rats with panic attack.

OBJECTIVES: To explore the effects of Chinese medicine prescription Zuogui Pill (, ZGP) on monoamine neurotransmitters and sex hormones in climacteric rats with induced panic attacks. METHODS: Forty-eight climacteric female rats were randomized into 6 groups with 8 rats in each group: the control group, the model group, the low-, medium- and high-dose ZGP groups and the alprazolam group. Rats in the low-, medium- and high-dose ZGP groups were administered 4.725, 9.45, or 18.9 g/kg ZGP by gastric perfusion, respectively. The alprazolam group was treated by gastric perfusion with 0.036 mg/kg alprazolam. The control and model groups were treated with distilled water. The animals were pretreated once daily for 8 consecutive weeks. The behaviors of rats in the open fifield test and the elevated T-maze (ETM) were observed after induced panic attack, and the levels of brain monoamine neurotransmitters and the plasma levels of sex hormones were measured. RESULTS: Compared with the control group, the mean ETM escape time and the levels of 5-hydroxytryptamine (5-HT) and noradrenalin (NE) of the model group were signifificantly reduced (P<0.05), Compared with the model group, the mean ETM escape time and the 5-HT and NE levels of all the ZGP groups increased signifificantly (P<0.05 or P<0.01). However, no signifificant difference was observed in the levels of sex hormones between the groups. CONCLUSION: Pretreatment with ZGP in climacteric rats may improve the behavior of panic attack, which may be related to increased 5-HT and NE in the brain.

Mismatch negativity indices of enhanced preattentive automatic processing in panic disorder as measured by a multi-feature paradigm.

Panic disorder (PD) is a mental disorder characterized by recurrent panic attacks and worrying about having subsequent attacks. Mismatch negativity (MMN) has been established as a correlate of preattentive automatic processing. The aim of the present study is to investigate the preattentive automatic information processing in PD patients as measured by MMN. Subjects included 15 medication-free patients with a DSM-IV diagnosis of PD and 15 age-matched healthy volunteers. MMN was investigated using event-related potentials. The protocol used a multi-feature paradigm. Mean amplitudes and peak latencies were subjected to repeated-measures ANOVAs. PD patients showed a significantly increased MMN of sound intensity and location compared with healthy participants. The correlation between the amplitudes of intensity-MMN and disease severity was also significant. These data provide evidence of anomalous preattentive automatic information processing in PD patients. In particular, the abnormality may be specific for PD.

Respiratory muscle tension as symptom generator in individuals with high anxiety sensitivity.

OBJECTIVE: Anxiety and panic are associated with the experience of a range of bodily symptoms, in particular unpleasant breathing sensations (dyspnea). Respiratory theories of panic disorder have focused on disturbances in blood gas regulation, but respiratory muscle tension as a source of dyspnea has not been considered. We therefore examined the potential of intercostal muscle tension to elicit dyspnea in individuals with high anxiety sensitivity, a risk factor for developing panic disorder. METHODS: Individuals high and low in anxiety sensitivity (total N=62) completed four tasks: electromyogram biofeedback for tensing intercostal muscle, electromyogram biofeedback for tensing leg muscles, paced breathing at three different speeds, and a fine motor task. Global dyspnea, individual respiratory sensations, nonrespiratory sensations, and discomfort were assessed after each task, whereas respiratory pattern (respiratory inductance plethysmography) and end-tidal carbon dioxide (capnography) were measured continuously. RESULTS: In individuals with high compared to low anxiety sensitivity, intercostal muscle tension elicited a particularly strong report of obstruction (M=5.1, SD=3.6 versus M=2.5, SD=3.0), air hunger (M=1.9, SD=2.1 versus M=0.4, SD=0.8), hyperventilation symptoms (M=0.6, SD=0.6 versus M=0.1, SD=0.1), and discomfort (M=5.1, SD=3.2 versus M=2.2, SD=2.1) (all p values<.05). This effect was not explained by site-unspecific muscle tension, voluntary manipulation of respiration, or sustained task-related attention. Nonrespiratory control sensations were not significantly affected by tasks (F<1), and respiratory variables did not reflect any specific responding of high-Anxiety Sensitivity Index participants to intercostal muscle tension. CONCLUSIONS: Respiratory muscle tension may contribute to the respiratory sensations experienced by panic-prone individuals. Theories and treatments for panic disorder should consider this potential source of symptoms.

Decreased hypothalamus volumes in generalized anxiety disorder but not in panic disorder.

BACKGROUND: The hypothalamus is a brain structure involved in the neuroendocrine aspect of stress and anxiety. Evidence suggests that generalized anxiety disorder (GAD) and panic disorder (PD) might be accompanied by dysfunction of the hypothalamus-pituitary-adrenal axis (HPA), but so far structural alterations were not studied. We investigated hypothalamic volumes in patients with either GAD or PD and in healthy controls. METHODS: Twelve GAD patients, 11 PD patients and 21 healthy controls underwent a 1.5T MRI scan. Hypothalamus volumes were manually traced by a rater blind to subjects' identity. General linear model for repeated measures (GLM-RM) was used to compare groups on hypothalamic volumes, controlling for total intracranial volume, age and sex. RESULTS: The hypothalamus volume was significantly reduced (p=0.04) in GAD patients, with significant reductions in both the left (p=0.02) and right side (p=0.04). Patients with PD did not differ significantly (p=0.73). Anxiety scores were inversely correlated with hypothalamic volumes. LIMITATIONS: The small sample size could reduce the generalizability of the results while the lack of stress hormone measurements renders functional assessment of the hypothalamus-pituitary-adrenal axis not feasible. CONCLUSIONS: The present study showed decreased hypothalamic volumes in GAD patients but not in those with PD. Future longitudinal studies should combine volumetric data with measurements of stress hormones to better elucidate the role of the HPA axis in GAD.

Opposing breathing therapies for panic disorder: a randomized controlled trial of lowering vs raising end-tidal P(CO2).

BACKGROUND: Teaching anxious clients to stop hyperventilating is a popular therapeutic intervention for panic. However, evidence for the theory behind this approach is tenuous, and this theory is contradicted by an opposing theory of panic, the false-suffocation alarm theory, which can be interpreted to imply that the opposite would be helpful. OBJECTIVE: To test these opposing approaches by investigating whether either, both, or neither of the 2 breathing therapies is effective in treating patients with panic disorder. METHOD: We randomly assigned 74 consecutive patients with DSM-IV-diagnosed panic disorder (mean age at onset = 33.0 years) to 1 of 3 groups in the setting of an academic research clinic. One group was trained to raise its end-tidal P(CO2) (partial pressure of carbon dioxide, mm Hg) to counteract hyperventilation by using feedback from a hand-held capnometer, a second group was trained to lower its end-tidal P(CO2) in the same way, and a third group received 1 of these treatments after a delay (wait-list). We assessed patients physiologically and psychologically before treatment began and at 1 and 6 months after treatment. The study was conducted from September 2005 through November 2009. RESULTS: Using the Panic Disorder Severity Scale as a primary outcome measure, we found that both breathing training methods effectively reduced the severity of panic disorder 1 month after treatment and that treatment effects were maintained at 6-month follow-up (effect sizes at 1-month follow-up were 1.34 for the raise-CO(2) group and 1.53 for the lower-CO(2) group; P < .01). Physiologic measurements of respiration at follow-up showed that patients had learned to alter their P(CO2) levels and respiration rates as they had been taught in therapy. CONCLUSIONS: Clinical improvement must have depended on elements common to both breathing therapies rather than on the effect of the therapies themselves on CO(2) levels. These elements may have been changed beliefs and expectancies, exposure to ominous bodily sensations, and attention to regular and slow breathing. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00183521.

Disorder-specific emotional imagery for differential and quantitative assessment of agoraphobia.

Visual emotional stimulation is supposed to elicit psycho-vegetative reactions, which are similar to as the ones elicited by exposure to actual experience. Visual stimulation paradigms have been widely used in studies on agoraphobia with and without panic disorder. However, the applied imagery has hardly ever been disorder- and subject- specific. 51 patients with an ICD-10 and DSM-IV diagnosis of agoraphobia with or without panic disorder (PDA) and matching healthy controls have been examined. Subjects were confronted with 146 picture showing characteristic agoraphobic situations (high places, narrow places, crowds, public transport facilities, or wide places) or pictures associated with acute physical emergency (panic) situations, which had been pre-selected by anxiety experts. Participants were asked to rate emotional arousal induced by the respective images on the Self- Assessment Manikin scale (SAM). Data on PDA severity (PAS) depressive symptoms (MADRS) and sociodemographic data were recorded. Saliva cortisol levels were measured before and after exposure in a second test applying the individually mostly feared stimuli combined with emotionally neutral pictures for every single patient. 117 of the PDA-specific images were rated significantly more fear-eliciting by patients than by healthy individuals. Sub-categorization into agoraphobia clusters showed differential effects of clusters with regard to gender distribution, severity of PDA and cortisol secretion during exposure. In this study disorder specific and individual characteristics of agoraphobia were assessed for use in future trials applying emotional imagery. It could be used for the differential assessment of PDA and associated neurobiological and psychological phenomena and in neuroimaging paradigms.

Stress response regulation in panic disorder.

Panic disorder is a frequent and disabling mental disorder characterized by recurrent periods or abrupt surges of intense fear or discomfort, the panic attacks. The clinical phenomenology of panic attacks suggests a prominent role of a disturbed stress response regulation in the aetiopathology of this disorder. We summarize the results of challenge tests of the hypothalamus-pituitary-adrenocortical (HPA) axis in panic disorder and give an overview of studies using psychosocial challenge paradigms. The results of HPA axis challenge tests suggest an increased expression of the hypothalamic neuropeptides, but an intact negative feedback inhibition at the level of the pituitary. Psychosocial challenge tests give evidence for dissociation between the subjective stress response and the HPA axis response in panic disorder, which might be the result of an over-focussed self-monitoring leading to an enhanced stress perception despite normal HPA axis activation. We integrated these findings in a cognitive stress control model suggesting that panic disorder patients develop efficient strategies to control the somatic stress response despite a hypothalamic hyperdrive of the HPA axis. To employ these strategies at the right time, patients acquired an enhanced perception of stress symptoms, leading to the reported dissociation of the subjective and HPA axis response. It can be inferred from these findings that cognitive behavioral therapy addressing over-focussed self-monitoring and maladaptive control strategies in combination with pharmacological treatment against over-expression of the hypothalamic neuropeptides should be an effective treatment in severe forms of panic disorder, which corresponds with recent treatment guidelines.

An animal model of panic vulnerability with chronic disinhibition of the dorsomedial/perifornical hypothalamus.

Panic disorder (PD) is a severe anxiety disorder characterized by susceptibility to induction of panic attacks by subthreshold interoceptive stimuli such as sodium lactate infusions or hypercapnia induction. Here we review a model of panic vulnerability in rats involving chronic inhibition of GABAergic tone in the dorsomedial/perifornical hypothalamic (DMH/PeF) region that produces enhanced anxiety and freezing responses in fearful situations, as well as a vulnerability to displaying acute panic-like increases in cardioexcitation, respiration activity and "flight" associated behavior following subthreshold interoceptive stimuli that do not elicit panic responses in control rats. This model of panic vulnerability was developed over 15 years ago and has provided an excellent preclinical model with robust face, predictive and construct validity. The model recapitulates many of the phenotypic features of panic attacks associated with human panic disorder (face validity) including greater sensitivity to panicogenic stimuli demonstrated by sudden onset of anxiety and autonomic activation following an administration of a sub-threshold (i.e., do not usually induce panic in healthy subjects) stimulus such as sodium lactate, CO(2), or yohimbine. The construct validity is supported by several key findings; DMH/PeF neurons regulate behavioral and autonomic components of a normal adaptive panic response, as well as being implicated in eliciting panic-like responses in humans. Additionally, patients with PD have deficits in central GABA activity and pharmacological restoration of central GABA activity prevents panic attacks, consistent with this model. The model's predictive validity is demonstrated by not only showing panic responses to several panic-inducing agents that elicit panic in patients with PD, but also by the positive therapeutic responses to clinically used agents such as alprazolam and antidepressants that attenuate panic attacks in patients. More importantly, this model has been utilized to discover novel drugs such as group II metabotropic glutamate agonists and a new class of translocator protein enhancers of GABA, both of which subsequently showed anti-panic properties in clinical trials. All of these data suggest that this preparation provides a strong preclinical model of some forms of human panic disorders.

Aversive imagery in panic disorder: agoraphobia severity, comorbidity, and defensive physiology.

BACKGROUND: Panic is characterized as a disorder of interoceptive physiologic hyperarousal, secondary to persistent anticipation of panic attacks. The novel aim of this research was to investigate whether severity of agoraphobia within panic disorder covaries with the intensity of physiological reactions to imagery of panic attacks and other aversive scenarios. METHODS: A community sample of principal panic disorder (n = 112; 41 without agoraphobia, 71 with agoraphobia) and control (n = 76) participants imagined threatening and neutral events while acoustic startle probes were presented and the eye-blink response (orbicularis oculi) recorded. Changes in heart rate, skin conductance level, and facial expressivity were also measured. RESULTS: Overall, panic disorder patients exceeded control participants in startle reflex and heart rate during imagery of standard panic attack scenarios, concordant with more extreme ratings of aversion and emotional arousal. Accounting for the presence of agoraphobia revealed that both panic disorder with and without situational apprehension showed the pronounced heart rate increases during standard panic attack imagery observed for the sample as a whole. In contrast, startle potentiation to aversive imagery was more robust in those without versus with agoraphobia. Reflex diminution was most dramatic in those with the most pervasive agoraphobia, coincident with the most extreme levels of comorbid broad negative affectivity, disorder chronicity, and functional impairment. CONCLUSIONS: Principal panic disorder may represent initial, heightened interoceptive fearfulness and concomitant defensive hyperactivity, which through progressive generalization of anticipatory anxiety ultimately transitions to a disorder of pervasive agoraphobic apprehension and avoidance, broad dysphoria, and compromised mobilization for defensive action.

Common limbic and frontal-striatal disturbances in patients with obsessive compulsive disorder, panic disorder and hypochondriasis.

BACKGROUND: Direct comparisons of brain function between obsessive compulsive disorder (OCD) and other anxiety or OCD spectrum disorders are rare. This study aimed to investigate the specificity of altered frontal-striatal and limbic activations during planning in OCD, a prototypical anxiety disorder (panic disorder) and a putative OCD spectrum disorder (hypochondriasis). METHOD: The Tower of London task, a 'frontal-striatal' task, was used during functional magnetic resonance imaging measurements in 50 unmedicated patients, diagnosed with OCD (n=22), panic disorder (n=14) or hypochondriasis (n=14), and in 22 healthy subjects. Blood oxygen level-dependent (BOLD) signal changes were calculated for contrasts of interest (planning versus baseline and task load effects). Moreover, correlations between BOLD responses and both task performance and state anxiety were analysed. RESULTS: Overall, patients showed a decreased recruitment of the precuneus, caudate nucleus, globus pallidus and thalamus, compared with healthy controls. There were no statistically significant differences in brain activation between the three patient groups. State anxiety was negatively correlated with dorsal frontal-striatal activation. Task performance was positively correlated with dorsal frontal-striatal recruitment and negatively correlated with limbic and ventral frontal-striatal recruitment. Multiple regression models showed that adequate task performance was best explained by independent contributions from dorsolateral prefrontal cortex (positive correlation) and amygdala (negative correlation), even after controlling for state anxiety. CONCLUSIONS: Patients with OCD, panic disorder and hypochondriasis share similar alterations in frontal-striatal brain regions during a planning task, presumably partly related to increased limbic activation.

Effects of reversible inactivation of the dorsomedial hypothalamus on panic- and anxiety-related responses in rats

The medial hypothalamus is part of a neurobiological substrate controlling defensive behavior. It has been shown that a hypothalamic nucleus, the dorsomedial hypothalamus (DMH), is involved in the regulation of escape, a defensive behavior related to panic attacks. The role played by the DMH in the organization of conditioned fear responses, however, is less clear. In the present study, we investigated the effects of reversible inactivation of the DMH with the GABA A agonist muscimol on inhibitory avoidance acquisition and escape expression by male Wistar rats (approximately 280 g in weight) tested in the elevated T-maze (ETM). In the ETM, inhibitory avoidance, a conditioned defensive response, has been associated with generalized anxiety disorder. Results showed that intra-DMH administration of the GABA A receptor agonist muscimol inhibited escape performance, suggesting an antipanic-like effect (P < 0.05), without changing inhibitory avoidance acquisition. Although a higher dose of muscimol (1.0 nmol/0.2 µL; N = 7) also altered locomotor activity in an open field when compared to control animals (0.2 µL saline; N = 13) (P < 0.05), the lower dose (0.5 nmol/0.2 µL; N = 12) of muscimol did not cause any motor impairment. These data corroborate previous evidence suggesting that the DMH is specifically involved in the modulation of escape. Dysfunction of this regulatory mechanism may be relevant in the genesis/maintenance of panic disorder.