Several lines of evidence suggest a neurophysiological basis for panic disorder, including genetic studies. The illness's medication responsiveness (discussed in the treatment section below) has been interpreted to imply a neurophysiological etiology. Evidence for a genetic basis for panic disorder has also been derived from studies of twins that demonstrate a higher rate of concordance for panic in monozygotic than dizygotic twins (Torgersen, 1983, Kendler et al., 1993; Skre et al., 1993).
Neurophysiological models of the etiology of panic disorder have developed primarily from animal models of brain functioning and studies of substances that provoke panic. The interpretation of these data by different theorists in developing models for panic will be described below. Neuroimaging studies are expected to be an increasingly important source of data.
An Oversensitive Fear Network. Gorman et al. (2000) hypothesize that panic originates in an abnormally sensitive fear network, which includes the prefrontal cortex, insula, thalamus, amygdala, and amygdalar projections to brainstem and hypothalamus (Fig. 12.1). The central nucleus of the amygdala is thought to be the center of this network. Amygdalar projections to various sites appear to coordinate physiological and behavioral responses to danger, including the parabrachial nucleus (increased respiratory rate), hypothalamus (activation of the sympathetic nervous system, release of corticosteroids), locus coeruleus (release of norepinephrine, increases in blood pressure
and heart rate), and periaqueductal gray region (defensive behaviors). In fact, data from animal models suggest that stimulation of the amygdala produces a fear response that has significant similarities to a panic attack (Ledoux et al., 1988; Davis, 1992). Medications effective in treating panic disorder diminish activity of the brainstem centers that receive input from the central nucleus of the amygdala.
The amygdala receives afferent input from brainstem structures and the sensory thalamus, which allow a more immediate response to danger, and from cortical regions involved in processing and evaluating sensory information. Neurocognitive deficits in cortical processing could result in misinterpretation of sensory information (bodily cues), and inappropriate activation of the fear network via misguided excitatory input to the amygdala. Gorman et al. (2000) and Ledoux (1996) postulate that psychotherapy may work by strengthening the ability of these cortical projections to assert reason over automatic behavioral and physical responses.
Gorman et al. (2000) interpret the data derived from substances that provoke panic attacks in patients with panic disorder at a much greater rate than in healthy controls or in patients with other psychiatric disorders, as being consistent with the sensitive fear network model. Rather than focusing on the specific biochemical impact of the various substances (sodium lactate, yohimbine, noradrenaline, adrenaline, and others), they emphasize the biological disparity of the various mechanisms of action. They therefore postulate that these agents trigger panic by causing precipitous somatic discomfort, nonspecifically triggering the fear network.
An abnormally sensitive fear network may result from an inherited tendency to fearfulness, perhaps a neurocognitive deficit, resulting in abnormal response to or modulation of the fear network. Disruptions of early attachment and traumatic events in childhood and adulthood may lead to persistent changes in the stress system and fear network. Gorman et al. (2000) speculate that a genetically based abnormality in the brain fear network may make the individual more susceptible to the emotional effects of trauma.
False Suffocation Alarm Model. Klein (1993) suggests an alternate model of a biological basis for panic disorder, a false suffocation alarm hypothesis. In this model, the brain is postulated to have an evolved suffocation alarm system that can be hypersensitive and can misfire in the absence of an actual suffocation risk. In Klein's view this misfire leads to an urge to flee, the onset of hyperventilation, shortness of breath, and panic. Panic, both spontaneous and carbon dioxide (CO2) and lactate-induced, differs from a typical emergency fear response in that it includes shortness of breath as a symptom and does not activate the hypothalamic-pituitary-adrenal (HPA) axis. Klein is therefore critical of cognitive theory and other literature that equate fear with panic, including Gorman's fear circuit model.
This debate recently focused on the interpretation of an experiment on susceptibility to CO2-induced panic in patients with various psychiatric diagnoses. Studies have shown that during inhalation of carbon dioxide, patients with panic and premenstrual dysphoric disorder (PMDD) are more likely to experience panic than healthy volunteers or patients with other psychiatric disorders (see Gorman et al., 2001). This susceptibility appears to decline after successful treatment of the panic disorder. The origins of this vulnerability could be secondary to specific abnormalities in the afferent neural pathways that respond to increased levels of CO2 (Klein's suffocation monitor hypothesis) or to nonspecific somatic distress from CO2 inhalation, including air hunger and breathlessness reminiscent of panic, triggering a central neural fear circuit.
Gorman et al. (2001) hoped to generate evidence with regard to these hypotheses by looking at ventilatory responses to CO2 to see if an increase was specific to patients with panic disorder or was found in any patient experiencing panic attacks, regardless of diagnosis. Panic disorder and PMDD were found to have increased rates of panic attacks compared to controls and to patients with MDD. Measures of ventila-tory response to 5 percent CO2, however, varied more with respect to whether a panic attack occurred than with diagnosis.
Thus, Gorman et al. (2001) conclude that there is nothing fundamentally abnormal about the ventilatory physiology of panic patients. This finding, in the view of these authors, suggests the importance of central brain circuits in panic disorder, rather than simply abnormalities in the pulmonary, peripheral, or medullary chemorecep-tors. CO2 stimulation triggers the fear circuit, including activation of the amygdala and its projection sites, in patients with panic disorder or in subjects who experience panic attacks.
In response to Gorman's study, Klein (2002) argues against Gorman et al.'s (2001) suggestion that CO2 and lactate produce panic via nonspecific distress that induces fear, noting that other substances that trigger distress do not trigger panic. In Klein's (1993, 2002) view, carbon dioxide sensitivity is due to a deranged suffocation alarm monitor. Thus, Klein believes that panic attacks represent a hyperreactivity of a common human adaptive mechanism, a view that is more specific than the conception of panic attacks as conditioned fear. He reemphasizes his view that panic attacks are not simply equivalent to fear, noting the lack of dyspneic air hunger in the fear response, the lack of HPA activation in panic, and the fact that imipramine and other antipanic antidepressants block panic attacks but not ordinary fear. He suggests that "vital requirements such as air, food and water require distinctive perceptual/emotional/motivational brain circuits that should not be subsumed under a fear circuit that, by conditioning, serves all purposes" (Klein, 2002, p. 568).
Separation Distress System. Panksepp (1998) suggests an alternate theory for the interrelationship of fear, panic, and neurophysiology. He differentiates a PANIC system in the brain, which he primarily views as related to separation distress, from a FEAR system associated with other types of fear, including anticipatory anxiety. The separation distress system is the origin of distress vocalizations (DVs), or isolation calls, which are primitive forms of communication by which an infant signals distress to elicit parental care. These communications are shared by all mammals and probably have a similar brain physiology. The PANIC system originates in the midbrain periaqueductal gray matter and continues in the medial diencephalon, the ventral septal area, the preoptic area, the bed nucleus of the stria terminalis, and in higher mammals the anterior part of the cingulate gyrus, the amygdala, and the hypothalamus.
Panksepp suggests that panic attacks may arise from sudden arousal of the separation distress system, thus the derivation of the term PANIC. This hypothesis was based in part on the link between a history of separation anxiety and panic disorder. In addition, tricyclics, which effectively treat panic, were found to diminish DVs. Panksepp also refers to Klein's (1964, 1981) early work on treatment of panic, in which he found that benzodiazepines, such as chlordiazepoxide and diazepam, had little impact on panic, whereas tricyclics affected panic but not anticipatory anxiety, again attesting to a separation between these two systems.
More recent clinical studies, however, cast doubt on the pharmacological discrepancy between these systems. Benzodiazepines, such as alprazolam and clonazepam, have been found to effectively treat panic. In addition, antidepressants, such as ven-lafaxine and paroxitene, have been found to effectively treat other forms of anxiety, such as generalized anxiety disorder. The impact of these agents on anticipatory anxiety has not been well studied.
The fear circuit network, the suffocation monitor alarm system, and the separation distress system may play a role in the onset and development of panic disorder or may play varying roles in the different forms or aspects of the panic syndrome. Further neurophysiological studies should help to clarify these factors.
Neuroimaging may provide another means of assessing neurobiological factors in panic disorder. An early study by Reiman et al. (1984), using positron emission topography (PET), suggested a focal asymmetry in cerebral blood flow in the region of the parahippocampal gyrus in panic patients responsive to lactate infusion, which was not present in normals or panic patients not responsive to lactate. However, the difficulty differentiating small brain structures, such as the amygdala, and capturing an image during a panic episode have limited the utility of imaging approaches (Gorman et al., 2000). In addition, hypocapnia-induced vasoconstriction caused by hyperventilation during a panic attack can obscure assessments of cerebral blood flow.
Further improvements in neuroimaging technology, including the use of functional magnetic resonance imaging (fMRI), may aid in further clarifying the brain structures involved in panic disorder. A recent study (Bystritsky et al., 2001) comparing fMRI in six patients with panic disorder in varying levels of anxiety-provoking situations to six normal controls found increased activity in the inferior frontal cortex, hippocampus, and the anterior and posterior cingulate, extending into the orbitofrontal cortex and to both hemispheres. The authors suggest that this is an important neural circuit in panic, related to retrieval of strong emotional events, facilitating recapitulation of traumatic experiences. There is limited overlap in this neural circuit with the various models described above.
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