Neuroanatomical Hypothesis Of Panic Disorder, Revised

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Neuroanatomical Hypothesis Of Panic Disorder, Revised

  1. 1. Special Article Neuroanatomical Hypothesis of Panic Disorder, Revised Jack M. Gorman, M.D., Justine M. Kent, M.D., Gregory M. Sullivan, M.D., and Jeremy D. Coplan, M.D. 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 behav- ioral 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 neuroanat- omy 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 hippocam- pus 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 misattri- butions at the level of the prefrontal cortex and hippocampus. Neuroimaging studies should help clarify whether these hypotheses are correct. (Am J Psychiatry 2000; 157:493–505) I n 1989, we (1) articulated a neuroanatomical hypoth- esis of panic disorder that was essentially an attempt to both be effective interventions. This theory posited that a panic attack itself stems from loci in the brain- understand how two seemingly diverse treatments— stem that involve serotonergic and noradrenergic medication and cognitive behavioral therapy—could transmission and respiratory control, that anticipatory anxiety arises after the kindling of limbic area struc- Received Feb. 25, 1999; revision received Aug. 3, 1999; tures, and, finally, that phobic avoidance is a function accepted Aug. 4, 1999. From the Department of Psychiatry, Col- of precortical activation. The hypothesis then asserted lege of Physicians and Surgeons, Columbia University; and the Department of Clinical Psychobiology, New York State Psychiatric that medication exerts its therapeutic effect by normal- Institute, New York. Address reprint requests to Dr. Gorman, izing brainstem activity in patients with panic disorder, Department of Psychiatry, College of Physicians and Surgeons, whereas cognitive behavioral therapy works at the cor- Columbia University, 1051 Riverside Dr., New York, NY 10032; tical level. jmg9@columbia.edu (e-mail). Supported in part by an NIMH grant to Drs. Kent and Sullivan In succeeding years, studies have continued to accu- (MH-15144), a Senior Scientist Award to Dr. Gorman (MH-00416), mulate demonstrating that medications, particularly and a Research Scientist Development Award to Dr. Coplan (MH- those that affect serotonergic neurotransmission (2), 01039). The authors thank Barbara Barnett, Christopher Tulysewski, and cognitive behavioral therapy (3) are indeed ro- David Ruggiero, and Jose Martinez for their help in the preparation bustly effective for patients with panic disorder. Fur- of this manuscript. ther, the notion that respiratory (4) and cardiovascular Am J Psychiatry 157:4, April 2000 493
  2. 2. PANIC DISORDER reactivity (5) is abnormal in panic disorder, pointing to lus. Further, because animals cannot tell us about the brainstem involvement, has also been strengthened. experience of anxiety and fear, we miss a rich source of However, our original hypothesis is now seen as clearly information that is readily obtained from humans with deficient because it is almost completely divorced from anxiety disorders. In addition, animal models of fear exciting preclinical and basic research that has ele- may not truly reflect anxiety status. Klein (8) has writ- gantly mapped out the neuroanatomical basis for fear. ten persuasively that there may be major biological dif- We now wish to revisit our neuroanatomical hypothe- ferences in humans between fear and the manifesta- sis of panic disorder and address these critical novel el- tions of anxiety disorders. ements. The result will propose that panic disorder Nevertheless, as we will detail, there are many as- may involve the same pathways that subserve condi- pects of conditioned fear in animals that make the tioned fear in animals, including the central nucleus of analogy with panic attacks irresistible. Most impor- the amygdala and its afferent and efferent projections. tant, it would be a mistake, in our view, to miss the op- portunity to study pathways in humans that have been carefully elucidated in animals during anxious re- ANATOMY OF CONDITIONED FEAR sponses. We take, then, as a starting point that a con- sideration of the neuroanatomy of conditioned fear in One of the greatest challenges in modern psychiatry rodents and other animals may give us important in- is to make use of advanced preclinical information sights that can then be studied in patients with panic from basic and behavioral neuroscience. Strides have disorder. been made in developing animal models of emotional The conditioned-fear paradigm used in neurobiolog- and behavioral states, a task seen as critical in devel- ical studies is well known to the most elementary stu- oping a coherent understanding of any human disease dents of behavior. In a typical study, a rat is presented state. However, it has been difficult to understand with a stimulus—usually a tone or flash of light—at how any animal, lacking the capacity to express in the same time it receives a mild electric shock. The words its emotional state, could meaningfully reflect former is called the conditioned stimulus, and the lat- human psychopathology. It is problematic to conceive ter, the unconditioned stimulus. After several pairings, of an animal model for depression or psychosis, for the rat learns to respond to the conditioned stimulus example, because these illnesses seemingly depend on with the same autonomic and behavioral array even the ability of the human patient to inform us verbally when no unconditioned stimulus is presented. The par- about symptoms that are necessary for diagnosis. Al- adigm originates from the work of Pavlov (9) and has though even in these instances cogent animal models occupied the time of countless psychology students for are now available, two human psychiatric syndromes generations. seem best suited for analogy with animal states: anxi- What is new is an understanding of the brain path- ety and substance abuse. In the latter case, it is possi- ways and neurotransmitters that are required for the ble to addict animals to a variety of substances and acquisition of conditioned fear. The critical pathways then study the neural pathways that subserve the con- are shown in figure 1. The sensory input for the condi- tinued acquisition of these substances. This has led to tioned stimulus runs through the anterior thalamus to remarkable insights into brain pathways necessary to the lateral nucleus of the amygdala and is then trans- sustain the abuse of substances like cocaine (6), some ferred to the central nucleus of the amygdala (10). The of which can be confirmed in humans with neuroim- central nucleus of the amygdala stands as the central aging techniques (7). point for dissemination of information that then coor- In the case of anxiety, it is well understood that fear, dinates autonomic and behavioral responses (11, 12). escape, or avoidance behavior and panic-like responses In preclinical work, amygdalar projections have been are ubiquitous throughout animal phylogeny. It takes established that may carry out these responses. Effer- relatively little intuition to recognize that a rodent that ents of the central nucleus of the amygdala have many avoids entering a cage in which an adverse stimulus targets: the parabrachial nucleus, producing an in- has been presented in the past appears similar to a pho- crease in respiratory rate (13); the lateral nucleus of the bic patient refusing to drive across a bridge on which hypothalamus, activating the sympathetic nervous sys- panic attacks previously occurred. Similarly, an animal tem and causing autonomic arousal and sympathetic manifesting increases in heart rate, blood pressure, res- discharge (14); the locus ceruleus, resulting in an in- piration, and glucocorticoid release after the presenta- crease in norepinephrine release and contributing to tion of a tone that had previously been paired with a increases in blood pressure, heart rate, and the behav- mild electric shock demonstrates many of the auto- ioral fear response (15); and the paraventricular nu- nomic features characteristic of a panic attack. cleus of the hypothalamus, causing an increase in the The analogy of panic attacks to animal fear and release of adrenocorticoids (16). A projection from the avoidance responses is, to be sure, imperfect. Most an- central nucleus of the amygdala to the periaqueductal imal models of anxiety states involve conditioning, and gray region is responsible for additional behavioral re- it is not at all clear that panic disorder or any other sponses, including defensive behaviors and postural anxiety disorder except posttraumatic stress disorder freezing, that may be the animal equivalent of phobic (PTSD) involves prior exposure to any aversive stimu- avoidance (17). In fact, it can readily be seen from 494 Am J Psychiatry 157:4, April 2000
  3. 3. GORMAN, KENT, SULLIVAN, ET AL. FIGURE 1. Neuroanatomical Pathways of Viscerosensory Information in the Braina Association Bundle Medial Prefrontal Cortex, Cingulate Insula Amygdala Central Lateral Nucleus Nucleus Sensory of the Thalamus Hippocampus Basal Amygdala Parabrachial Nucleus Hypothalamus Paraventricular Lateral Periaqueductal Nucleus Nucleus Gray Region Nucleus of the Locus Solitary Tract Ceruleus Pituitary Autonomic pathways Visceral Adrenal glands Afferents a Viscerosensory information is conveyed to the amygdala by two major pathways: downstream, from the nucleus of the solitary tract via the parabrachial nucleus or the sensory thalamus; and upstream, from the primary viscerosensory cortices and via corticothalamic relays al- lowing for higher-level neurocognitive processing and modulation of sensory information. Contextual information is stored in memory in the hippocampus and conveyed directly to the amygdala. Major efferent pathways of the amygdala relevant to anxiety include the follow- ing: the locus ceruleus (increases norepinephrine release, which contributes to physiologic and behavioral arousal), the periaqueductal gray region (results in defensive behaviors and postural freezing), the hypothalamic paraventricular nucleus (activates the hypothalamic- pituitary-adrenal axis, releasing adrenocorticoids), the hypothalamic lateral nucleus (activates the sympathetic nervous system), and the parabrachial nucleus (influences respiratory rate and timing). figure 1, which is based mainly on the work of Joseph nation of “upstream” (cortical) and “downstream” LeDoux et al. (11) and Michael Davis (12), that the au- (brainstem) sensory information, which results in tonomic, neuroendocrine, and behavioral responses heightened amygdalar activity with resultant behav- that occur during panic attacks are remarkably similar ioral, autonomic, and neuroendocrine activation. to the symptoms occurring in animals as a result of ac- One must pause at this point, however, to consider tivity in these brain regions during fearful response to how often patients with panic disorder actually demon- conditioned stimuli. This striking overlap between the strate autonomic and neuroendocrine activation during consequences of stimulation by the central nucleus of attacks. Studies here are incomplete and somewhat in- the amygdala of brainstem sites and the biological consistent. For example, some, but not all, ambulatory events that occur in humans during panic attacks is monitoring studies have shown an increase in heart rate compelling. However, this is not the complete story. It is (19) and respiration (20) during panic attacks recorded clear that there are important reciprocal connections outside of the laboratory. Although patients with panic between the amygdala and the sensory thalamus, pre- disorder respond to CO2 inhalation with more anxiety, frontal cortex, insula, and primary somatosensory cor- panic, and increase in respiratory rate than do normal tex (18). So although the amygdala receives direct sen- volunteers or patients with other psychiatric illnesses sory input from brainstem structures and the sensory (21), studies of the most sensitive measure of physiolog- thalamus, enabling a rapid response to potentially ical response to CO2 inhalation—the ratio of change in threatening stimuli, it also receives afferents from corti- minute ventilation to change in end tidal CO2 concen- cal regions involved in the processing and evaluation of tration—have yielded conflicting results (22). Although sensory information. Potentially, a neurocognitive defi- some investigators have found evidence for CO2 hyper- cit in these cortical processing pathways could result in sensitivity, others have found that patients with panic the misinterpretation of sensory information (bodily fall within the normal range on this measure. Cortisol cues) known to be a hallmark of panic disorder, leading elevation in patients with panic disorder is reliably ob- to an inappropriate activation of the “fear network” served only during the anticipation of panic attacks via misguided excitatory input to the amygdala. Al- (23), not during the attacks themselves (24). Taken to- though much remains to be elucidated regarding the gether, the evidence suggests that some, but not all, amygdala’s role in panic, it seems reasonable to specu- panic attacks are accompanied by autonomic and neu- late that there may be a deficit in the relay and coordi- roendocrine activation. Am J Psychiatry 157:4, April 2000 495
  4. 4. PANIC DISORDER This last point serves to highlight what we think is widely across patients with panic. These observations an important error in our original neuroanatomic hy- are clearly in line with what both researchers and clini- pothesis of panic disorder. If, as argued there, panic cians observe. attacks are the direct result of abnormal autonomic control at the level of the brainstem, we would expect to find autonomic and neuroendocrine activation a ROLE OF MEDICATION common property of all panic attacks. The fact that this is not the case suggests that brainstem activation It is useful to consider how medications might act at is probably an epiphenomenon of activity in another the level of the central nucleus of the amygdala and its area of the brain. The finding in preclinical research projections to reduce the severity and frequency of that activity in the central nucleus of the amygdala ini- panic attacks. Although many classes of medication tiates stimulation of all of the relevant brainstem cen- have been shown to be more effective than placebo in ters and that disrupting specific projections from the treating panic disorder, we select only one class for this central nucleus of the amygdala to brainstem neurons discussion—the selective serotonin reuptake inhibitors selectively interferes with autonomic responses is con- (SSRIs). We do this because SSRIs are rapidly becom- sonant with this idea. Thus, for example, if the projec- ing the first-line medication treatment for panic disor- tion from the central nucleus of the amygdala to the der (34), their acute mechanism of action in the central central gray region is lesioned, all autonomic re- nervous system is fairly well understood (35), and they sponses are seen, but the animal does not posturally may be more effective than other classes of medication freeze or attempt to flee (17). for panic disorder (36). Another finding that continues to contradict the idea SSRIs have in common the property of inhibiting the that there is a specific abnormality in autonomic brain- protein responsible for transporting serotonin (5-HT) stem control in panic disorder is that a variety of back into the presynaptic neuron. This effectively in- agents with dissimilar biological properties all produce creases the amount of 5-HT available in the synapse to panic attacks in patients with panic disorder but not in bind to both pre- and postsynaptic receptors. There are healthy comparison subjects or patients with other at least 13 subtypes of 5-HT receptors established in psychiatric illnesses. The list of such agents is long, humans (37), although the function and anatomical seems to grow annually, and includes sodium lactate distribution of all of them have not been fully charac- (25), CO2 (26), yohimbine (27), fenfluramine (28), m- terized. Nevertheless, functional studies demonstrate CPP (29), noradrenaline (30), adrenaline (31), hyper- that over time, treatment with SSRIs leads to an in- tonic sodium chloride (32), and analogues of cholecys- crease in overall serotonergic neurotransmission in the tokinin (33). It remains difficult to understand what central nervous system (38). abnormal brainstem nucleus could be specifically trig- When attempting to understand the mechanism of gered by such a diverse group of agents. action of SSRIs in panic disorder, a paradox arises as An alternative explanation that takes into account soon as animal models are considered. Acutely increas- the inconsistency of autonomic responses and the het- ing 5-HT levels either globally or regionally in the erogeneity of agents capable of producing panic at- brain of an experimental animal has been shown by tacks in susceptible patients is that panic originates in many—although not all studies—to increase fear and an abnormally sensitive fear network, which includes avoidance (39). Although long-term studies are not the prefrontal cortex, insula, thalamus, amygdala, and available, and there are contradictory data, even some amygdalar projections to the brainstem and hypothal- longer-term administrations of 5-HT precursors or ag- amus. When administering an agent that causes panic onists appear to maintain this increase in fear. By con- attacks, sometimes called a panicogen, we are not in- trast, although some patients initially complain of in- teracting with a specific brainstem autonomic area but, creased anxiety and agitation when given treatment rather, activating the entire fear network. Patients with with SSRIs, these adverse events are generally mild and panic disorder experience unsettling somatic sensa- subside over subsequent weeks. By 4 weeks, most pa- tions on a regular basis. The administration of a pa- tients with panic report feeling less anxious and are nicogenic substance represents nonspecific activation; having fewer panic attacks (and of diminished inten- because each of the panicogens produces acutely un- sity) than before medication was initiated. comfortable physical sensations, we suppose that they The solution to this paradox may come from a more act to provoke a sensitized brain network that has been refined understanding of the pathways involved in se- conditioned to respond to noxious stimuli. Over time, rotonergic neurotransmission. Serotonergic neurons various projections from the central nucleus of the originate in the brainstem raphe region and project amygdala to brainstem sites such as the locus ceruleus, widely throughout the entire central nervous system periaqueductal gray region, and hypothalamus may (40). Three of these projections are of particular rele- become stronger or weaker. There may be interindivid- vance to an understanding of the SSRI antipanic effect. ual differences in the strength of these afferent projec- First, the projection of 5-HT neurons to the locus tions as well. Hence, the actual pattern of autonomic ceruleus is generally inhibitory (41), such that the and neuroendocrine responses during panic may vary greater the activity of the serotonergic neurons in the within any given patient with panic over time and even raphe, the smaller the activity of the noradrenergic 496 Am J Psychiatry 157:4, April 2000
  5. 5. GORMAN, KENT, SULLIVAN, ET AL. neurons in the locus ceruleus. Indeed, Coplan et al. hibits excitatory cortical and thalamic inputs from ac- (42) showed that after 12 weeks of fluoxetine treat- tivating the amygdala. ment, patients with panic who responded to treatment We propose, then, that it is most likely that medica- showed a decrease in plasma levels of 3-methoxy-4-hy- tions known to be effective in treating panic disorder droxyphenylglycol, the main metabolite of noradrena- diminish the activity of brainstem centers that receive line. This suggests that SSRIs, by increasing serotoner- input from the central nucleus of the amygdala and gic activity in the brain, have a secondary effect of control autonomic and neuroendocrine responses dur- decreasing noradrenergic activity. This would lead to a ing attacks. In addition to their psychic effects, drugs decrease in many of the cardiovascular symptoms as- such as SSRIs may eliminate most of the troubling sociated with panic attacks, including tachycardia and physical effects that occur during panic by affecting increased diastolic blood pressure. heart rate, blood pressure, breathing rate, and gluco- Second, the projection of the raphe neurons to the corticoid release. This would then lead to a secondary periaqueductal gray region appears to modify defense/ decrease in anticipatory anxiety as a patient recognizes escape behaviors. Viana and colleagues (43) have that the seemingly life-threatening physical manifesta- shown that stimulation of the dorsal raphe nucleus tions of panic have been blocked. It is not uncommon, dramatically increases 5-HT release acutely in the dor- particularly in the early stages of medication treatment sal periaqueductal gray region, resulting in diminished of a patient with panic disorder, to hear “I sometimes periaqueductal gray region activity. This finding sup- feel as if the attack is coming on, especially when I am ports the original suggestion of Deakin and Graeff (44) in a situation in which attacks have occurred in the that serotonergic projections from the dorsal raphe nu- past. I get afraid, but then nothing happens. No palpi- clei play a role in modifying defense/escape responses tations, no dizziness, no difficulty breathing. My by means of their inhibitory influence on the periaque- thoughts don’t seem to be able to cause a panic attack ductal gray region. anymore.” We interpret this to suggest that the projec- Third, evidence now suggests that long-term treat- tions from the central nucleus of the amygdala to the ment with an SSRI may reduce hypothalamic release of brainstem and hypothalamus have been inhibited by corticotropin-releasing factor (CRF) (45). CRF, which medication treatment. initiates the cascade of events that leads to adrenal cor- tical production of cortisol, is also a neurotransmitter in the central nervous system and has been shown on NEUROIMAGING AND PANIC DISORDER numerous occasions to increase fear in preclinical models (46). When administered directly into the If the amygdala, thalamus, periaqueductal gray re- brain, CRF also increases the firing rate of the locus gion, parabrachial nucleus, locus ceruleus, and hypo- ceruleus (47). CRF antagonists decrease both physio- thalamus are so important in coordinating the mani- logical (48) and behavioral consequences of CRF stim- festations of panic, it would be a logical next step to ulation (49). Indeed, CRF antagonists are now being attempt to image these brain regions during attacks examined for their potential as anxiolytics in both an- and determine if they are particularly active compared imals and humans. to other brain regions. This has proven to be a daunt- Hence, by looking at the specific pathways that orig- ing task. First, although the amygdala occupies a sig- inate from serotonergic neurons in the raphe, one can nificant portion of the anterior part of the temporal find at least three mechanisms by which increased sero- lobe, it is a small structure in the human brain and is tonergic activity produced by long-term SSRI adminis- therefore difficult to distinguish with all but the most tration might produce an antipanic effect. By diminish- sensitive positron emission tomography (PET) cam- ing arousal, defense/escape behavior, and levels of the eras. Separating the amygdala from adjoining brain anxiogenic substance CRF, SSRIs are likely to block structures and the cortex is not a trivial task. Further, many of the downstream manifestations of panic. it is not yet possible with PET to distinguish among Equally intriguing as the three examples given above smaller brainstem nuclei. Functional magnetic reso- is the possibility that SSRIs, by increasing serotonergic nance imaging (fMRI) potentially has the resolution to activity, have an effect on the central nucleus of the make this possible, but the technology is still in devel- amygdala itself. Studies here are in the early stages, but opment to clearly image deeper subcortical and brain- it is already known that serotonergic neurons originat- stem structures. ing in the dorsal and medial raphe nuclei project di- Sensitive PET cameras can now resolve the amygdala rectly to the amygdala via the medial forebrain bundle and other structures in the fear network like the thala- (40). At the level of the amygdala, Stutzmann and mus as distinct neuroanatomical loci, but at least two LeDoux (50) have demonstrated that 5-HT modulates other problems exist in learning whether they play a sensory input at the lateral nucleus of the amygdala, special role in panic. The first is in trying to capture the inhibiting excitatory inputs from glutamatergic tha- attack itself. Because panic attacks occur at seemingly lamic and cortical pathways. Because the amygdala is random intervals, it is obviously impossible to place a known to receive dense serotonergic input from the patient in a scanner and wait for a spontaneous panic raphe nuclei, this may be a prime site for the anxiolytic attack to occur. This means that some panicogenic action of the SSRIs, whereby an increase in 5-HT in- agent must be administered that will reliably produce Am J Psychiatry 157:4, April 2000 497
  6. 6. PANIC DISORDER FIGURE 2. Change in Global CBF, Corrected for Degree of Hy- tain structures. Most of the neuroimaging studies in pocapnia, During Voluntary Hyperventilation in Three Patients populations with panic disorder have reported re- With Panic Disorder and Three Normal Comparison Subjectsa gional reductions in CBF or metabolism. Because the degree of hypocapnia (end tidal CO2) has not generally been controlled in these studies, it is difficult to inter- Panic disorder patient treated with cognitive behavioral therapy pret the results knowing that patients with panic disor- der have a greater tendency to hyperventilate in stress- Acutely ill panic disorder patient ful situations than normal comparison subjects (22). In support of this idea is a study by Stewart and col- Acutely ill panic disorder patient leagues (54), in which rCBF was measured during rest and immediately after a lactate infusion with xenon- Panic disorder patient 133 single photon emission computed tomography treated with SSRI ([133Xe]-SPECT). Normal comparison subjects and nonpanicking patients with panic disorder showed an Normal subject increase in CBF after lactate infusion, whereas patients with panic disorder who panicked after lactate infu- Normal subject sion demonstrated a smaller increase or an actual de- crease in CBF. This finding may be accounted for by Normal subject the vasoconstrictive effect of hyperventilation in over- coming the expected lactate-induced increase in CBF in –3 –2 –1 0 1 2 3 the panicking patients. We suspect this is likely because we have previously shown that patients who panic Ratio of CBF to End Tidal CO2 during lactate infusion do hyperventilate more than a Significant difference between groups, with the patient taking an those who do not panic (55). SSRI excluded (t=3.26, df=4, p=0.03, N=6). In addition, there is growing evidence that patients with panic disorder are more sensitive to the vasocon- strictive effects of hyperventilation-induced hypocap- an attack. Several are available, as discussed above, nia than are comparison subjects. Ball and Shekhar but the attacks that occur when they are administered (56) have reported a differentially greater hyperventi- are, like naturally occurring panic attacks, brief. Ra- lation-induced decrease in basilar arterial blood flow diotracers like [18F]fluorodeoxyglucose (FDG) that en- in patients with panic attacks than in comparison sub- able quantification of regional brain metabolism can- jects by means of transcranial Doppler ultrasonogra- not capture events that occur over periods of time as phy. Dager et al. (57) measured brain lactate levels by short as a few minutes. Hence, PET scanning using using magnetic resonance spectroscopy during volun- FDG may not be able to tell us definitively if a change tary hyperventilation in a group of patients with panic in metabolism has occurred acutely during the actual disorder and a group of normal comparison subjects. panic attack itself. Radiotracers such as [15O]water do Although they controlled for differing degrees of hy- provide temporal resolution compatible with captur- perventilation by monitoring PCO2 with capnometry, ing a panic attack, but they only allow us to measure hyperventilating subjects with panic disorder increased regional cerebral blood flow (rCBF), not metabolism. their brain lactate levels disproportionately, suggesting The majority of studies have shown that there is a high that they may have an exaggerated hypersensitivity to correlation between brain metabolism and blood flow the vasoconstrictive effect of hypocapnia. in healthy subjects (51, 52), such that increased neu- Our group has recently generated pilot data consis- ronal activity in a given region is accompanied by in- tent with this notion (figure 2). A small number of pa- creased blood flow to that region. However, other tients with panic disorder, one of whom had been studies have suggested that this relationship may not treated with cognitive behavioral therapy and was en- hold consistently during physiologic activation (53). tirely asymptomatic at the time of the study, one of The possibility always exists that the uncoupling of whom had been successfully treated with fluoxetine, CBF and metabolism may occur under circumstances and healthy comparison subjects, were asked to hyper- of heightened stress, such as a panic attack. However, ventilate during [133Xe]-SPECT scanning. When cor- this uncoupling would be expected to be global, and, rected for level of hypocapnia, as measured by the end therefore, specific regional differences in CBF would tidal CO 2 level, the patients showed significantly be expected to still reflect changes in local neuronal greater decreases in CBF than the healthy comparison metabolic activity. subjects. The only exception was the remitted patient A second problem for brain imaging studies is that who was taking fluoxetine at the time and who ap- patients with panic hyperventilate when they are peared by inspection to have the same level of vasocon- anxious, and the resultant hypocapnia-induced vaso- striction as the healthy comparison subjects. constriction may obscure results, especially by coun- Conclusions from so preliminary a study are obvi- teracting expected increases in blood flow, reflecting ously perilous, but the results are consistent with those neuronal activation and increased metabolism in cer- of many other neuroimaging observations with pa- 498 Am J Psychiatry 157:4, April 2000
  7. 7. GORMAN, KENT, SULLIVAN, ET AL. tients with panic disorder. The greater vasoconstriction PET studies attempting to look at changes in the brains found in the patients with panic disorder cannot be of healthy subjects during aversive classical (fear) con- secondary to more hyperventilation or greater hypo- ditioning (62) demonstrated significant increases in capnia because these were carefully controlled, and ob- rCBF in several subcortical structures implicated in the served levels were equivalent to those found in the fear network, including the thalamus, hypothalamus, healthy comparison subjects. Some additive mecha- and periaqueductal gray region, in addition to soma- nism must be involved. Two possibilities arise. First, as tosensory and associative cortices and the cingulate. discussed earlier, it is well known from the work of However, most PET studies have not found activation Goddard et al. (58) and others that the noradrenergic of the amygdala during fear conditioning paradigms system is more active and more sensitive in patients using subtractive PET methods (62–65). Although with panic than in healthy comparison subjects. Mat- these studies did not find an outright increase in thews (59) has argued convincingly that this, plus the amygdalar rCBF in fear conditioning, a positive corre- fact that noradrenergic fibers innervate cerebral blood lation between nonspecific electrodermal fluctuations vessels and cause vasoconstriction (60), explains the (reflecting degree of conditioning) and rCBF in the heightened vasoconstriction in patients with panic right amygdala was reported (64). during hyperventilation. Patients with panic may re- Recently, fMRI has been used to overcome some of spond with more fear during hyperventilation than do the difficulties evident in PET approaches, such as tem- healthy comparison subjects, thus activating the locus poral sequencing and nonassociative effects, and one ceruleus and causing noradrenergic-mediated vasocon- group has successfully demonstrated activation of the striction that adds to the effects of hyperventilation. amygdala and periamygdaloid cortical areas during A second possibility arises from the preclinical stud- conditioned fear acquisition and extinction (66). In ad- ies of Marovitch and colleagues (61), showing that dition, several investigators have shown specific acti- stimulation of the parabrachial nucleus, which is adja- vation of the amygdala in response to presentations of cent to the locus ceruleus in the brainstem, also causes affectively negative or fearful visual stimuli using fMRI cerebral vasoconstriction. The widespread reduction in techniques (67). fMRI permits far better anatomical CBF seen with stimulation of the parabrachial nucleus and temporal resolution than PET or SPECT; however, may be mediated by yet another subcortical site, since its ability to delineate deeper subcortical and brain- projections of the parabrachial nucleus do not reach the stem structures has been limited in the past by field in- entire cortex. Marovitch and colleagues have suggested homogeneity. With the advent of cardiac gating and that the rostral raphe nuclei, which are capable of mod- other advances in fMRI technology, this problem is be- ulating cortical vasoconstriction through serotonergic ing overcome. fMRI is therefore a logical technology projections, may be such a site. In this role, the raphe to extend to the study of patients with panic disorder, nuclei might relay information from the parabrachial nucleus to the cerebral cortex, resulting in a more glo- since its superior anatomical and temporal resolution bal vasoconstrictive effect. In either event, we postulate should allow the investigation of fear network struc- once again that activation of the amygdala during a tures during a real-time panic attack. fearful episode—in this case, hyperventilating in the en- What is specifically needed for the study of panic dis- closed space of a PET or SPECT scanner—may produce order is a method that can provoke anxiety or panic by its projections an increase in activity in either the lo- without causing hyperventilation-induced hypocapnia. cus ceruleus, the parabrachial nucleus, or both. This One possibility is to ask subjects to inhale small would increase the amount of vasoconstriction in pa- amounts of CO2 during brain imaging studies. Con- tients with panic relative to healthy comparison sub- centrations as low as 5% in room air have been shown jects, leading to the exaggerated decreases in CBF ob- to increase anxiety levels in most subjects, with pa- served in several neuroimaging studies. tients with panic disorder showing significantly more The observation that one patient with panic treated anxiety and higher rates of frank panic (21). Inhalation with an SSRI did not show exaggerated vasoconstric- of CO2 does produce increases in both tidal volume tion during hyperventilation is consonant with our the- and respiratory rate (68), but because CO2 is continu- ory. If, indeed, SSRIs produce inhibition of the locus ously supplied, there is no opportunity for hypocapnia ceruleus or parabrachial nucleus, either directly or to develop. The difficulty with this technique, however, through an effect on the amygdala, one would expect to is that CO2 inhalation produces a global increase in see a normalization of the vasoconstrictive effect of hy- CBF, making it unclear whether regional activation of perventilation. This speculation obviously calls for fur- a network responsible for panic would once again be ther studies because it could be a marker for the success obscured by blood flow changes, albeit in the opposite of SSRI therapy in the treatment of panic disorder. direction as those caused by hyperventilation. Corfield Although neuroimaging studies to date in patients and colleagues (69) recently showed that there are re- with panic disorder have not implicated fear network gional differences in response to CO2 inhalation, with structures established in preclinical models (perhaps the amygdala showing particularly strong effects. Such because of methodological and technical limitations), preliminary findings suggest that CO2 inhalation may neuroimaging studies in human fear conditioning have provide a method of overcoming the problems associ- demonstrated the importance of these structures. Early ated with hyperventilation-induced hypocapnia that Am J Psychiatry 157:4, April 2000 499
  8. 8. PANIC DISORDER attend most neuroimaging studies in panic disorder gotic than between dizygotic twins for a disease im- reported so far. plies a genetic basis. For psychiatric illness we must make the additional assumption that parents maintain as similar an environment for dizygotic twins as they GENETICS OF FEAR AND PANIC DISORDER do for monozygotic twins. At least three studies (75– 77) have examined the concordance rates for panic dis- If we accept the hypothesis that patients with panic order among twins, and all find a higher concordance disorder suffer from an abnormally sensitive fear net- for monozygotic than for dizygotic twins, with one work that includes the central nucleus of the amyg- (75) specifically showing a higher concordance rate for dala, hippocampus, periaqueductal gray region, and panic attacks than for the syndromal disorder itself. other brainstem areas, the next issue to address is why The conclusion at first glance seems clear: panic disor- this is the case. One possibility is that there is an inher- der must have a genetic component. ited tendency for fearfulness, perhaps manifested as a A closer examination of the twin studies, however, neurocognitive deficit resulting in an abnormal re- suggests a retreat from such a broad statement. In none sponse to or modulation of the fear network. Once of the studies was the concordance rate for panic be- again, an appeal to preclinical work is helpful. tween monozygotic twins even close to 50% (range= A number of studies have now indicated that quanti- 14%–31%). This means that although genetically tative trait loci on specific chromosomes are associated identical twins are more likely to both have panic dis- with heightened emotionality and with fear-condition- order than are twins who are no more genetically iden- ing in rodents. For example, Flint et al. (70) showed tical than ordinary brothers and sisters, there are many that three loci on mouse chromosomes 1, 12, and 15 cases in which one identical twin has panic disorder were associated with decreased activity and increased and the other does not. The conclusion seems clear. If defecation in a novel environment. They concluded genes are involved in causing panic disorder, they can- that these loci were responsible for heightened “emo- not be the whole story. tionality” and speculated that “there are cogent rea- Taking the preclinical studies and the twin studies sons for expecting that the genetic basis of emotional- together, the most logical assumption is that what is in- ity is similar in other species and that it may underlie herited is a susceptibility to panic, not panic disorder the psychological trait of susceptibility [emphasis itself. It is well known that children exhibit varying added] to anxiety in humans. The pattern of behav- levels of anxiety and fear. Some children are extremely ioral effects of anxiolytic drugs in rodents together anxious and have been called “behaviorally inhibited with the results of electrophysiological and lesion ex- to the unfamiliar” by Kagan and colleagues (78). The periments suggest conservation between species of a presence of an anxiety disorder in childhood or adoles- common neural substrate, probably determined by ho- cence confers a substantially increased risk for having mologous genes” (p. 1434). Both Wehner et al. (71) a recurrent anxiety disorder in young adulthood (79). and Caldarone et al. (72) found quantitative trait loci Nevertheless, many anxious children do not develop associated with contextual fear conditioning in rodents anxiety disorders as adults, and many people with on several chromosomes, with both groups implicating first-degree relatives, even identical twins, with panic chromosome 1. In an editorial accompanying the Weh- disorder never have a panic attack themselves. ner et al. and Calderone et al. studies, Flint (73) com- mented that “the locus on chromosome 1 that was The elegant behavioral genetic work of Flint and identified by both groups has in fact already been others suggests that it is possible to inherit a vulnera- shown to influence fearfulness in two independent bility to fearfulness and anxiety. Further, this may be studies…the fact that four studies working on such dif- traced to relatively few genes and may involve areas of ferent measures of the same trait have succeeded in the brain such as the amygdala and its projection sites identifying the same chromosomal region is very en- or the cortical areas involved in modulating amygdalar couraging” (p. 251). activity. We conclude, then, that patients with panic Is there evidence that panic disorder is genetic? disorder very likely inherit a susceptibility to panic that There is no question that it is highly familial. A num- has its basis in an unusually sensitive fear network, ber of studies have now shown that the chance of hav- with the central nucleus of the amygdala playing a sig- ing panic disorder is substantially elevated over the nificant role. base rate in the population if one has a first-degree rel- ative with panic disorder (74). But this is hardly evi- dence of a genetic cause; one can easily imagine that ENVIRONMENTAL BASIS FOR PANIC DISORDER growing up with anxious relatives could condition an individual to develop heightened levels of fear, anxiety, The most likely candidate for the part of panic disor- or even panic attacks. The next best data come from der etiology not likely to be explained by genetics is an studies comparing the concordance rate for panic dis- environmental insult. In our original neuroanatomical order between monozygotic (identical) and between hypothesis, we made a similar claim, but since then the dizygotic (fraternal) twins. For most medical illnesses, evidence that this is plausible has increased both from finding a higher rate of concordance between monozy- animal and human studies. 500 Am J Psychiatry 157:4, April 2000
  9. 9. GORMAN, KENT, SULLIVAN, ET AL. Several studies have now suggested that disruptions over time. The infants raised under the variable forag- of early attachment to parents may be associated with ing demand condition appear normal in most respects, the later development of panic disorder. For example, but they exhibit more fearfulness and less social gre- using data from the Epidemiological Catchment Area gariousness throughout their lives when compared to study, Tweed et al. (80) reported that adults whose animals raised under low foraging demand conditions mothers died before they were age 10 were almost (88). As adults, the animals raised under the variable seven times more likely than those without a history of foraging demand condition also exhibit increased CRF early maternal death to be diagnosed with agorapho- levels in CSF (89), exaggerated behavioral response to bia with panic attacks. Those adults whose parents noradrenergic stimulation, blunted behavioral re- separated or divorced before age 10 also had a greater sponse to serotonergic agonists (90), and blunted likelihood of being diagnosed with agoraphobia with growth hormone response to a clonidine treatment panic attacks—almost four times the rate of those condition (Coplan et al., unpublished 1997 presenta- without a history of early parental separation. Stein et tion). Thus, even years after a relatively subtle disrup- al. (81) found that patients with panic disorder re- tion of maternal-infant interaction, animals whose ported more instances of childhood sexual and physi- mothers underwent an uncertain variable foraging de- cal abuse than did healthy comparison subjects. The mand condition are fearful and shy and show evidence idea that disrupted emotional attachments with signif- of enduring biological disruption. icant caregivers during childhood may be a risk factor There is evidence that experiencing traumatic events for panic disorder is consonant with the clinical obser- during childhood and adulthood is associated with the vation that patients with panic disorder are unusually development of panic disorder (91–94). Nevertheless, sensitive to perceived, threatened, or actual separa- our model asserts that patients with panic disorder, by tions. Indeed, patients with panic are less likely to ex- virtue of a genetically imposed abnormality in the in- perience a panic attack when surrounded by trusted trinsic brain fear network, are more susceptible to the companions. One study showed that having a compan- effects of trauma, particularly those involving separa- ion present reduced the likelihood of a panic attack tion and disrupted attachment, than are individuals during CO2 inhalation (82). This is striking because without panic disorder. That recent traumatic stress our attempts to reduce the rate of panic during CO2 in- may also play a role in stimulating the onset of panic is halation by cognitive manipulation have not proven clearly compatible with this model. This abnormality successful (83). could take a number of forms, including tonic auto- The preclinical literature now strongly indicates that nomic hyperactivity or a neurocognitive defect that early disruptions of the attachment between infants would prevent the appropriate interpretation of fear and mothers (in animals fathers rarely play a substan- network signals and/or the appropriate cortical feed- tial role in rearing offspring) produce long-lived behav- back to limit anxiety and panic responses. Hence, we ioral and biological changes. For example, Michael Meaney, Paul Plotsky, and others (84–87; Plotsky et propose an interaction between life stress and genetic al., unpublished 1996 presentation) have shown that susceptibility as the root cause of panic disorder in in rodents, alterations in mother-offspring interactions adults. produce changes in the infant’s subsequent hormonal The invocation of adverse life events may help us un- and physiological responses to stress that endure derstand why anxious children may grow up to be de- throughout the lifetime. These altered responses ap- pressed, have one or more of a number of different pear to be mediated at least in part by changes in cen- anxiety disorders, or exhibit no psychopathology at tral CRF function. Furthermore, these changes vary all. It is possible that a similar genetic vulnerability is across different genetic strains of rodent so that “in rel- common to several of these conditions and whether, or atively hardy animals the early-life manipulations may which, one of them is actually expressed in adult life have less obvious effects” (85). depends on the kind of environmental influences to Andrews, Rosenblum, Coplan, and colleagues (88– which a child is exposed. The same fear network that 90; Coplan et al., unpublished 1997 presentation) have we have posited to be abnormal in panic disorder may pursued an interesting behavioral paradigm in nonhu- also function abnormally in social phobia, PTSD, gen- man primates. Infant bonnet macaques are exposed to eralized anxiety disorder, or depression. The relation- either a low foraging demand condition, in which ships among the different parts of the network may mothers are given immediate direct access to food, or a differ, however, among these disorders. Such a theory variable foraging demand condition, in which, at ran- would explain the commonly observed high levels of domly selected intervals, the mother is forced to search comorbidity among anxiety disorders and between for food, thus interfering with her attention to the in- anxiety and depression. It would also explain why the fant. Both infant and mother receive adequate nutri- same medications are effective for all of these condi- tion in both conditions. It is of interest that infants ex- tions—presumably because all involve some hyperac- posed to the variable foraging demand condition do tivity of the amygdala and its projections—but cogni- not seem particularly distressed while the mother tive behavioral therapies differ, perhaps because of searches for food, but the mothers appear stressed, and different degrees of abnormality in the hippocampus some begin to neglect the emotional needs of the infant and prefrontal cortex. Am J Psychiatry 157:4, April 2000 501
  10. 10. PANIC DISORDER This hypothesis imposes learned reactions and un- ment. Such patients often require and do well when of- conscious emotional states onto genetic vulnerability. fered behavioral therapy aimed at desensitizing them It predicts in at least two ways that psychotherapy of to feared contexts. several types should be useful in treating panic disor- Perhaps the reaction of the patient with panic to mi- der. First, we will argue that phobic avoidance repre- nor physical discomfort also represents a kind of con- sents a type of contextual learning analogous to that textual fear conditioning. Many patients with panic seen in fear-conditioned animals. This learned phe- disorder are unbearably sensitive to relatively trivial nomenon has its neural basis in the memory systems of somatic sensations such as mild dizziness, increase in the hippocampus. Second, we will argue that sensitiv- heart rate, or slight tingling in a limb. Although it is ity to separation, fear of impending doom and death, difficult to make analogies with animal models of fear and overreaction to somatic cues are mediated by conditioning, it is plausible that somatic sensation is a higher cortical centers. In both cases, behavioral, cog- kind of context that becomes capable of triggering nitive, and possibly psychodynamic therapies play a panic over time. role in modifying these systems. Cognitive behavioral therapy for panic disorder fo- cuses, in part, on eliminating contextual fear by desen- sitizing the patient to both physical and somatic cues CONTEXTUAL LEARNING IN PANIC DISORDER for panic (98). This may represent an effect on memory mediated by the hippocampus. Imaging studies should As we noted in our introduction, one of the puzzles be very helpful in determining if this is indeed the case. in understanding panic disorder is the frequent obser- vation that even when patients report few or no panic attacks, they still exhibit avoidant behavior. This has ROLE OF HIGHER CORTICAL CENTERS led to the widespread recommendation that clinical tri- IN PANIC DISORDER als examining antipanic treatments should measure the effect of the putative treatment on more domains than Beyond contextual learning, patients with panic dis- just the reduction in frequency or severity of panic at- order frequently exhibit widespread catastrophic tacks (95). A patient who has stopped having attacks thinking (99) and an increased risk for the develop- but will not leave the house is probably not appropri- ment of major depression (100). They can become tied ately considered a responder to treatment. to “phobic partners,” sometimes maintaining attach- It is well known that animals who have undergone a ments that are not in their best interest because of an fear-conditioning experience also become conditioned exaggerated fear that separation will cause life-threat- to the context in which the experience occurred (96). ening consequences. The toll on the patient and signif- For example, a rat conditioned to have the same be- icant others can be substantial, and marital discord havioral and autonomic reaction to a tone as was elic- among patients with panic disorder is frequently ob- ited by mild electrical shock will also demonstrate served (101). these reactions when simply placed in the cage in There are many neuroanatomical sites that likely which the conditioning experiment took place, even subserve the cognitive and relationship difficulties that without presentation of the tone. This contextual con- ultimately may be the worst part of panic disorder. We ditioning is known to require intact hippocampal neu- have suggested that cortical sites, particularly those rons (97). If after conditioning to the tone has occurred that process higher-order sensory information such as the amygdala is lesioned, the animal will no longer ex- the medial prefrontal cortex, are important in modu- hibit a fearful response to the tone but will respond lating anxiety responses. As LeDoux has suggested fearfully when placed back in the cage. If on the other (102), psychotherapy may work, in part, by strength- hand, the hippocampus is lesioned, the animal main- ening the ability of these cortical projections to assert tains the response to the tone but no longer responds reason over automatic behavioral and physical re- to placement in the cage. sponses. Medications, in our opinion, are only par- The analogy with patients with panic disorder ap- tially helpful in reversing the incessantly gloomy pre- pears obvious. Phobic avoidance arises, in part, from dictions of patients with panic disorder or in helping an association of panic attacks with the context in them rearrange relationships that are based on safety which they occurred. Patients who have had, for exam- and dependency. Depending on the severity of these ple, a panic attack in a car while driving over a bridge problems, which often correlates with how long a pa- in rush hour traffic remain fearful of cars, traffic, and tient has had panic disorder, psychotherapy becomes bridges. This can generalize to any situation in which invaluable. egress is not immediately possible and help not auto- We propose then that psychotherapies that are ef- matically available. It is of interest that clinicians ob- fective for panic disorder, including cognitive behav- serve that some patients treated with medication no ioral therapy and possibly psychodynamic treatment, longer panic but still maintain some level of phobic operate upstream from the amygdala and exert pow- avoidance. This may improve over time as decondi- erful inhibitory effects on a variety of learned re- tioning occurs, but in many patients it becomes a life- sponses. At least in the case of cognitive behavioral long problem despite adequate pharmacological treat- therapy, for which most evidence now exists, these 502 Am J Psychiatry 157:4, April 2000
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