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The field of psychodynamic psychotherapy would benefit from a comprehensive model that integrates its constructs with neurobiology. Research on the autonomic nervous system activity during the psychotherapeutic process is necessary because it is key in affective experiences and defensive behavior. The current case study reports physiological findings on heart rate dynamics in a patient suffering from panic disorder during two therapeutic sessions in which we used Davanloo's Intensive Short-term Dynamic Psychotherapy. We looked at various metrics of heart rate variability during the therapeutic process leading to breakthrough of unconscious feelings. The measurements included sympathetic and parasympathetic indices, vagal tone, and their responses. Our results suggest that the sympathetic system activates during defensive responses associated with anxiety and during the passage of unconscious-aggressive impulses. Following the experience of unconscious guilt, there is an increased vagal tone corresponding to the phase of reunification with the attachment figure. Findings are discussed integrating developmental neurobiology and clinical psychodynamics.

Objective: Although exposure-based cognitive-behavioral therapy (CBT) is an effective treatment option for panic disorder with agoraphobia, the neural substrates of treatment response remain unknown. Evidence suggests that panic disorder with agoraphobia is characterized by dysfunctional safety signal processing. Using fear conditioning as a neurofunctional probe, the authors investigated neural baseline characteristics and neuroplastic changes after CBT that were associated with treatment outcome in patients with panic disorder with agoraphobia., Method: Neural correlates of fear conditioning and extinction were measured using functional MRI before and after a manualized CBT program focusing on behavioral exposure in 49 medication-free patients with a primary diagnosis of panic disorder with agoraphobia. Treatment response was defined as a reduction exceeding 50% in Hamilton Anxiety Rating Scale scores., Results: At baseline, nonresponders exhibited enhanced activation in the right pregenual anterior cingulate cortex, the hippocampus, and the amygdala in response to a safety signal. While this activation pattern partly resolved in nonresponders after CBT, successful treatment was characterized by increased right hippocampal activation when processing stimulus contingencies. Treatment response was associated with an inhibitory functional coupling between the anterior cingulate cortex and the amygdala that did not change over time., Conclusions: This study identified brain activation patterns associated with treatment response in patients with panic disorder with agoraphobia. Altered safety signal processing and anterior cingulate cortex-amygdala coupling may indicate individual differences among these patients that determine the effectiveness of exposure-based CBT and associated neuroplastic changes. Findings point to brain networks by which successful CBT in this patient population is mediated.

Objective: Individuals with panic disorder perceive panic attacks as unpredictable. Because predictability is fundamental to Pavlovian conditioning, failure to predict panic attacks could be due to a basic deficit in conditioning. The present study examined trace eyeblink conditioning in order to test the hypothesis that individuals with panic disorder are impaired in associative learning tasks that depend on declarative memory., Method: Delay and trace eyeblink conditioning were tested in separate experimental sessions in 19 individuals meeting DSM-IV criteria for panic disorder and 19 sex- and age-matched healthy comparison subjects. In the delay paradigm, a mild puff was delivered to the eye at the end of a 500-msec tone; in the trace paradigm, the puff was delivered after a 700-msec empty "trace" interval that followed the end of the tone., Results: Patients and comparison subjects showed similar rates of conditioned responses in the delay paradigm, but patients showed reduced rates of conditioned responses in the trace paradigm., Conclusions: These results suggest that individuals with panic disorder suffer from a deficit in declarative associative learning. Such a deficit points to impaired hippocampal function that may disrupt cognitive processing of internal and external cues predictive of a panic attack.

Objective: Lack of appropriate top-down governance by frontal cortical regions over a hypersensitive amygdala-centered fear neurocircuitry has been hypothesized to be central in the pathophysiology of panic disorder. The aim of this study was to examine regional cerebral blood flow changes in response to anxiety/panic provocation in subjects with panic disorder and healthy comparison subjects., Method: Quantitative water method positron emission tomography was used to obtain brain images of five untreated subjects with panic disorder and five healthy comparison subjects before and during anxiogenic challenge with intravenous doxapram, an acute respiratory stimulant., Results: Baseline perfusion of the orbitofrontal cortex predicted panic attacks: lower perfusion was associated with heightened anxiety in response to doxapram challenge., Conclusions: The orbitofrontal cortex may be important in the regulation of responding to fear and is a potential area of aberrant functioning in panic disorder.

Objective: Disturbances in the metabolism of the brain amino acid transmitter gamma-aminobutyric acid (GABA) may contribute to the pathophysiology of human anxiety disorders. Animal studies indicate that deletions or reductions in the expression of the gene for the GABA synthetic enzyme, glutamate decarboxylase 65 (GAD(65)), reduce basal cortical GABA levels or stress-induced release of GABA in the cerebral cortex and increase fear behaviors. Complementing these findings, the authors recently observed lower than normal cortical GABA levels in patients with panic disorder. In the current study, the authors tested the hypothesis that panic disorder patients have a deficient GABA neuronal response to benzodiazepine (clonazepam) administration., Method: In a parallel-group, repeated-measures design, occipital cortex GABA responses to acute oral, open-label benzodiazepine administration were tested in 10 panic disorder patients and nine healthy comparison subjects. Occipital cortex total GABA levels were measured before and after medication administration by means of a novel proton magnetic resonance spectroscopic technique., Results: Panic disorder patients had a deficient GABA neuronal response (blunted reduction of occipital cortex GABA level) to acute benzodiazepine administration, compared to the healthy subjects, who exhibited a significant decrease in occipital cortex GABA levels after this intervention. The patients also appeared to have persistently low occipital cortex GABA after chronic benzodiazepine treatment., Conclusions: Overall, these data are consistent with the hypothesis that a trait-like abnormality in GABA neuronal function contributes to the pathogenesis of human panic disorder. The data raise the possibility that GAD(65) enzyme dysfunction could be a pathogenic factor in panic disorder.

Objective: Considerable evidence suggests a connection between panic disorder and respiration, but the nature of the respiratory abnormalities in panic disorder remains unclear. The authors investigated the breath-by-breath complexity of respiration dynamics in panic disorder., Method: Respiratory physiology was assessed in 40 patients with panic disorder and 31 healthy comparison subjects by using a breath-by-breath stationary system for testing cardiorespiratory function. Irregularity in the breathing pattern was determined by applying the approximate entropy index, which is an indicator of the irregularity and the "disorder" of the measure., Results: The patients with panic disorder showed significantly higher approximate entropy indexes than the healthy subjects for the measured respiratory parameters. Sighs contributed to the irregularity of breathing patterns but did not account for all the differences in approximate entropy between the patients with panic disorder and the comparison subjects. Anxiety state, severity of illness, and somatic and individual variables such as participation in sports and cigarette smoking did not seem to influence the results., Conclusions: Patients with panic disorder showed greater entropy in baseline respiratory patterns, indicating higher levels of irregularity and complexity in their respiratory function. Greater respiratory entropy could be a factor in vulnerability to panic attacks.

Objective: The authors examined possible cerebral gray matter abnormalities in patients with panic disorder., Method: Gray matter concentration in 18 panic disorder outpatients and 18 healthy subjects was compared by using a voxel-based morphometry approach., Results: Gray matter density of the left parahippocampal gyrus was significantly lower in patients with panic disorder compared with healthy subjects., Conclusions: This result provides further support for the involvement of the parahippocampal area in the pathophysiology of panic disorder.

Objective: In a 1989 article, the authors provided a hypothesis for the neuroanatomical basis of panic disorder that attempted to explain why both medication and cognitive behavioral psychotherapy are effective treatments. Here they revise that hypothesis to consider developments in the preclinical understanding of the neurobiology of fear and avoidance., Method: The authors review recent literature on the phenomenology, neurobiology, and treatment of panic disorder and impressive developments in documenting the neuroanatomy of conditioned fear in animals., Results: There appears to be a remarkable similarity between the physiological and behavioral consequences of response to a conditioned fear stimulus and a panic attack. In animals, these responses are mediated by a "fear network" in the brain that is centered in the amygdala and involves its interaction with the hippocampus and medial prefrontal cortex. Projections from the amygdala to hypothalamic and brainstem sites explain many of the observed signs of conditioned fear responses. It is speculated that a similar network is involved in panic disorder. A convergence of evidence suggests that both heritable factors and stressful life events, particularly in early childhood, are responsible for the onset of panic disorder., Conclusions: Medications, particularly those that influence the serotonin system, are hypothesized to desensitize the fear network from the level of the amygdala through its projects to the hypothalamus and the brainstem. Effective psychosocial treatments may also reduce contextual fear and cognitive misattributions at the level of the prefrontal cortex and hippocampus. Neuroimaging studies should help clarify whether these hypotheses are correct.

Objective: The authors evaluated respiratory response to cholecystokinin tetrapeptide (CCK-4) in healthy volunteers., Method: Subjects were randomly assigned to either a CCK-4 (N = 15) or placebo (N = 15) challenge under double-blind conditions., Results: Dyspnea was reported by all of the subjects who received CCK-4 but only one subject who received placebo. CCK-4 caused a significant increase in tidal volume and minute ventilation but had no effect on breathing frequency. Placebo had no effect on any of the respiratory measures., Conclusions: These data indicate that the behavioral effects of CCK-4 are accompanied by changes in respiration in healthy volunteers.

Objective: Respiratory abnormalities may play a central role in the pathophysiology of panic disorder. The current study was undertaken to examine the respiratory response in the largest series of subjects to date during three respiratory challenges that used improved methodology., Method: Fifty-nine patients with DSM-III-R panic disorder and 39 normal volunteers were challenged with 5% and 7% CO2 inhalation and room air hyperventilation separated by room air breathing with continuous spirometry., Results: Patients with panic disorder were more sensitive to the anxiogenic effects of CO2 than were normal subjects, and CO2 was a more potent stimulus to panic than hyperventilation. Patients increased their respiratory rate more quickly during CO2 inhalation than did comparison subjects, and this increase preceded the panic attacks. Patients who panicked in response to 5% CO2 demonstrated continued rise in end-tidal CO2, while the end-tidal CO2 of the comparison groups stabilized. Low end-tidal CO2 and high variance in minute ventilation at baseline predicted panic attacks during CO2 inhalation. Following CO2 or hyperventilation challenges, respiratory rate dropped sharply, while tidal volume remained elevated longer in patients than in comparison subjects., Conclusions: The findings confirm the greater behavioral and physiological sensitivity of patients with panic disorder to CO2 inhalation and identify a series of respiratory abnormalities. Panic attacks in panic disorder may be explained by inefficient compensatory mechanisms, primarily of respiratory rate.

Objective: The purpose of this study was to measure the response of basilar artery blood flow to hyperventilation in patients with panic disorder., Method: Transcranial Doppler ultrasonography was used to measure basilar artery flow during rest and after hyperventilation in 16 patients with panic disorder and eight normal comparison subjects. The subjects rated their dizziness at each phase., Results: The patients with panic disorder demonstrated greater reduction in flow rates and greater increases in dizziness than the normal comparison subjects., Conclusions: The greater basilar artery sensitivity to hyperventilation shown by panic disorder patients suggests a possible mechanism for the development of neurological symptoms during panic attacks.

Objective: Autonomic dysregulation and cerebral blood flow (CBF) abnormalities have been reported in patients with anxiety disorders and, more recently, in panic disorder. Variations in the middle cerebral artery velocity (measured by transcranial Doppler technique), heart rate, and blood pressure during a tilting-table test were used as nonanxiogenic procedures to explore these abnormalities., Method: Mean flow velocity in the right middle cerebral artery, heart rate, and blood pressure were monitored at rest and during a 70 degrees tilting-table test. Three groups of patients were studied: 11 patients (eight women and three men; mean age = 31.1 years, SD = 8.0) with a diagnosis of panic disorder within 6 months of the onset of the disorder, nine asymptomatic patients (two men and seven women; mean age = 35.0, SD = 6.3) with a previous diagnosis of panic disorder who were in full remission of symptoms and had been drug free for at least 6 months, and 10 normal comparison subjects (two men and eight women; mean age = 31.1, SD = 5.2)., Results: Both patients with acute panic disorder and patients with remitted panic disorder showed a significant percent reduction of right middle cerebral artery mean flow velocity compared with normal subjects following tilting to the upright position. No significant differences were observed for blood pressure and heart rate., Conclusions: Patients with panic disorder, both during the acute phase of the illness and after clinical recovery, show an exaggerated drop in CBF during tilting. Since these findings are similar, although attenuated in intensity, to those which are observed in dysautonomic illnesses, one possible interpretation is that of panic disorder as a subclinical form of autonomic dysreactivity.

Objective: The authors sought to determine whether hypothalamic-pituitary-adrenal (HPA) axis activity in patients before their treatment for panic disorder can predict follow-up functional status. Although baseline HPA axis disturbances in patients with panic disorder appear to attenuate with treatment, there is evidence that they may be linked to poorer long-term outcomes., Method: Follow-up clinical data were obtained for 18 of 20 patients with panic disorder who participated in a detailed study of HPA axis activity in panic, both before and during their treatment with alprazolam. HPA axis assessment included monitoring of adrenocorticotropin and cortisol over a full circadian cycle. The relationships between disability and clinical status at 2-year follow-up and HPA axis overactivity at entry were examined., Results: Mean 24-hour cortisol levels before treatment provided a strong, positive predictor of disability scores at follow-up. Those patients who achieved the treatment goal of medication-free remissions had less evidence of HPA axis overactivity at entry than those who were not in remission., Conclusions: HPA axis activity before treatment did predict outcome 2 years later. This relationship appears robust and reproducible. Further work is needed to define the neuroendocrine mechanisms underlying the HPA axis markers that are linked to long-term functioning and to determine the biological, psychological, and social processes that link HPA axis disturbance to poorer outcomes.

Objective: Neuropeptide Y is a pancreatic polypeptide closely associated with noradrenergic activity both in the central and peripheral nervous systems. The objective of this study was to assess plasma neuropeptide Y-like immunoreactivity in panic disorder., Method: Radioimmunoassays were performed in 12 patients with DSM-III-R panic disorder and two groups of normal comparison subjects (N = 22 and N = 16)., Results: Markedly higher plasma neuropeptide Y-like immunoreactivity was found in patients with panic disorder., Conclusions: Higher plasma neuropeptide Y-like immunoreactivity suggests that this peptide may be implicated in the etiology or expression of symptoms of panic disorder.

Objective: This study examined cardiac and respiratory activity in panic disorder patients and healthy comparison subjects during sleep, when the effects of anxious cognition and expectancy set are minimized., Method: Heart rate, respiratory rate, end-tidal PCO2, and oxygen saturation were recorded for 11 panic disorder patients and 12 comparison subjects before and during sleep and before and after infusions of sodium lactate and a saline control., Results: Panic disorder patients had higher oxygen saturations than comparison subjects before sleep onset and during sleep stages 0 and 2 before any infusions. The two groups did not differ on other respiratory variables and heart rate. Panic disorder patients responded to lactate infusions during stage 3-4 sleep with greater increases in heart rate and oxygen saturation, and possibly in respiratory rate and end-tidal PCO2, than comparison subjects. The saline control infusion had little effect., Conclusions: These findings suggest that panic disorder patients have greater cardiac and respiratory reactivity than healthy comparison subjects during sleep, when the influence of cognitive factors is minimal or absent.

Using spectral analysis of the continuous time series signal before and during lactate and placebo infusions, the authors studied heart rate variability in six patients with panic disorder and nine normal comparison subjects. The decrease in high-frequency (0.20-0.50 Hz) power and the increase in sympathovagal ratios (mid-frequency [0.07-0.15 Hz] to high-frequency powers) after the administration of intravenous sodium lactate were significantly greater in the patients than in the normal subjects after correction of the values for the amount of lactate infused. This result suggests an exaggerated cardiac vagal withdrawal in patients with panic disorder during lactate infusions.

Objective: It has been hypothesized that individuals who cannot perceive elevations of CO2 will be less anxious than individuals with intact CO2 perception. To test this hypothesis, children with congenital central hypoventilation syndrome, who have a potentially lethal chronic illness associated with lack of CO2 perception and thus provide a natural experimental group, were studied., Method: Rates of anxiety symptoms and disorders in children with congenital central hypoventilation syndrome (N = 13) were compared with rates in an age-matched, nonreferred group of community subjects (N = 292) that included subgroups of children with asthma (N = 15) and other chronic medical illnesses (N = 66). Anxiety symptoms were assessed with information obtained from structured interviews of the parents, which provided both total symptom scores and DSM-III-R diagnoses., Results: The children with congenital central hypoventilation syndrome exhibited significantly fewer anxiety symptoms than all other comparison subjects. Two of these children (15%) met criteria for anxiety disorders, a rate lower than that of the whole community group (24%) and of the chronically ill comparison subgroups (32%-47%). The largest difference in the prevalence of disorder emerged between the children with congenital central hypoventilation syndrome (15%) and those with asthma (47%). In the comparison of children with congenital central hypoventilation syndrome and children with other chronic illnesses, a priori analysis showed that the former had significantly lower rates of disorders that have been linked to panic in the literature., Conclusions: This study supports theories of anxiety that implicate CO2 perception in the pathophysiology of panic and related anxiety states.

The authors compared the maximal duration of voluntary breath-holding in patients with panic disorder (N = 23), patients with generalized social phobia (N = 10), and healthy subjects (N = 26). Patients with panic disorder had significantly shorter breath-holding durations than either comparison group. Groups did not otherwise differ in physiologic response to the breath-holding. Implications for a false suffocation alarm in panic disorder are discussed.

Objective: This study was designed to clarify the nature of the reduced function of the peripheral beta adrenoceptor system observed in panic disorder with agoraphobia. The authors hypothesized that this phenomenon reflected a regulatory and adaptive process., Methods: Lymphocyte beta adrenoreceptor density and affinity, basal lymphocyte cAMP level, and isoproterenol-stimulated cAMP generation were measured in 27 untreated outpatients with panic disorder with agoraphobia and 24 healthy comparison subjects. Lymphocyte beta receptor attributes were again assessed in patients after 4 weeks of double-blind treatment with adinazolam (slow-release form) or placebo. Panic frequency, agoraphobic symptoms, overall anxiety, and improvement with treatment were assessed with standard rating instruments., Results: Multivariate statistics revealed significantly lower beta receptor density and isoproterenol-stimulated cAMP generation in patients than in comparison subjects. beta receptor density tended to normalize after adinazolam but not after placebo. Pretreatment beta receptor density was lower in treatment responders than nonresponders. Patients with mild agoraphobia had lower cAMP responsivity than patients with moderate or severe agoraphobia., Conclusions: Decreased function of lymphocyte beta receptors in panic disorder with agoraphobia is expressed as both decreased density and decreased cAMP responsivity. This pattern of changes, and the tendency for receptor density to normalize with treatment, is consistent with an active, regulatory process rather than a structural deficit in the beta receptor system. Preliminary clinical findings suggest that these changes may reflect adaptive processes associated with a favorable clinical course in panic disorder with agoraphobia.

Objective: The purpose of this article is to offer a comprehensive, data-based explanation of the relationship between hyperventilation and panic disorder linking CO2 hypersensitivity, cognitive/behavioral factors, and the respiratory effects of antipanic pharmacologic and psychological treatments., Method: The authors conducted a computerized search of MEDLINE for relevant articles., Results: Some panic patients have a chronic, subtle respiratory disturbance. Acute hyperventilation is neither necessary nor sufficient for panic to occur. Respiratory abnormalities in panic patients may adaptively aim at coping with a hypersensitive CO2 chemoreceptor system. Pharmacologic panicogens also stimulate the respiratory system, causing hyperventilation. Triggering this hypersensitive respiratory control mechanism may incite panic. Antipanic medications may reset the receptor threshold. Misattribution and catastrophic interpretation of somatic symptoms or the sense of loss of control may contribute to panic symptoms. Behavioral interventions such as desensitization or breathing retraining may block the full-blown attack. Cognitive strategies through cognitive control of respiration may supplement and accentuate these interventions., Conclusions: Panic disorder may be due to an inherently unstable autonomic nervous system, coupled with cognitive distress.

Objective: Continuing the long history of interest in the relation of anxiety disorders to cardiovascular function and symptoms, this study investigated the level of anxiety and prevalence of panic disorder in cardiac patients and the possible associations between specific abnormal ECG results and a diagnosis of panic disorder., Method: Consecutive patients referred for ambulatory ECG recordings were assessed with the seven anxiety items of the Hospital Anxiety and Depression Scale. Then, 50 patients with scores higher than 8 (the anxious group) were interviewed with the Schedule for Affective Disorders and Schizophrenia--Lifetime Version Modified for the Study of Anxiety Disorders (SADS-LA)., Results: Of the 50 anxious patients (26 male and 24 female) interviewed with the SADS-LA, 62% (N = 31) met the DSM-III-R criteria for panic disorder. Patients with panic disorder had a higher mean maximal heart rate and a shorter P-R interval than patients without panic disorder. Unlike the patients without panic disorder, the patients with panic disorder showed no correlation between maximal heart rate and minimal P-R interval., Conclusions: The rate of panic disorder was high in the patients referred for ECG. Moreover, the prevalence of panic disorder was similar in the patients with and without ECG abnormalities, indicating that in anxious patients the presence of panic disorder does not rule out organic cardiac disease. On the other hand, the higher maximal heart rate and shorter P-R interval of the panic patients may be attributable to hypersensitivity of beta-adrenergic receptors in panic disorder.

Basilar artery blood flow was measured by transcranial Doppler ultrasonography before and during hyperventilation in nine patients with panic disorder and nine normal comparison subjects. The hyperventilation-induced decrease in basilar artery blood flow was significantly greater in patients with panic attacks than in comparison subjects. Two patients with decreases in basilar flow greater than 80% were successfully treated with nimodipine, a centrally active calcium channel blocker.

Twenty panic disorder patients with mitral valve prolapse showed amelioration of prolapse on repeat echocardiogram after treatment for panic disorder. This effect was significant when compared to repeat echocardiograms in eight psychiatrically normal control subjects with mitral valve prolapse.

Cholecystokinin concentrations in the CSF of 25 patients with panic disorder and 16 normal comparison subjects were ascertained by radioimmunoassay. The patients with panic disorder had significantly lower CSF concentrations of cholecystokinin, which may reflect increased CNS cholecystokinin receptor sensitivity, reduced numbers of receptors, or a compensatory reduction in cholecystokinin octapeptide secondary to theoretically increased central cholecystokinin tetrapeptide activity.