The Neurobiology of Anxiety Disorders

ANXIETY DISORDERS: LONGITUDINAL COURSE AND TREATMENT

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THE NEUROBIOLOGY OF ANXIETY DISORDERS Michael R. Johnson, MD, and R. Bruce Lydiard, PhD, MD

Improvements in the techniques for assessing the neurochemistry and neuroanatomy of patients w ith anxiety disorders during the past few decades have led to the development of a clearer picture of the biologic conditions associated with normal and abnormal anxiety states. The current data available from studies of pathologic anxiety have suggested that the pathophysiology of the anxiety disorders is quite complex and that none of the anxiety disorders emerge from a single pathologic state. Instead, the growing biochemical data base has supported the idea that pathologic anxiety states are associated with disruptions of multiple neurotransmitter systems. Similarly, brain imaging studies have implicated the involvement of multiple brain structures in the pathophysiology of the anxiety disorders. This growing information base has allowed the recent development of several integrated neuroanatomic models of normal and abnormal anxiety states that serve to guide future research by providing testable hypotheses. The goals of this article are to review the available data from neurochemical and neuroanatomic studies of patients with anxiety disorders, to present several of the models regarding the pathophysiology and neuroanatomy of anxiety disorders, and to consider the implications of these models for future research in this area. We consider here only data pertaining to panic disorder, social phobia, generalized anxiety disorder, and simple/specific phobia. Two other anxiety disorders that also have an extensive base of biologic research, post-traumatic stress disorder and obsessive-compulsive disorder, are not considered here as they have been well-reviewed recently. 6• 59• 123

From the Department of Psychiatry, Medical University of South Carolina, Charleston, South Carolina.

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In the first section, we summarize the data available on adrenergic (Table 1), serotonin (Table 2), dopamine, and gamma-aminobutyric acid (GABA) function as well as chemoreceptor sensitivity (Table 3) in these anxiety disorders. The biologic systems we have chosen to review are those that have some clear connection to anatomic structures implicated in the pathophysiology of anxiety. Studies of anxiety patients, which have examined the function of other biologic systems such as cholecystokinin and adenosine, are not considered here but are reviewed elsewhere.8· 126 As it would be difficult to include all the biochemical data available, we primarily focus on studies that used biochemical challenges that have yielded some of the clearest findings. In the second section, we summarize the data available from neuroimaging studies of these disorders (Table 4). In the third section, we present several of the current neuroanatomic hypotheses of anxiety disorders that have arisen from these data. Finally, we consider some of the hypothetical implications of these models and suggest some directions for future research. ADRENERGIC FUNCTION IN ANXIETY DISORDERS Panic Disorder

Abnormal adrenergic function has been implicated in the pathophysiology of panic disorder since Redmond and Huang109 discovered that stimulation of the primate locus ceruleus caused anxiety reactions very similar to those of a human panic attack. Challenge studies that have examined the behavioral, physiologic, and neuroendocrine effects of agents affecting various adrenergic receptors have provided support for the involvement of noradrenergic systems in some aspects of panic disorder (Table 1). Panic patients have been found to have abnormal responsivity to stimulation of peripheral 13-adrenergic receptors. Isoproterenol, a 13adrenergic receptor agonist that rarely causes panic attacks in nonanxious controls, has been found to produce a high rate of panic attacks in patients with panic disorder. 5• 103 It has not been made clear, however, whether the panic patients' sensitivity to isoproterenol is caused by increased sensitivity of adrenergic receptors, a cognitive hypersensitivity to the induced physical sensations, or some other unknown mechanism. Evidence against the first hypothesis comes from a report that panic patients have blunted heart rate response to isoproterenol, suggesting that they actually have down-regulated or subsensitive peripheral 13adrenergic receptors. 91 The significance of this 13-adrenergic sensitivity among panic patients remains to be explained. Abnormalities in the function of central a. 2-adrenergic receptor also have been demonstrated among patients with panic disorder. One technique for assessing a. 2-adrenergic receptor function has involved assessing the neuroendocrine, physiologic, and psychological responses to intravenous or oral clonidine challenge. A blunted growth hormone

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Table 1. ADRENERGIC CHALLENGE STUDIES IN ANXIETY DISORDERS Authors

Subjects (Number)

Challenge Agent (Dose)

Findings

Pohl et al'°3

PD (86) NC (45)

lsoproterenol (1 µg/min)

Panic attacks PD > NC HR response PD < NC

Charney et a1 1 •

PD (68) NC (20)

Yohimbine (20 mg, PO)

Panic attacks PD > NC SBP increase PD > NC MHPG increase PD > NC

Charney et al 17

PD (38) NC (15)

Yohimbine (0.4 mg/kg, IV)

Panic attacks PD > NC

Charney et a121

PD/PA (24) PD/NPA (14) NC (15)

Yohirnbine (0.4 mg/kg, IV)

MHPG increase PD/ PA > PD/NPA =NC (Note: the PD/NPA group also had blunted GH response to clonidine compared with other two groups)

Gurguis et al 54

PD (11) NC (7)

Yohimbine (20 rng, PO)

Anxiety response PD > NC

Uhde et al 138

PD (11) Dep (11) NC (11)

Clonidine (2 µg/kg, IV)

GH response Dep = PD

Charney & Henninger"

PD + AG (26) NC (21)

Clonidine (0.15 mg, IV)

GH response PD + AG < NC MHPG decrease PD + AG >NC SBP decrease PD + AG > NC

Nutt 93

PD (16) NC (16)

Clonidine (1.5 µg/kg, IV)

GH response PD < NC MHPG decrease PD > NC SBP decrease PD > NC

Tancer et al 131

PD (13) NC (20)

Clonidine (2 µg/kg, IV)

GH response PD

Abelson et al2

PD (10) NC (14)

Clonidine (2 µg/kg, IV)

GH response PD < NC MHPG decrease PD = NC SBP decrease PD = NC

Uhde et a11• 0

PD (12) NC (10)

Clonidine (2 µg/kg, IV)

SBP decrease PD = NC

Abelson et al'

GAD (11) NC (14)

Clonidine (2 µg/kg, IV)

GH response GAD < NC MHPG, HR, BP, ANX response GAD = NC

Charney et a120

GAD (20) NC (20)

Yohimbine (20 rng, PO)

Panic attacks GAD = NC (1/20) Anxiety response GAD = NC Increase MHPG GAD < NC

Papp et al97

soc

Epinephrine (2.5- 4.0 µg/kg/ min, IV)

Anxiety increase in only one patient

Tancer et al 130

soc

(16) PD (12) NC (28)

Clonidine (2 µg/kg, IV)

GH response PD = SP

Tancer 12•

soc

Clonidine (5 µg/kg, PO)

GH response SOC = NC

(11)

(21) NC (22)

< NC

< NC

< NC

NC = Normal control; PD = panic disorder; PD + AG = panic disorder with agoraphobia; PD/PA = panic patients with panic attack after yohimbine infusion; PD/NPA = panic patients with no panic attack after yohimbine infusion; Dep = depression; MHPG = 3-methoxy-4-hydroxyphenyl-glycol; SBP = systolic blood pressure; GH = growth hormone; SOC = social phobia; GAD = generalized anxiety disorder; IV = intravenous; PO = oral ; HR = heart rate; BP = blood pressure; ANX = anxiety.

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response to the clonidine challenge among patients with panic disorder has been noted in five of the seven studies that examined this.2• 15• 93• 131• 138 Some studies also have found enhanced MHPG response15• 93 and a greater drop in systolic blood pressure among panic patients,15• 93 although other studies have not replicated these findings .2• 140 Although clonidine does appear to affect growth hormone release via its effects at the cx2-adrenergic receptor, there is some evidence to suggest that growth hormone response in panic patients is impaired when it is stimulated through other neurotransmitter systems as well. 137 Uhde136 has speculated that impaired growth hormone response may reflect a " global decrease" in growth hormone function possibly localized to an abnormality associated with hypothalamic function rather than a phenomenon specific to cxradrenergic receptor function. The absence of consistent abnormalities in blood pressure, MHPG, or pulse responses to clonidine challenge call into the question the validity of concluding the presence of cxradrenergic receptor dysfunction from these data. Another approach to testing the functional status of the central cxr adrenergic receptor function has been intravenous challenge with the cx2 antagonist yohimbine. Panic patients have demonstrated consistently to be significantly more sensitive to the anxiogenic and physiologic effects of yohimbine compared with normal control subjects. 17• 18• 21 • 54 These data provide more convincing support for the presence of abnormally enhanced sensitivity of central cx 2-adrenergic receptors in panic disorder. Generalized Anxiety Disorder

Generalized anxiety disorder (GAD) has many features in common with panic disorder including symptoms of peripheral sympathetic arousal (e.g., palpitations, tremor). Whereas some studies have demonstrated abnormally decreased peripheral cx2-adrenergic receptors13• 122 or increased levels of norepinephrine and its metabolites,84• 122 other studies have not replicated these findings. 1• 20• 83• 90 The few available studies that used adrenergic challenge agents also have not demonstrated significant abnormalities in noradrenergic function among patients with GAD (Table 1). Abelson et aP reported that patients with DSM-III-diagnosed GAD had abnormal growth hormone release but normal physiologic and subjective responses to a clonidine challenge. Another study demonstrated that GAD patients had normal physiologic and subjective responses to intravenous yohimbine challenge, although there was evidence of some blunting of the MHPG response to this challenge.20 Social Phobia

The utility of ~-blocking drugs in treating performance an xiety among patients w ith social phobia47 has led to the hypothesis that catecholamines may play a role in the pathophysiology of social phobia.

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The limited biologic data available have not given strong support to this hypothesis. Social phobic patients were found in one study to have abnormally increased resting serum norepinephrine levels, 124 but this has not been replicated in two subsequent studies. 74 ' 125 Moreover, during a behavioral challenge of social phobic patients with a public speaking task, changes in peripheral noradrenaline and epinephrine were not different between patients and controls. 74 Biologic challenge studies also have failed to demonstrate clear abnormalities in noradrenergic function among social phobic patients (Table 1). Papp et al97 reported that only 1 of 11 patients with DSMIII-diagnosed social phobia reported significant anxiety in response to epinephrine infusion. Although abnormal blunting of growth hormone response to intravenous clonidine challenge was found in one study of DSM-III-diagnosed social phobic patients, Tancer et al1 30 noted that the social phobic patients appeared to have a less blunted response than did the panic patients in the same study. Moreover, a follow-up study using oral clonidine failed to demonstrate any abnormality in growth hormone response .129 Summary

Although data on peripheral indices of noradrenergic activity in panic disorder have not shown consistently abnormal levels of norepinephrine or its metabolites, biologic challenge studies support the presence of abnormally increased central a 2-adrenergic receptor sensitivity in many panic patients, There is little evidence to support a similar abnormality among patients with GAD or social phobia. In fact, the blunted MHPG response to yohimbine among patients with GAD found in one study suggests the possibility that these patients may have, if anything, a decreased a 2-adrenergic receptor sensitivity, Nevertheless, it should be noted that the available data are too limited to draw meaningful conclusions regarding noradrenergic function in patients with GAD and social phobia. The significant changes in diagnostic criteria for these diagnoses from DSM-III to DSM-IV make it necessary to repeat these studies using patients that meet the more recently developed criteria for these disorders before more definitive conclusions can be reached, SEROTONERGIC FUNCTION IN ANXIETY DISORDERS Panic Disorder

The fact that panic patients often have abnormal sensitivity to activation from serotonin reuptake inhibitors has led to the hypothesis that these patients may have abnormally enhanced responsivity of postsynaptic serotonin receptors. Early serotonin challenges in panic patients

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using the indirect serotonin agonists tryptophan16 and 5-hydroxytryptophan,143 however, did not find abnormal behavioral sensitivity among these patients (Table 2). In fact, the panic patients tended to respond to the tryptophan challenge with a decrease in anxiety rather than the increase that might be predicted by the theory that these patients would have hypersensitive central serotonergic receptors. Moreover, panic patients did not exhibit abnormal neuroendocrine responses to these challenges. Using the intravenous administration of a direct 5-HT agonist, methchlorophenylpiperazine (MCPP-a 5-HTlA agonist and 5-HT2 antagonist), Charney et al1 9 demonstrated similarly increased anxiety and panic reactions in both panic patients and controls and no differences in neuroendocrine responses to this challenge. These data suggested that, although serotonin agonism might cause anxiety, patients with panic disorder did not have a unique serotonin sensitivity. Other studies, however, have reached a different conclusion. Kahn et al64 repeated the MCPP challenge but used an oral form of MCPP rather than the intravenous form used by Charney and colleagues. In contrast to the earlier findings, they reported that 60% of the panic patients experienced a panic attack in response to the MCPP whereas no significant anxiety was reported by a group of depressed patients and a group of normal comparison subjects. Moreover, they subsequently reported that panic patients had an augmented cortisol response to oral MCPP compared with the controls. 62 They speculated that the abnormal sensitivity to serotonin agonism in panic disorder is only apparent at lower agonist doses such as were used in this study. Interestingly, when Kahn and colleagues63 repeated the MCPP challenge in a group of 8 male and 12 female patients they found augmented prolactin and ACTH responses only in the female patients. They suggested that the abnormality in serotonin receptor sensitivity may be limited to female panic patients. Germine et al44 also reported abnormal prolactin responses in female panic patients in response to an intravenous challenge with MCPP, although, in contrast to the previous findings with the oral MCPP challenge, they reported a blunted, not augmented, prolactin response. The reason for these contradictory findings is unclear. Studies using other direct serotonin agonists generally have found evidence for abnormal serotonin receptor responses among patients with panic disorder. Lesch and colleagues73 challenged panic patients and controls with the 5-HTlA agonist ipsapirone and found the panic patients to have impaired hypothermic responses and blunted ACTH and cortisol responses. Targum and Marshall135 reported augmented anxiety responses and abnormally elevated cortisol and prolactin responses to oral fenfluramine (an indirect agonist that promotes serotonin release and blocks serotonin reuptake) in a group of female panic patients compared with female depressives and normal controls. These findings have since been replicated in two of three studies that used fenfluramine as the challenge agent. 3, 61 ' 132 In the one negative study, however, subjects were given only 30 mg of fenfluramine rather than the 60 mg used in the other studies. 61 When panic patients with and without alcoholism

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Table 2. SEROTONERGIC CHALLENGE STUDIES IN ANXIETY DISORDERS Authors

Subjects (Number)

Challenge Agent (Dose)

Findings

Charney & Heninger1•

PD (23) NC (21)

L-tryptophan

PRL increase PD = NC

Westenberg & den Boer'"

PD (7) NC (7) (all females)

5-HTP (60 mg, IV)

13-END increase PD = NC CORT increase PD = NC

Charney et al' 9

PD (23) NC (19)

MCPP (0.1 mg/kg, IV)

ANX increase PD = NC PROL increase PD = NC CORT increase PD = NC GH increase PD = NC

Kahn et al 64

PD (10) DEP (10) NC (11)

MCPP (0.25 mg/kg, PO)

ANX PD > DEP = NC Panic attacks PD > DEP = NC

Kahn et a1•2

PD (13) NC (15)

MCPP (0.25 mg/kg, PO)

CORT increase PD > NC

Kahn et al•3

PD (20) NC (20)

MCPP (0.25 mg/kg, PO)

CORT increase PD > NC females only PRL increase PD > NC females only

Germine et al44

PD (29) NC (22)

MCPP (0.05 mg/kg, IV)

PRL increase NC > PD females only

Lesch et al73

PD (14) NC (14)

lpsapirone (0.3 mg/kg, PO)

Body temp decrease PD < NC ACTH increase PD < NC CORT increase PD < NC

Targum & Marshall135

PD (9) DEP (9) NC (9) (all females)

Fenfluramine (60 mg, PO)

ANX increase PD > Dep = NC PRL increase PD > Dep = NC CORT increase PD = Dep, PD > NC

Targum 132

PD (17) PD + DEP (12) DEP (27) NC (12)

Fenfluramine (60 mg, PO)

ANX increase PD = PD + DEP > DEP = NC PRL increase PD > PD + DEP = DEP = NC CORT increase PD > PD + DEP = DEP = NC

Targum' 34

PD/L +(PD) NC (8)

Fenfluramine (60 mg, PO)

CORT increase PD/L + > NC

Apostolopoulos et al3

PD (11) NC (12)

dl-Fenfluramine (30 mg, PO)

PRL increase PD > NC

Judd et al61

PD (16) NC (14)

dl-Fenfluramine (30 mg, PO)

PRL increase PD = NC CORT increase PD = NC

George et al41

ALC (19) (14 males) ALC + PD (10) (9 males) PD (6) (all females) NC (10) (5 females, 5 males)

Clomipramine (12.5 mg IV)

1. PRL increase ALC = ALC + PD = PD= NC 2. CORT increase ALC = ALC + PD = PD = NC 3. ANX/DEP response PD = PD + ALC > ALC = NC

Germine et al43

GAD (10) NC (19)

MCPP (0.1 mg/kg, IV)

Anger and ANX increase GAD > NC

da Rosa Davis et al25

GAD (8) NC (8)

Ritanserin (5 mg, PO)

Slow wave sleep increase GAD = NC

Hollander"

SP (6)

MCPP (0.5 mg/kg, PO)

Increased ANX in 4 of 6 PRL responses similar to normals

Tancer12•

SP (21) NC (22)

Fenfluramine (60 mg, PO)

PRL increase SP = NC CORT increase SP > NC

ACTH = Adrenocorticotrophic hormone; ALC = alcoholic; ANX = anxiety; ~-E N D = ~-endorphin; CORT = cortisol; DEP = depression; GAD = generalized anxiety disorder; GH = growth hormone; 5-HTP = 5-hydroxytryptophan; MCPP = M-chloro-phenyl-piperazine; NC = normal control; PD = panic disorder; PD/L + = lactate-sensitive panic disorder; PRL = prolactin.

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were challenged with intravenous clomipramine, no neuroendocrine abnormalities were noted but the panic patients demonstrated strong affective responses (depression or panic attacks) not noted in the control subjects or in the subjects with alcoholism alone. 40 The normal pattern of cortisol and prolactin responses in the panic group may be caused by a difference between fenfluramine and clomipramine in the pattern of serotonin receptor activation or possibly by the large number of male subjects included in these groups. It appears clear, however, that serotonergic agonism induces abnormal subjective responses in most panic patients and abnormal neuroendocrine responses in many female panic patients. Some observers have suggested that serotonergic stimulation induces a state of high anticipatory anxiety rather than panic anxiety. 56 Targum 134 examined this question by comparing the subjective and neuroendocrine responses of a small group of panic patients who responded positively to both lactate and fenfluramine challenges. He reported that the anxiety response to fenfluramine was more gradual in onset and more sustained than that seen with lactate. Moreover, anxiety induced by fenfluramine was associated with abnormally increased cortisol response whereas there was no evidence for change in cortisol in response to the lactate infusion. He interpreted these results as supportive of the connection between serotonin and anticipatory anxiety rather than panic anxiety. Interestingly, Targum has reported that only 36% (9 of 26) of a group of panic patients responded positively to both challenges.133 The patients who had responded positively to both challenges had experienced many more spontaneous panic attacks in the prior week than those who responded to only one of the challenges. He hypothesized that the anticipatory anxiety induced by the recent panic attacks may have contributed to the general sensitivity to challenge induced anxiety reactions. It is possible that the serotonergic abnormality is induced, in part, by the more frequent panic attacks, although trait anticipatory anxiety is also likely to contribute independently to a high panic frequency. Serotonin function is affected by a number of different variables including sex, age, 86 and seasonal factors. 9 Inconsistencies in results from different studies may be caused by, in part, differences between studies in age or sex ratio of the samples or in the time of year the studies were performed. This makes interpretation of the present studies difficult, and future studies will need to control carefully for these variables. Additionally, within the serotonin system there are numerous receptor subtypes that can differ markedly in their effects on neuroendocrine release. For example, there is some evidence to suggest that prolactin release is stimulated by 5-HTl receptors but inhibited by 5-HT2 receptors whereas cortisol release may be stimulated by both receptors. 10 The differences between challenge agents in their activity at these different receptors is likely to account for some of the inconsistent findings between studies.

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Generalized Anxiety Disorder

The efficacy of some serotonergic drugs in the treatment of GAD suggests that this system may play an important role in the pathophysiology of this disorder. In support of the relationship between GAD and serotonin, we recently found that patients with GAD have an abnormally low lumbar cerebrospinal fluid serotonin (Brewerton T, Lydiard RB, Johnson M, et al, unpublished data, February, 1995). There are few data examining the effects of serotonergic challenges on patients with GAD (Table 2). Germine et al43 demonstrated exaggerated anger and anxiety responses in GAD patients compared with controls challenged w ith intravenous administration of MCPP. One study that examined specifically the effects of a 5-HT2 antagonist on slow wave sleep found no differences in response between patients with GAD and controls. 25 These data suggest the possibility that GAD is associated with a specific abnormality in 5-HTl receptor function. Social Phobia

Patients with social phobia have been found to respond to serotonin reuptake inhibitors in several open trials 7• 127 and at least one controlled trial, 29 although the doses needed for response are typically much higher than those used to treat panic disorder or depression. In contrast to patients with GAD, controlled trials of the 5-HTlA agonist buspirone have not shown significant efficacy in the treatment of social phobia.11· 121 Moreover, clinical experience does not suggest that social phobic patients have abnormal subjective anxiety in response to medications acting as serotonergic agonists. These clinical data suggest that abnormal serotonin function may be involved in the pathophysiology of social phobia but that the nature of the dysfunction may differ from that found in panic disorder and GAD. There are few data from biologic challenges available to evaluate the validity of this hypothesis (Table 2). Hollander et al55 found that oral MCPP induced substantial anxiety responses in four of six social phobic patients challenged, but the prolactin response to the challenge did not appear abnormal. In contrast, Tancer129 recently reported normal prolactin response but abnormally enhanced cortisol responses to a challenge with oral fenfluramine. These data need to be replicated, but the presence of a specific abnormality in cortisol release suggests that social phobia might be associated with abnormal function of only a subset of serotonin receptors that also are involved in hypothalamic-pituitaryadrenal (HPA) axis regulation. Summary

The demonstrated anxiolytic efficacy of many serotonergic drugs has suggested that serotonin plays an important role in the pathophysi-

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ology of some or all of the anxiety disorders. Currently available data support the presence of some abnormality in serotonergic function associated with panic disorder but it remains unclear which receptor subtype(s) or subsystems may be involved in this abnormality, whether it is limited to certain patient subgroups (e.g., female), or whether it is related to the phenomenon of panic anxiety or anticipatory anxiety. Patients with GAD also may have disruptions in serotonergic function, and there are limited data to suggest that the abnormality may primarily involve 5-HTl receptors. Social phobia also has been associated with abnormal neuroendocrine and behavioral responses to serotonin challenge but the limited data available do not indicate clearly what aspect of serotonergic function may be abnormal. Assessment of serotonergic function is complicated by the number of factors that may influence serotonin function and by the complexity of the actions of serotonin at various receptor subtypes. Future studies will need to control for confounding variables such as age, sex, and season. Studies that use challenge agents that are specific for certain receptor subtypes will be important in better understanding the complex role serotonin plays in modulating different types of anxiety. DOPAMINERGIC FUNCTION IN ANXIETY DISORDERS Panic Disorder

Although controlled studies are lacking, clinical experience suggests that primarily dopaminergic agents such as neuroleptic medications or the antidepressant bupropion are not effective in treating panic disorder. The few studies of dopamine function in panic disorder have yielded mixed findings. Pitchot et al1°2 reported an elevated growth hormone response to the dopamine agonist apomorphine among panic patients compared with major and minor depressives, but Roy-Byrne et al116 found no difference in plasma homovanillic acid (HVA) between panic patients and controls. The latter study did, however, find a bimodal distribution of HVA values, with patients in the high HVA group being more symptomatic than patients in the low HVA group. Studies of plasma dopamine120 and CSF HVA34• 78 have failed to demonstrate abnormal dopamine metabolism in patients with panic disorder. These data do not provide strong support for the importance of dopamine in the pathophysiology of panic disorder. Social Phobia

Liebowitz and colleagues75 have speculated that social phobia might be associated with decreased central dopaminergic function. Evidence for this theory is based on a number of different observations. Clinically,

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there have been reports of social phobic symptoms developing in the course of treatment with dopamine-blocking agents.88 Medications that enhance dopaminergic activity, such as monoamine oxidase inhibitors and bupropion, have been found to be effective in treating social phobia.33· 77 Moreover, medications such as tricyclic antidepressants, which have little dopaminergic activity, appear to be much less effective in treating conditions characterized by social anxiety. 45 Biologic studies of social anxiety also have provided some support for the low-dopamine theory. Low central nervous system (CNS) dopamine activity has been found in "timid" mice, one animal model of social phobia. 85 Also, among patients with depression, lumbar cerebrospinal fluid dopamine levels were found to be associated with intraversion.66 We recently reported that the presence of comorbid social phobia among patients with panic disorder was associated with low lumbar cerebrospinal fluid HVA. 60 In the only study that used a dopaminergic challenge in social phobic patients, however, Tancer129 found no differences between social phobic patients and matched controls in either of two measures of dopamine activity, the eye-blink and prolactin responses to levodopa. Summary

The limited efficacy of primarily dopaminergic drugs in treating anxiety suggests that dopamine may play a less substantial role in mediating anxiety than it does in the mediation of affective and psychotic disorders. Nevertheless, the data that are available cannot exclude the possibility of abnormal dopamine function in at least some patients with panic disorder. Social phobia has been linked theoretically to abnormal dopamine function but the limited data available have not yet supported this association. More studies examining this system would be useful in clarifying the role of dopamine in the pathophysiology of the anxiety disorders. GABA/BENZODIAZEPINE FUNCTION IN ANXIETY DISORDERS Panic Disorder

Evidence that the GABA/benzodiazepine complex plays a significant role in the physiology of anxiety comes in part from studies of normals who have experienced severe anxiety reactions to agents that act as inverse agonists at the benzodiazepine receptor.31 · 39 The efficacy of benzodiazepines in treating panic disorder suggests that this system may be involved in the pathophysiology of panic. Surprisingly, there have been few studies examining function of the GABA/benzodiazepine system in panic patients.

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Peripheral platelet benzodiazepine receptors were found in one study to be significantly lower in patients with panic disorder than in patients with obsessive-compulsive disorder or in normal controls. 80 The authors cite animal studies in which peripheral benzodiazepine receptor levels changed in parallel to central receptor levels to hypothesize that there may be a similar decrease in receptor density in the central nervous system. Roy-Byrne and colleagues have reported a series of studies demonstrating that benzodiazepines have less effect on saccadic eye movement velocity and plasma catecholamines in panic patients compared with normal controls, 113• 115 although no difference in the effect of benzodiazepines on neuroendocrine responses was found. 114 This suggests that panic disorder may be associated with a decreased reactivity of benzodiazepine receptors in some, but not all, areas of the CNS. It also has been suggested that panic anxiety might result from abnormally high levels of an endogenous substance acting as an inverse agonist at the benzodiazepine receptor. Nutt et al95 tested this hypothesis by giving intravenous doses of flumazenil, a benzodiazepine receptor antagonist, to 10 panic patients and 10 controls. If an endogenous inverse agonist were present, the authors expected the benzodiazepine receptor antagonist to reduce anxiety in the patients. What was found, however, was that flumazenil caused panic attacks in 8 of 10 patients compared with 0 of 10 controls. Woods et al1 48 reported similar findings, w ith panic attacks occurring in 4 of 10 patients given 200 mg of oral flumazenil. These data have led Nutt and colleagues to hypothesize that some panic patients may have an alteration in their benzodiazepine receptor "set point." They suggest that this "receptor shift" causes antagonists to act like inverse agonists and agonists to be less potent This observation has been used to explain why patients with panic disorder may require higher doses and higher-potency benzodiazepines to obtain symptom control than do patients with other anxiety disorders.

Generalized Anxiety Disorder

Although GAD has been demonstrated to respond to treatment with benzodiazepines, there are few data available that examine the function of this system in patients with this disorder. The neuroendocrine response to diazepam did not differ among patients with GAD, panic disorder, and normal controls in one study.114 Patients with GAD have, however, been found to have abnormally low levels of peripheral lymphocyte benzodiazepine receptors, which normalize after treatment with benzodiazepines. 35 This suggests that GAD, like panic disorder, might be associated with an abnormal down regulation of benzodiazepine receptors, although the expected decrease in response to benzodiazepines has not been found.

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Summary

Given the well-established efficacy of benzodiazepines in the treatment of most anxiety disorders, the lack of biochemical data that examine the function of this system in anxiety patients is quite striking. The limited data available have suggested that patients with panic disorder have an abnormal sensitivity to antagonism of the benzodiazepine receptor site and some decreased sensitivity to the effects of benzodiazepines. Some patients with GAD have down-regulated benzodiazepine receptors, although it is not clear whether they also have a decreased receptor response to benzodiazepine agonists. More studies need to be done to further clarify the role of this system in the pathophysiology of the anxiety disorders. CHEMORECEPTOR FUNCTION IN ANXIETY DISORDERS Panic Disorder

The anxiogenic effects of lactate infusion and carbon dioxide inhalation procedures have been documented extensively. Among patients with panic disorder, the rate of panic in response to lactate infusion has been reported to range from 26% 70 to as high as 100%4 with an average rate of about 67% compared with 13% in normal controls. 22 The attacks produced by lactate infusion are similar to those experienced during naturally occurring panic30 and are blocked by pharmacologic treatment of panic disorder.14, 24, 3s, n2, 151 Inhalation of either a 5% to 7% or a 35% carbon dioxide mixture, which induces anxiety in a small percentage of nonanxious controls, has been found to induce panic attacks in a high proportion of patients with panic disorder. 46, 49, 52, 57, 99-1oi, 106, 146 Carbon dioxide- induced panic is subjectively similar to naturally occurring panic attacks 117 and is also blocked by treatment with benzodiazepines 147 or tricyclic antedepressants.145 The mechanism by which these challenges induce panic has been proposed to involve acute changes in vagal tone41 or in GABA receptor function .119 Papp and colleagues98 have hypothesized that the biologic abnormality responsible for lactate sensitivity involves hypersensitive brain stem chemoreceptors. They also speculated that some of the medications used to treat panic may in part act by decreasing the sensitivity of these chemoreceptors. Klein elaborated on this idea by presenting evidence to suggest the existence of a "suffocation alarm," which is normally activated by rising C02 and lactate levels associated with suffocation. He hypothesizes that the response threshold for this "suffocation alarm" is abnormally depressed in many patients with panic disorder, causing chronic hyperventilation, which adaptively reduces C02 levels below this threshold.

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An alternative hypothesis attributes the anxiety response to these challenges to catastrophic misinterpretation of the induced physical sensations.104 This hypothesis is supported by studies demonstrating that cognitive instructions prior to a lactate or C0 2 challenge substantially reduced the anxiety response 105· 141 and that patients who believed they could control a C02 inhalation had substantially reduced anxiety responses compared with patients who believed they had no control. 118 Interestingly, intravenous lactate infusions of panic patients and controls during stage 3 and 4 sleep have not been found to induce panic attacks, but have been found to produce greater physiologic responses in the patients as compared with controls. 67· 68 The results from these sleep lactate infusions suggest that lactate stimulation of a full panic attack is facilitated by conscious cognitive activity, but they also suggest that lactate induces abnormal physiologic arousal in the absence of significant cognitive activity. It is likely that both biologic and psychological factors are important in the etiology of panic attacks induced by lactate and C02 • Generalized Anxiety Disorder

We are aware of only two studies examining the response of patients with GAD to lactate infusion (Table 3). LaPierre et aF0 found that the rate of lactate-induced panic among a group of patients with DSMIII-diagnosed GAD (13%) did not differ from a group of patients with panic disorder (26%). In this study, a panic attack was defined as the patient signaling that they were having panic symptoms. History of panic attacks among the GAD patients was not reported. Cowley et al23 reported a lactate-induced panic rate of 41 % among panic patients and 11 % among patients with DSM-III-diagnosed GAD without a history of panic attacks. In this study, a panic attack was defined as the development of enough symptoms to meet DSM-III criteria for a panic attack (defined as a positive response) as well as being defined by the patient as sudden in onset and similar to the attacks experienced spontaneously. When the patients who had a positive response were included in the analysis, the rate of response to lactate was 56% among patients with GAD and 55% among patients with panic disorder. These results are complicated by differences in patient selection, but both studies indicate that patients with GAD have stronger than normal anxiety responses to lactate infusion. The rate of panic response, however, appears lower than that seen in panic patients although this is likely to depend upon the presence or absence of a history of panic attacks in the GAD patients. Patients with GAD also have been found to have low rates of panic in response to C0 2 inhalation (Table 3). Gorman et al46 reported that none of three patients with DSM-III-diagnosed GAD had panic responses to 5% C0 2 inhalation. Similarly, Holt and Andrews 57 reported that 5% C02 induced panic attacks in none of the 10 DSM-III-diagnosed GAD patients (with no history of panic attacks) compared with 64% of the agoraphobic patients, 44% of the panic patients, 21 % of the social

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Table 3. LACTATE AND C0 2 CHALLENGE STUDIES IN GAD, SOCIAL PHOBIA, AND SPECIFIC PHOBIA Authors

Subjects (Number)

Challenge Agent (Dose)

Findings

LaPierre et al 70

PD (23) GAD (16)

Lactate (0.5 M, 10 mUkg, IV, 20 min)

PA%: PD = 26, GAD = 13

Cowley et al 23

GAD (9) PD (22 NC (10)

Lactate (0.5 M, 10 mUkg, IV, 20 min)

PA%: PD= 41, GAD= 11, NC= 0 Anxiety response : GAD = PD> NC

Holt & Andrews 57

GAD (10) soc (19) AG/PA (25) PD (25) NC (16)

C02 (5%, 8 min)

PA%: AG/PA = 64, PD = 44, SOC= 21, NC= 6, GAD= 0 Anxiety response: AG/PA = PD > SOC = GAD = NC

Rapee et al 106

GAD (33) soc (38) SP (27) PD (35) PDA (40) NC (25)

C02 (5.5%, 15 min)

PA% (liberal criteria): PD = 66, PDA = 64, GAD = 33, SP = 30, SOC = 27, NC = 12 PA% (conservative criteria): PD = 49, PDA = 33, GAD = 21,SP = 19,SOC = 16, NC = 0

Liebowitz et al76

soc (15) AG (9) PD (20)

Lactate (0.5 M, 10 mUkg, IV, 20 min)

PA%, PD = 50, AG = 44, soc= 17

Gorman et al 46

soc (8) GAD (3) PD (31) NC (13)

C02 (5%, 20 min)

PA%: PD = 39, NC = 8, SOC = 0, GAD = 0

Gorman et al 46

soc (3) PD (9) NC (6)

C02 (7%, 20 min)

PA%: SOC = 100, PD = 67, NC= 0

Gorman et al 50

soc (22) PD (26) NC (14)

C02 (35%, doublebreath)

PA%: PD = 50, SOC = 36, NC= 21

Papp et al 98

soc (20) PDA (18) NC (23)

C02 (35%, 30 sec)

PA%: PDA = 72, SOC = 30, NC= 4

Verburg et a1 1 • 2

SP-Anm (13) SP-Sit (15) NC (30)

C02 (35%, singlebreath)

Anxiety response: SP-Sit > SP-Anm = NC

AG/PA = Agoraphobia with panic attacks; Dep = depression; NC = normal control; PA = panic attack; PD = panic disorder; PDA = panic disorder with agoraphobia; SOC = social phobia; SP = specific phobia; SP-Anm = animal phobia; SP-Sit = situational phobia.

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phobic patients, and 6% of the normal control (NC) group. The somatic and psychic anxiety responses of the GAD patients were significantly less than those seen in the panic/ agoraphobic patients although they were consistently, but not significantly, greater than the responses among controls. The anxiety-related cognitive responses, particularly the fears of impending doom, occurred only among the panic/ agoraphobic patients. These results contrast somewhat from Rapee et al1° 6 who reported a somewhat higher rate of panic and anxiety in response to 5.5% C0 2 challenge among a group of 33 patients with a primary diagnosis of DSM-III-R GAD. Using a liberal definition of panic attack, they found that 5.5% C0 2 inhalation induced panic attacks in approximately 33% of patients with GAD compared with 64% of patients with panic and agoraphobia, 66% of patients with panic disorder without agoraphobia, 27% of patients with DSM-III-R social phobia, 30% of simple phobic patients, and 12% of nonanxious controls. Using a conservative definition, these panic rates were approximately 21 %, 33%, 49%, 16%, 19%, and 0%, respectively. Although the rate of panic attacks was lower in the GAD group, with the exception of the cognitive symptom intensity, the anxiety responses were not different than those in the panic groups. In this study, Rapee and colleagues used patients with DSM-III-R diagnosed GAD but did not exclude patients who had a history of panic attacks or even a history of panic disorder. It is unclear whether either or both of these factors may have accounted for the high rates of panic and anxiety responses found. Taken together, the results of these studies suggest that, compared with patients with panic disorder, patients with GAD respond to lactate infusion with a lower rate of panic attacks but a comparable degree of somatic and physical anxiety response. Although GAD patients appear to be less sensitive to 5% C0 2 inhalation than are patients with panic disorder, methodologic differences between the studies make it difficult to draw firm conclusions. A history of panic attacks may be an important factor in determining C0 2 or lactate sensitivity. Also, it is unclear whether the changes in diagnostic criteria from DSM-III to DSM-IV will make a difference in the types of patients chosen for these studies. Studies that use patients with DSM-IV-diagnosed GAD with and without panic attacks will be helpful in clarifying these issues. Social Phobia

In the only study we are aware of that has tested the lactate sensitivity of social phobic patients, Liebowitz and colleagues76 reported that panic attacks occurred during lactate infusion in 10 of 20 panic patients, 4 of 9 agoraphobic patients, but only 1 of 15 patients with DSM-III- diagnosed social phobia (a rate similar to that found among nonanxious controls). The C0 2 sensitivity of social phobic patients has been studied more extensively and, although social phobic patients do appear to be more

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sensitive than nonanxious controls to C0 2 challenge, they are generally less sensitive than patients with panic disorder. As reported previously, Holt and Andrews 57 found the rate of induced panic attacks with 5% C02 inhalation in DSM-III-diagnosed social phobic patients (21 %) to be greater than that for controls but less than that for panic patients. This rate was comparable to the 27% panic rate (16% using more conservative criteria for panic) reported by Rapee et al. 106 In both of these studies, the social phobic patients also were rated as having significantly less intense somatic and cognitive anxiety reactions to C02 than did the panic patients. Social phobic patients appear to have responses more similar to those of panic patients when higher concentrations of inhaled C0 2 are used (Table 3). Gorman and colleagues 46 reported that 5% C0 2 inhalation induced panic attacks in 12 of 31 panic patients, 0 of 8 DSM-IIIdiagnosed social phobic patients, and 0 of 13 normal controls. When a subgroup of subjects was given a 7% C0 2 challenge, however, panic attacks occurred in 6 of 9 patients with panic disorder, 3 of 3 patients with social phobia, and 0 of 6 controls. In another study using 35% C0 2 , the rate of panic among 26 panic patients (50%) was not significantly different from the panic rate among 22 DSM-III-diagnosed social phobic patients (36%). 50 The rate of panic response in both groups differed from that found in normal controls (21 %). When this study was later replicated, 99 the two groups did differ, but the difference appeared to be related more to a higher rate of panic among the panic patients (72%). The panic rate among the DSM-III-R-diagnosed social phobic patients in this later study (30%) was comparable to that seen in the earlier study, and was significantly greater than that seen among the normal controls (4%). Although the methods used in these studies differ in some ways (e.g., diagnostic criteria used for social phobia), these data suggest that social phobic patients may have a chemoreceptor sensitivity that is somewhere between that of normals and patients with panic disorder. Simple/Specific Phobia

Two studies have examined the response to C0 2 challenge of patients with simple/specific phobia (Table 3). The group of simple/ specific phobic patients reported in the study by Rapee et al 106 were found to have rates of panic induced by C0 2 inhalation that were less than those seen in panic patients, greater than those seen in nonanxious controls, and similar to panic rates among patients with GAD and social phobia. Measures of cognitive and physical responses to the challenge were similar to those seen among social phobic patients. Although there may have been some comorbidity in this group of simple phobic patients, these data suggested that simple phobia is associated with a moderately abnormal sensitivity to C0 2 challenge. A study by Verburg et al1 42 recently re-examined this question using 35% C0 2 challenges in a group of 28 DSM-III-R-diagnosed simple/ specific phobic patients and 30 normal controls. The most striking find-

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ing from this study was that the patients with situational phobias (e.g., heights, tight spaces) had substantially greater anxiety reactions than did the normal controls whereas the patients with animal phobias (e.g., spiders) had reactions that were essentially identical to those of the controls. This suggests that the pathophysiology of the simple phobias may differ by subgroup and that situational phobia, but not animal phobia, is associated with abnormal C02 sensitivity. Summary

Hypersensitivity to C02 and lactate challenges has been demonstrated in all of the anxiety disorders evaluated here. This abnormality has been linked theoretically to dysfunction of the suffocation alarm system, which would involve, in part, hypersensitivity of brain stem chemoreceptors. The interpretation of these data are complicated, however, by the possibility that anxiety reactions are mediated primarily by abnormal cognitive reactions rather than by enhanced responsivity of brain stem receptor systems. Moreover differences in the rate of response to the two challenges suggests that these two challenges may produce anxiety responses through somewhat different mechanisms. Results also have differed depending upon the concentrations of C02 used and other differences in experimental technique. Despite these complications, there does appear to be an emerging pattern of enhanced chemoreceptor sensitivity across the anxiety disorders with the most severe abnormality being demonstrated by patients with panic disorder and more modest abnormalities seen among patients with GAD, social phobia, and simple phobias. There is also a heterogeneity within disorders that is illustrated most strikingly by the finding that C0 2 sensitivity among simple phobic patients was present only in the situational phobic patients. Clearly within other patient groups there exists a substantial proportion of patients who do not appear to have abnormal chemoreceptor sensitivity. These findings suggest that examination of patients who differ in their chemoreceptor sensitivity may lead to the identification of biologically distinct subgroups. NEUROIMAGING STUDIES IN ANXIETY DISORDERS Pan ic Disorder

Panic patients were not found to have structural abnormalities of the brain in several studies that used CT scans. 65• 69 • 72 • 139 Studies that used the more sensitive MR imaging technology, however, have demonstrated such abnormalities in a significant proportion of these patients. Fontaine et al3 6 compared the MR imaging scans of 31 DSM-IIIdiagnosed panic patients with those of 20 controls. They identified significantly more CNS lesions in the patient group (40%) compared

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with the controls (10%) . Moreover, the majority of these abnormalities involved abnormal signal activity or asymmetric atrophy in the right temporal lobe. The location of these abnormalities provided support for the hypothesis that the limbic system plays a central role in the pathophysiology of panic disorder. Ontiveros et al96 got similar results when they compared MR imaging scans of 30 lactate-sensitive panic patients with those of matched control subjects and found evidence of structural abnormalities (most involving the right temporal lobe) in 43% of the patients compared with 10% of controls. They found that the presence of a structural abnormality was associated with earlier age of disease onset and more frequent panic attacks. More recently, Dantendorfer et al, 26 demonstrated a high rate of abnormal EEG readings among DSM-III-R-diagnosed panic patients (31.4%) and, among the patients with abnormal EEG readings, a high rate (61.1 %) of abnormal MR images, with about half representing lesions within the limbic system. Abnormalities in regional cerebral blood flow patterns also have been found in studies of panic patients through the use of functional brain imaging techniques (Table 4). Reiman et al1°9 used PET imaging to study resting cerebral blood flow in lactate-sensitive panic patients and non-lactate-sensitive panic patients and normal comparison subjects. In the lactate-sensitive panic patients they identified abnormally increased whole brain blood flow and oxygen metabolic rate and an abnormal right/left hemispheric asymmetry of parahippocampal blood flow, blood volume, and oxygen metabolism compared with the non-lactatesensitive patients and controls. They suggested that this latter difference may have been caused by increased neuronal activity in the right parahippocampal area rather than a decrease in left parahippocampal activity although they could not rule out the possibility that these findings were due to structural asymmetries or differences in local blood-brain barrier permeability. This abnormal activity in the area of the hippocampus has been reported in other imaging studies of panic patients. Through the use of PET scans, Nordahl et al93 compared the cerebral glucose metabolic rates (GMR) of 12 panic patients and 30 normal volunteers during an auditory continuous performance task. The greatest differences between the groups were a relatively decreased GMR in the left inferior parietal lobe and relatively increased GMR in the occipital lobe and the right anterior frontal cortex of the panic patients. There were also trends for increased GMR in the right hippocampal region and anterior medial orbital frontal cortex and for decreased GMR bilaterally in the anterior cingulate cortex. Although patients were not identified by their lactate sensitivity, a subgroup had undergone a caffeine challenge and the author reported that the hippocampal abnormality did not appear to be related to the degree of reaction to this challenge. This would suggest that the hippocampal abnormality associated with the lactate-sensitive patients does not involve a general sensitivity to anxiogenic challenges. Abnormal blood flow in the area around the hippocampus (combined blood flow in hippocampus, parahippocampal gyrus, and amyg-

g

Table 4. FUNCTIONAL IMAGING STUDIES IN ANXIETY DISORDERS

Authors

Subjects (Number)

Scan Type (Tracer/Functions Measured)

Experimental Condition

Findings

Reiman et a1 109

PD/L + (8) PD/L - (8) NC (25)

PET At rest-eyes closed (rCBF, blood volume, oxygen metabolic rate)

1. L/R parahippocampal rCBF ratio 2. PD/L+ < PD/L - = NC

Nordahl et al92

PD (12) NC {30)

PET (GMR)

1. Decreased GMR L inferior parietal lobe 2. Increased GMR occipital and R anterior frontal cortex 3. Trend to increased G MR R hippocampal and medial

During vigiliance task

orbital frontal cortex 4. Trend to decreased GMR R & L anterior CG DeCristofaro et al 28 PD/L + (7) NC (5)

SPECT (rCBF)

At rest-eyes open

Lepola et aF2

PD (17) NC (11)

SPECT/MRI (rCBF, BZD receptor binding)

At rest

Stewart et al 128

PD (10) NC (5)

SPECT (rCBF)

At rest and during lactate infusion

Woods et al 149

PD {6) NC (6)

SPECT (rCBF)

At rest (eyes covered , ears blocked) During yohimbine challenge , 0.4 mg/kg, IV

Reiman et a111 0

PD (24) NC (18)

PET (rCBF)

During lactate infusion

1. Decreased rCBF in R&L hippocampal region 2. Increased rCBF in L occipital, R prefrontal cortex 3. Abnormal asymmetry of frontal cortical rCBF i. 6/17 PD increased rCBF in PFC 2. 11/17 PD increased BZD receptor binding prefrontal cortex 1. Occipital rCBF increased during panic 2. Trend for decreased frontal rCBF during panic 3. Increased baseline whole brain CBF in lactatesensitive patients only 1. Increased anxiety in 6/6 PD patients and 1/6 NC 2. Decreased frontal rCBF in PD patients during yohimbine challenge 3. Abnormal R/L TH rCBF ratio in patients and in the one anxious NC 4. Increased frontal rCBF in NC 1. Increased rCBF during panic in temporal poles, subcortical area (near insula, claustrum and lateral putamen), in the midbrain area (near the PAG and superior colliculus), and in L cerebellar vermis 2. No change in NC or PD/L- patients

O'Carroll et al 95

SP mixed types (10)

......

Relaxation tape followed by audio tape description of phobia

1. Decreased RrCBF L anterior CG, R post temp cortex, R/L occipital cortex 2 . No BG changes 3. Higher anxiety associated with less RrCBF decrease

Mountz et al 89

Animal phobics (7) PET NC (8) (rCBF, rCBF corrected for Paco2)

Rest, exposure to live animal, 1. Decreased rCBF in all areas (basal ganglia, cortical, rest, exposure, rest limbic) during exposure Eyes closed during scans 2. No changes when corrected for Paco2

Wik et al' 44

Snake phobics (6) PET (RrCBF corrected for Paco2)

Neutral video Aversive video Phobic video

Fredrikson et al 37

Snake phobics (6) PET (RrCBF corrected for PAco2)

Neutral video Aversive video Phobic video

Rauch et al 107

Animal phobics (7) PET (RrCBF, no Paco2 correction)

Innocuous stimulus Visual or visual and tactile exposure to live animal (picture in one subject) Scans done during subsequent imaginal exposure with eyes closed

Davidson et al 27

Social phobics (20) MRS At rest NC (20) (metabolic activity-Cho and CR/NAA ratios)

Mathew et al 83

'I 0

SPECT (RrCBF)

GAD (9) NC (9)

Xenon inhalation (CBF, rCBF)

At rest

1. Increased RrCBF in secondary visual cortex during phobic exposure 2 . Decreased RrCBF in hippocampus, orbitofrontal cortex, PFC, temporopolar cortex, and posterior cingulate cortex during phobic exposure 1. Increased rCBF secondary visual cortex 2. No change in frontal cortex, putamen, TH or caudate 3 . Cortical and TH rCBF correlated only during phobic exposure Increased RrCBF in L post med orbitofrontal cortex, L insular cortex, L TH, R anterior temp cortex, anterior CG, L somatosensory cortex

1. Caudate and TH metabolic activity SOC < NC 2 . Social anxiety inversively associated with TH activity

1. Global CBF nonsignificantly decreased among GAD patients 2 . CBF inversely related to state anxiety Table continued on following page

~

N

Table 4. FUNCTIONAL IMAGING STUDIES IN ANXIETY DISORDERS (Continued)

Authors

Subjects (Number)

Mathew & Wilson•2 GAD (13) NC (13) Buschbaum et al 12 GAD (18}

Wu et al 159

GAD (18) NC (15)

Scan Type (Tracer/Functions Measured)

Experimental Condition

Findings

Xenon inhalation (CBF, rCBF) PET (GMR , RGMR)

At rest During 5% C0 2 inhalation

1. C02 -induced CBF increase GAD = NC 2. CBF change inversely associated with anxiety

At rest During vigilance task before and after 3 weeks BZD or PBO treatment

1. Decreased GMR in visual cortex during treatment 2. Increased RGMR in BG and TH

PET (GMR , RGMR)

At rest During vigilance task before and after 3 weeks of BZD or PBO treatment

1. Basal ganglia, temporal poles, cortex, CG resting rGMR GAD < NC 2. Cerebellum, L occ cortex, R pos R precentral frontal cart resting GAD > NC 3. BG, parietal lobe rGMR task > 4. Temporal and occipital cortex task < rest 5. BZD treatment caused decreased GMR except increase in medial cortex 6. Anxiety reduction in PBO associated with increased GMR

BG = Basal ganglia; BZD = benzodiazepine; CG = cingulate gyrus; Cho = choline ; CR = creatinine; GMR = glucose metabolic rate; MRS = magnetic resonance spectroscopy; NAA = n-acetyl aspartate; NC = normal control; PAG = periaqueductal gray; PD = panic disorder; PD/L- = lactate nonresponders; PBO = placebo; PET = positron emission tomography; PFC = prefrontal cortex; R = right; rCBF = regional cerebral blood flow; RrCBF = relative regional cerebral blood flow; SPECT = single photon emission computed tomography; TH = thalamus.

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dala) also was reported by De Cristofaro et al,2 8 who compared single photon emission computed tomographic (SPECT) brain images of seven lactate-sensitive panic patients with those of five normal volunteers. They found evidence among the panic patients of significantly decreased resting blood flow in both the right and left hippocampal areas and significantly increased resting blood flow in the left occipital cortex. Trends also were reported for increased regional cerebral blood flow (rCBF) in the right inferior frontal cortex, the right occipital cortex, and the left temporal pole. The panic patients also had a greater right/left asymmetry for CBF in the inferior frontal cortex than did the controls, indicating greater right frontal perfusion in the patients. The decreased rCBF in the right and left hippocampal region reported by De Cristofaro et al appears to contrast with the apparently increased rCBF in the right parahippocampal gyrus reported by Nordahl et al92 and Reiman et al. 109 This difference could be attributed to technical differences between the studies. The use of SPECT imaging resulted in a lower image resolution, and the rCBF measure included other structures, such as the amygdala, which were not included in the two PET studies. Additionally, in both of the studies that demonstrated increased parahippocampal activity, patients were scanned with their eyes closed. In contrast, in the De Cristofaro study, patients were scanned with their eyes opened. Finally, the De Cristofaro study included patients who had never been treated with antipanic medication other than episodic benzodiazepine use whereas the other studies included previously treated patients. This factor suggests that the patient populations might have differed in their illness severity or in the effects of prior pharmacotherapy on brain activity. Nevertheless, there appears to be a consistently demonstrable abnormality in brain function in the area of the hippocampus among a subgroup of panic patients. Increased activity in the right frontal cortex found in these studies also was found in a recent study that used SPECT imaging,71 which demonstrated increased rCBF as well as increased benzodiazepine receptor density at rest in the right prefrontal cortex of some, but not all, patients with panic disorder (lactate sensitivity was not evaluated). Additionally, some of the patients had a panic attack during the scan and the occurrence of an attack was associated with this increased right prefrontal activity and greater benzodiazepine receptor density. The rCBF in the parahippocampal region was not reported. Taken together, these data suggest that elevated frontal cortex activity, particularly on the right side, is present in a large group of panic patients. It is possible that the increase in frontal benzodiazepine receptor density reflects a counter-regulatory increase of these receptors in response to chronically increased prefrontal activity in these patients. Several studies have examined rCBF in panic patients during experimentally induced anxiety states (Table 4). Through the use of SPECT scans, Stewart et al1 28 studied rCBF changes in panic patients and controls during lactate infusions. They reported significantly increased occipital rCBF during lactate-induced panic attack and a trend toward

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significantly decreased rCBF in the frontal lobes in the patients who panicked but not the non-lactate-sensitive patients or the nonanxious controls. Additionally, they reported abnormal baseline increases in whole brain blood flow among the lactate-sensitive patients, which confirmed the finding by Reiman et al. 109 Limbic, basal ganglia, and midbrain areas were not examined in this report. Woods et al1 49 challenged six panic patients and six matched controls with yohimbine and assessed changes in rCBF using SPECT scans. They found significant decreases in frontal cortical blood flow among patients (all experienced increases in anxiety) in comparison with controls (only one experienced increased anxiety) who actually showed increased frontal cortical flow. They also noted differences between the groups in thalamic blood flow symmetry, which did not reach statistical significance. Interestingly, the only control subject who experienced yohimbine-induced anxiety demonstrated the thalamic abnormality found among the panic patients. No changes were noted in the other cortical areas or in the basal ganglia. Using PET technology, Reiman et al110 found that lactate-induced panic attacks were associated with blood flow increases bilaterally in the temporal poles, bilaterally in the area near the insula, claustrum, and lateral putamen, bilaterally in the area near the midbrain periaqueductal gray and superior colliculus, and in the left anterior cerebellar vermis. Changes in cortical function were not reported. No significant changes in blood flow was noted in the nonpanicking patients or in the normal controls, although there was a consistent trend among the control subjects for blood flow increases in the area near the periaqueductal gray and superior colliculi and in the left anterior cerebellar vermis. The authors suggested that the blood flow cha~
Functional imaging studies of phobic patients undergoing exposure have yielded some apparently contradictory results (Table 4). O'Carroll et al95 studied 10 p atients with simple phobia by comparing SPECT

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brain scans taken during relaxation and during phobic exposure. The phobic exposure was done by having patients listen to an audiotaped description of their feared object or situation. They found significant rest-to-exposure decreases in brain activity in the left anterior cingulate gyms, right posterior temporal cortex, and bilaterally in the occipital cortex. There were no changes noted in the frontal lobe, the thalamus, the caudate, or the putamen. Unexpectedly, the degree of brain activity was not correlated generally w ith measures of state anxiety. When there were correlations, higher anxiety was associated with less decrease in brain activity. The authors noted that areas such as the occipital cortex have a high density of GABA complexes and that decreased brain activity mediated through increased activation of these complexes actually may reflect an effective defensive response that would be associated with less anxiety. Mountz et al89 studied seven patients with animal phobias by comparing their resting PET scans to scans from a group of eight normal controls and to the patient scans during exposure to a phobic object held directly over them (snake, spider, or rat) was held. They analyzed scans for measures of CBF in the brain as a whole and within several specific brain areas including the parahippocampal cortex, the caudate and lentiform nuclei, the thalamus, the orbitofrontal cortex, and the visual cortex. They found decreases in whole brain and regional blood flow during fear states but when they corrected for fear-induced hypocapnia, these changes disappeared. They also found no differences between patients and controls in baseline measures of whole brain and regional blood flow. Wik et al144 used PET scans to study relative rCBF (ratio of regional to whole brain blood flow) changes in six female snake phobic patients during visual exposure to a neutral stimulus (a video depicting people walking in a park), an aversive stimulus (a video depicting authentic war scenes and an execution), and a phobic stimulus (a video of snakes). Relative rCBF was found to be increased in the secondary visual cortex, and decreased in the hippocampus, prefrontal cortex, orbitofrontal cortex, temporopolar cortex, and posterior cingulate cortex only during the phobic exposure condition. The authors suggested that the use of relative rCBF eliminated potential errors in the correction for changes in Paco2, which may have affected the results of previous studies. In the discussion on the pattern of rCBF decreases in multiple cortical areas and in the hippocampus, the authors speculated that these changes might be related to a fight-or-flight condition elicited by phobic exposure. In this condition, the organism would be expected to divert resources from cognitive and evaluative processes taking place in the cortex and limbic structures, into increased activity of areas associated with sympathetic activation and defensive behavioral responses. Theoretically, then, it would be likely that phobic exposure would be associated with relatively increased blood flow in areas of the brain associated with behavioral and autonomic activation such as the brain stem and basal ganglia. Unfortunately, these structures were not evaluated in this study. The increased rCBF in the visual cortex reported in this study contrasted

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with the decreased occipital flow reported by O'Carroll et al95 and with the absence of visual cortex rCBF change reported by Mountz et al. 89 The authors suggested that the absence of visual cortex activation in the Mountz study may have been due to the technique they used of presenting the phobic object prior to the scan and having the patient's close their eyes during the scan. The O'Carroll study differed in both the imaging technique (i.e., SPECT vs. PET) and by the use of an auditory rather than visual mode for inducing phobic anxiety. Fredrikson and colleagues37 used basically the same experimental technique as was used in the study by Wik et al1 44 and found a similar increase in rCBF in the secondary visual cortex but, in contrast to a phobia-induced decrease in certain parts of the frontal cortex, they found no changes in frontal cortex rCBF. Given the similar experimental techniques used, these differences are hard to reconcile, but it is possible that small differences in analysis of imaging data may have contributed to these contrasting findings. Although no significant phobia-induced rCBF changes were noted in the subcortical areas, significant correlations were found between rCBF in the thalamic and cortical areas during phobic stimulation that were not apparent during the neutral and aversive stimulus conditions. The authors noted that this finding gave support to the hypothesis that the thalamus acts as an important relay station for stimulus processing during phobic fear. Moreover, nonsignificant increases in rCBF noted in several subcortical structures (caudate, putamen, thalamus) during phobic exposure would be consistent with the theoretical activation of these structures under fight-or-flight conditions. Rauch et al1°7 studied the PET scans from seven animal/insect phobic patients before and during exposure to the feared object. With the exception of one patient who was presented with a picture of a snake, the rest of the subjects were shown live animals/insects during the exposure phase of the test that consisted of three of the six subjects actually touching the container with the phobic object. Measures of rCBF normalized to whole brain blood flow demonstrated significantly increased blood flow in the left posterior medial orbitofrontal cortex, left insular cortex, left thalamus, right anterior temporal cortex, anterior cingulate cortex, and left somatosensory cortex. They did not find any significant rCBF changes in the parahippocampal gyms, the anterior medial orbitofrontal cortex, the amygdaloid complex, or in any other brain region. These results differ from the previous studies in several interesting ways. Unlike the studies by Fredrikson et al3 7 and by Wik et al,1 45 no blood flow changes were found in the visual association cortex. They did, however, report increased blood flow in the somatosensory cortex. This difference was interpreted as reflecting the different sensory modalities used for exposure (visual vs. tactile or imaginal), causing activation of cortical areas involved with processing these different sensory modalities. The increased flow found in many paralimbic structures as well as parts of the orbitofrontal cortex is also in contrast to the data from Wik et al, 144 which demonstrated decreased relative rCBF in the hippocampus, prefrontal cortex, orbitofrontal cortex, temporopolar

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cortex, and posterior cingulate cortex, and to the report by Fredrikson37 in which no changes in frontal cortical rCBF were found . The different findings lead to quite opposite conclusions regarding the involvement of frontal and paralimbic structures in phobic anxiety. The use of imaginal versus visual exposure during imaging may be important in explaining these results. A study of patients with obsessive-compulsive disorder under separate conditions of imaginal and in vivo exposure found that imaginal exposure was associated with increased blood flow in most cortical areas whereas in vivo exposure was associated with decreased blood flow in these areas. 152 The reason for such substantial differences in the pattern of cerebral activation under conditions of imaginal versus in vivo exposure is unclear but will need to be accounted for in future imaging studies of phobic exposure. Overall, differences in experimental technique have likely contributed to the presence of apparently contradictory findings concerning the pattern of cerebral activation during phobic exposure. The current data demonstrates that phobic exposure induces significant changes in the pattern of cortical activation but that these changes depend upon the nature of the phobic exposure. Visual/in vivo exposure appears to induce activation in the visual association cortex and is associated with reduced or unchanged activity in certain frontal and paralimbic cortical structures. Imaginal exposure appears to induce a pattern of increased activity in somatosensory, paralimbic, and certain frontal cortical structures. The thalamus may be activated during both types of exposure and appears to be associated positively with changes in cortical activity. This association suggests that the thalamus may function as a relay station for emotionally relevant sensory information during anxiety states. The role of other basal ganglia structures, limbic structures, and brain stem structures during phobic anxiety states remains unclear although enhanced basal ganglia and midbrain activity might be predicted to occur during states of severe anxiety. Future studies of brain activity during phobic exposure will need to more fully assess these areas. Social Phobia

In the only available study of functional brain activity among social phobic patients, Davidson and colleagues 27 reported a study of MR spectroscopy in 20 social phobic patients and 20 age- and sex-matched controls. They used the stimulated echo acquisition mode (STEAM) volume element localization (voxel) technique with chemical shift imaging in order to derive measures of localized physiologic activity in specific brain regions. They found that in the resting state, the social phobic patients had lower levels of CNS metabolic activity in certain cortical and noncortical gray matter areas including the caudate nucleus. They speculated that these abnormalities might be caused by a lower number of neurons or a decrease in neural activity in these areas. They also reported low signal-to-noise ratios (SNR- an approximation of the

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local concentration of these chemical metabolites) for choline and creatine in the thalamus and caudate nucleus, and for N-acetylaspartate (NAA) in the thalamus and caudate. The severity of social phobic fear was related to concentrations of these metabolites only in the thalamus. Measures of avoidance and physiologic arousal did not correlate with any of the metabolite concentrations. The authors admit that the meaning of the SNR measures is currently vague but, nevertheless, these findings are intriguing. They speculated that the NAA SNR might be a neuronal marker and that low levels might reflect a decrease in the local concentration of neurons. The decreased choline SNR might reflect a lower rate of acetylcholine production or a reduced rate of membrane turnover. Because choline activity is modulated by dopaminergic and serotonergic neurons, they speculated that this abnormality may be secondary to abnormal function in one or both of these neuronal systems. The significance of the reduced creatine SNR is also unclear but they proposed that it might be a marker of the local "energy state." They also reported follow-up data from four subjects who had participated in a double-blind trial of clonazepam and found evidence that many of these measures were reversible with treatment. Overall, they suggested that these findings pointed to the importance of state-dependent abnormalities in caudate and thalamic function associated with social phobia and that these abnormalities may be related to dysfunction of serotonergic or dopaminergic neurons. In support of this hypothesis, they cited the finding of reduced levels of dopamine and D1 and D 2 receptors in the caudate nucleus of a socially inhibited mouse strain.85 Although still quite experimental, these data do provide some additional support for the importance of dopaminergic and possibly serotonergic mechanisms in the pathophysiology of social phobia. Generalized Anxiety Disorder

Neuroimaging studies of rCBF and cerebral GMR of patients with GAD have yielded some interesting but contradictory data (Table 4). An early study of nine DSM-III-diagnosed patients with GAD81 using xenon inhalation (a two-dimensional technique in comparison with PET and SPECT scanning, which are three-dimensional techniques), which assesses blood flow primarily in the cortical areas, found that under resting conditions, the pattern of global and rCBF did not differ between patients and controls. They did, however, note that anxiety measures for both groups were inversely correlated with measures of cortical rCBF. The same group82 reported a similar finding in a more recent study in which the same technique was used to assess changes in CBF in 13 GAD patients and 13 matched controls before and during 5% C02 inhalation. Both groups showed comparable increases in CBF during C02 inhalation although neither group showed significant changes in measures of state anxiety. In fact, about half of all the subjects in both groups actually experienced a decrease in anxiety. Their most interesting

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finding was that for both groups, the subjects who had decreased anxiety showed significantly greater increases in CBF than did those who had increased anxiety. Through the use of PET scans to assess GMR, Wu et al150 studied a group of 18 patients with DSM-III-diagnosed GAD and 15 normal controls at rest and during a vigilance task, and then repeated scans on patients following 3 weeks of treatment with either a benzodiazepine or placebo. In the resting pretreatment condition, the GAD patients demonstrated significantly reduced absolute metabolic rates in the basal ganglia (average of caudate, putamen, and globus pallidus), in the temporal poles, in the superior temporal lobe, and in the cingulate gyms. The metabolic rates in the amygdala and hippocampus also were reduced but this difference was not significant. When relative metabolic rates (the ratio of local metabolism to whole brain metabolism) were analyzed they found evidence for a higher resting metabolic rate among the patients in the cerebellum, the left inferior area 17 in the occipital lobe, right posterior temporal lobe, and the right precentral frontal gyms. Notably, they found no evidence for abnormal right/left asymmetry in the parahippocampal gyrus as has been seen in panic disorder. Overall, then, baseline metabolic rate among GAD patients appeared to have been reduced in the basal ganglia, the cingulate gyrus, the temporal poles, and the superior temporal gyrus and increased in specific occipital, frontal, and temporal cortical areas. Activity in the hippocampus and amygdala was not found to differ between patients and controls. When patients were given a vigilance task, which would theoretically increase anxiety I arousal state, increased activity was noted in the basal ganglia and parietal lobe whereas a significant decrease in activity was demonstrated in the temporal and occipital lobes. No changes were found in limbic activity. The effect of the task on frontal lobe activity was not reported. Following treatment with either a benzodiazepine or a placebo, effective treatment with benzodiazepines was associated with decreased absolute metabolic rates in all brain areas (cortical, limbic, basal ganglia, midbrain) with the exception of the medial cortex, which showed increased activity after treatment. These findings are consistent with data from a previous study of patients with GAD in which cortical GMRs were found to be decreased after 3 weeks of benzodiazepine treatment. 12 The two studies differed somewhat in their findings regarding changes in the relative metabolic activity. The first study noted significant relative increases in basal ganglia activity with benzodiazepine treatment whereas the more recent study demonstrated no changes in relative basal ganglia activity. The later study did, however, find that decreases in anxiety among the placebo-treated patients were associated with relative increases in basal ganglia activity and relative decreases in limbic activity. Overall, these indicate that anxiety induced by C02 inhalation in GAD patients and normal controls is correlated inversely with global CBF. GAD is associated specifically with decreased absolute activity in

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the basal ganglia and in certain paralimbic structures (i.e., cingulate gyms, temporal poles, and the superior temporal gyms) as well as increased relative activity in the cerebellum and specific cortical structures (i.e., the left inferior area 17 in the occipital lobe, right posterior temporal lobe, and the right precentral frontal gyms). Increased stress with a vigilance task as well as decreased stress after benzodiazepine treatment were both associated with relative increases in basal ganglia activity and decreased temporal and occipital activity. Summary

Structural brain abnormalities have been found in the temporal lobe and other limbic structures in some patients with panic disorder. There are few available data examining whether similar abnormalities may be associated with the other anxiety disorders. The interpretation of data from functional imaging studies of patients with anxiety disorders has been complicated by the use of different imaging and experimental techniques that, at times, have led to seemingly contradictory findings. Nevertheless, the available data have indicated that there are some abnormalities in the pattern of cerebral activation in patients with anxiety disorders. Some panic patients have increased resting activity in the right prefrontal cortex,28, 71 and there is evidence for decreased activity in this area during panic attacks,128, 149 Increased right frontal cortex activity has been found at baseline in patients with GAD150 and during phobic exposure in simple phobic patients. 107 Increased activity in the occipital cortex has been found among panic28 ' 92 and GAD150 patients at rest and, in most studies of patients with specific phobia, during exposure involving visual stimulus presentation.37' 144 These data suggest that the frontal and occipital areas play important roles in certain types of anxiety responses. The pattern of temporal lobe activity in anxiety states was complex, with certain temporal regions showing anxiety-related increases and others showing anxiety-related decreases. Given its connections to the limbic system, it is likely that temporal lobe structures also are involved in modulating different anxiety states, but more precise imaging techniques will be required to tease out the complex pattern of interactions in this area. The responses of subcortical structures during anxiety states are also complex, and data are further complicated by differences in measurement technique. Most consistent has been the finding of abnormal activity in the area of the right hippocampus among a subgroup of a group of panic patients possibly identified by their sensitivity to lactate infusion. 28, 92, 109 Interestingly, this abnormality h as been reported as both an increased and a decreased activity in this area. At least one study of simple phobic patients demonstrated a decrease in hippocampal activity during phobic exposure. The limited data available on patients with GAD have nc:t demonstrated abnormal hippocampal activity.

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Abnormal thalamic activity has been reported in patients during panic attacks149 during phobic exposure37' 107 and in social phobic patients at rest. 27 There is some evidence that change in thalamic activity generally parallels change in cortical activity during anxiety states,37, 149 which may reflect the function of the thalamus in processing threat-related sensory information, The other basal ganglia structures have not been found to be as affected by changes in anxiety state, although when changes were noted, increased basal ganglia activity was associated with states of high and low anxiety whereas decreased basal ganglia activity was associated with moderate anxiety states. 12, 27, 3 7, no, 150 Available data suggest that the pattern of cortical response to anxiety is dependent on the nature of the anxiogenic stimulus. Data from studies of phobic anxiety, for example, have shown that visually presented threats will initiate activation of the visual cortex whereas other cortical areas will be activated to process threat stimuli received from other sensory systems, The importance of the type of anxiogenic stimulus in the pattern of cortical response also was demonstrated in a study of patients with obsessive-compulsive disorder in which anxiety induced by imaginal flooding caused increased blood flow to all the cortical areas studied, particularly in the temporal lobes, whereas anxiety induced by in vivo exposure caused decreased activity in all these same areas,153 The severity of the stressor is also likely to be involved in determining the nature of the cortical response. There have been a number of studies demonstrating an "inverted U" -shaped relationship between cerebral metabolism/blood flow and anxiety, Decreased metabolism/blood flow occurs in low and high anxiety states with increased metabolism/ blood flow in moderate anxiety states. 53, rn, 152 Differences in results between studies could reflect intrastudy as well as intrasubject differences in the degree of anxiety induced. These factors need to be considered in evaluating the significance of findings from functional imaging studies, NEUROANATOMIC MODELS OF ANXIETY

The large available data base on the physiology and pathophysiology of anxiety has led to the development of several neuroanatomic models of the anxiety disorders. One of the most well-known models was proposed by Gray,51 who postulated the presence of several distinct neuroanatomic circuits modulating different aspects of the anxiety reaction. In this model, anticipatory anxiety is proposed to be analogous to the state of "behavioral inhibition" seen in animals who are presented with a threat. In this state, the animal stops what it is doing and becomes vigilant for any sign of danger. He summarized data from animal studies to conclude that this state is activated in the presence of stimuli associated with punishment or nonreward or in the presence of novel stimuli. The actual experience of punishment or nonreward activates a different system, he called the "fight-or-flight" system, in which the

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animal responds with species-specific defensive reactions such as biting, striking, hissing, or attempting escape. This system is proposed to be most similar to the panic reaction. The behavioral inhibition system initiates enhanced processing of threat relevant stimuli along with suppression of ongoing motor programs. Gray presented evidence from animal studies suggesting that the primary anatomic elements of this system include the septohippocampal areas, the locus coeruleus, and the median raphe nucleus. He theorized that the primary function of the septohippocampal formation is to act as a comparator, which assesses stimuli for the presence of "danger." This "comparator" function is ongoing at a low level when the organism is not in the presence of threat, but when threat is detected, the septohippocampal system would activate the behavioral inhibition circuit, which reciprocally will cause increased monitoring of sensory stimuli for evidence of threat as well as inhibition of ongoing behavioral programs. Activation of the raphe nucleus would, in part, initiate enhanced serotonergic inputs to the hippocampus that allows an increased flow of information through this system. Activation of the locus coeruleus initiates both increased flow of information through the hippocampus and, among other changes, enhanced noradrenergic stimulation of the septum. The increased noradrenergic input into the septum causes a raising of the threshold at which the septum will produce the theta rhythm. The theta rhythm is sent from the septum to the hippocampus and appears to suppress hippocampal activation. This signal would act as an "all clear"/"don't worry" signal, and enhanced noradrenergic output would inhibit its transmission, causing the hippocampus to maintain an enhanced state of activity. Anxiolytic drugs that affect the behavioral inhibition system might then act by either reducing the noradrenergic or the serotonergic inputs into the hippocampal septal formation. Either of these actions would have the effect of reducing hippocampal activation. GABAergic drugs theoretically would reduce function in these systems by acting on inhibitory GABA receptors in the raphe nucleus, in the locus coeruleus and in the hippocampal formation itself. Data from imaging studies of patients w ith anxiety disorders have provided mixed support for Gray's prediction of increased hippocampal activity during anticipatory anxiety states. Panic patients have been found to demonstrate increased right parahippocampal blood flow, 92• 109 and increased blood flow in paralimbic structures was demonstrated in one study of phobic anxiety. 107 Another study of phobic anxiety144 and one study of panic patients at rest,28 however, found decreased limbic flow. Patients with GAD were found to have, if anything, decreased limbic activity both at rest and during a vigilance task although decreased anxiety was correlated positively with decreased limbic activity in placebo-treated GAD patients. 150 It is possible that discrepancies between studies in the degree of limbic activation might be caused by differences in the degree of anxiety produced. As noted previously, states of moderate anxiety more consistent with anticipatory anxiety have been associated with increased cortical blood flow whereas states

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of severe anxiety, which are more similar to panic attacks, are generally associated with decreased cortical blood flow. 53• 111 • 152 Data from neuroendocrine challenge studies demonstrating enhanced cortisol output in states of moderate anxiety with no change or a decrease in cortisol levels during panic anxiety also have been interpreted to reflect the differential cortical activation during these different anxiety states. 56 In light of the importance of glucocorticoids in modulating activity in the hippocampus, 87 these data provide some support for Gray's hypothesis that the hippocampus is activated during anticipatory anxiety, but not in panic anxiety. Behavioral inhibition would be expected to be associated with suppressed behavioral activity and relatively decreased activity in the basal ganglia whereas defensive responding during severe anxiety states (fight-or-flight conditions) would involve activation of defensive behavioral programs and possibly increased basal ganglia activity. Although changes in basal ganglia activity were not noted in many of the studies, when changes were noted, increased basal ganglia activity was noted during low and high anxiety states and decreased basal ganglia activity was noted in moderate anxiety states. 12• 27 • 37• 110• 150 It is possible that these patterns may reflect a generally enhanced level of cortical activity and decreased nonthalamic basal ganglia activity in moderate anxiety states (e.g., behavioral inhibition) with a generally reduced level of cortical activity and enhanced nonthalamic basal ganglia activity in states of severe anxiety (fight-or-flight response) and low anxiety. Gray proposes that the prefrontal cortex may modulate septohippocampal activity separately from the activity of the midbrain noradrenergic and serotonergic inputs. The prefrontal cortex, then, would be an important route through which neocortical information processing would modulate anticipatory anxiety states. The relationship between hippocampal and prefrontal cortical activity is supported by data from animal studies in which the stress-reducing effects of early handling appears to be modulated through enhanced concentrations of glucocorticoid receptors in the hippocampus and prefrontal cortex. 87 The hypothetical relationship between glucocorticoid activity and anticipatory anxiety states56 was noted earlier. The enhancement of activity in the prefrontal cortex in resting panic patients28 • 71 as well as the enhanced prefrontal cortical activity in states of imaginal phobic exposure 107• 152 also provide support for the importance of the prefrontal cortex in states of anticipatory anxiety. The enhanced thalamic activity noted to be associated with cortical activation in many of the imaging studies suggests that this structure may play a role as an important relay station in the processing of threat-related sensory information. The reciprocal connections between the thalamus and the prefrontal cortex would suggest that sensory information may be relayed through the thalamus and then to the prefrontal cortex, which then could relay highly processed information to the septohippocampal area. Gray proposed that the key neuroanatomic components of the fightor-flight system are the amygdala, the medial hypothalamus, and the periaqueductal gray matter. Because of the high resolution required to

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examine these structures, very little of the imaging data available are useful in assessing the validity of this proposed system. Reiman et al1°9 did report activation of an area near the periaqueductal gray matter during lactate-induced panic attacks, but no changes were noted in the area of the hypothalamus or amygdala. None of the other studies that examined function of the amygdala found evidence that it was activated specifically in any of the anxiety conditions assessed. Hsiao and Potter58 have derived a model of a "panic circuit" from an examination of the biochemical effects of antipanic drugs. They noted that there appears to be no common mechanism by which antipanic drugs have their effects. As such, they speculated that these drugs must act at different sites within a "panic circuit" in order to "modulate the activity or sensitivity of these circuits." In their model, they assign central importance to the medullary nucleus paragigantocellularis (nPGi), which, unlike the locus coeruleus, receives inputs from multiple systems making it a likely information processing center. Inputs to the nPGi (1) provide somatosensory information via the periaqueductal gray matter, the dorsal motor nucleus of the vagus, and the nucleus tractus solitarius; (2) metabolic information from central chemoreceptors (some of which lie within the nPGi); and (3) cognitive and affect state information from cortical and limbic centers via connections with the periaqueductal gray matter, amygdala, and hypothalamus. The nPGi can send processed information through efferents to centers that are likely to be involved in the cognitive (prefrontal cortex), affective (amygdala and hypothalamus), and somatic (intermediolateral cell column, locus coeruleus, dorsal motor nucleus of vagus, and AS noradernergic cell group) aspects of a panic attack. Hsiao and Potter speculated that the monoamine oxidase inhibitors (MAOis) and tricyclic antidepressants (TCAs) act by increasing noradrenergic tone, which then may act to decrease the sensitivity of noradrenergic neurons within this system to noise. The nPGi contains large numbers of noradrenergic neurons as well as neurons modulated by enkephalins, serotonin, acetylcholine, and excitatory amino acids. The antipanic effects of the MAOis and TCAs, they speculated, may be due to the increased response threshold of noradrenergic neurons in the nPGi. They pointed out, however, that there are very few GABAergic neurons in this nucleus. Thus, the site of action of the benzodiazepines is likely to be elsewhere in this circuit. The hippocampus has the densest concentration of GABA receptors and they speculate that this may be the site of anxiolytic action for the benzodiazepines in general anxiety states. Antipanic effects, however, require higher doses of benzodiazepines than do antianxiety effects. Thus, the locus of benzodiazepine antipanic effects is likely to be at a site that is less densely innervated by GABA neurons. Because of the intermediate GABA receptor density in the periaqueductal gray matter, they speculated that this may be the locus of benzodiazepine antipanic action. In support of this, they noted that the periaqueductal gray matter has limited effects on sympathetic nervous system activity, which would agree with the findings that

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measures of peripheral catecholamine activity do not change during treatment of panic patients with benzodiazepines.79 Gorman and colleagues 48 proposed a neuroanatomic model of panic disorder that shares some of the features of the other models but includes some specific predictions regarding the brain structures specifically involved in phobic anxiety as well as those involved in panic and anticipatory anxiety. They emphasized the importance of brain stem structures, including the medullary chemoreceptors, the locus coeruleus, the midbrain raphe nucleus, and the nucleus reticularis paragigantocellularis, in initiating a panic attack. One of the hypothesized functions of this brain stem system would be to monitor the status of peripheral autonomic activity such as respiratory and heart rates and compare this with metabolic demands. Peripheral autonomic inputs would be relayed into this system through the vagus nerve, which sends information through the tract of the nucleus solitarius to the nucleus reticularis paragigantocellularis into the locus coeruleus. Metabolic demand would be assessed by the medullary chemoreceptors that relay information to the locus coeruleus through the nucleus reticularis paragigantocellularis. Gorman and colleagues speculated that when functioning normally, this system would initiate a panic reaction if a mismatch between autonomic activity and metabolic demand suggested a state of physiologic danger. Pathologic panic attacks would occur when some of these brain stem structures misfunction, causing an inappropriate signal of metabolic mismatch to the locus coeruleus, which then activates the panic circuit. Gorman and colleagues leave open the possibility that limbic dysfunction also could initiate a pathologic panic attack. In fact, evidence that abnormal discharges in the area of the right parahippocampal region can induce panic attacks was presented by George and Ballenger,42 who cited numerous cases of patients who presented with panic attacks that were associated with epileptiform discharges in this region. They also noted that chronic cocaine abuse, which is associated with increased risk of panic disorder, can induce spiking activity in the temporal lobes via neuronal kindling. In the model proposed by Gorman et al, 48 the modulation of anticipatory anxiety is assigned to limbic structures such as the hippocampus and the amygdala. They proposed that the prefrontal cortex is of central importance in the development and maintenance of phobic anxiety. The evidence regarding involvement of the hippocampus in anticipatory anxiety states is reviewed previously. In proposing the connection between phobic anxiety and activity in the prefrontal cortex, they predicted that exposure-induced anxiety would activate this area. Studies to date have provided mixed support for this idea. Studies of phobic patients have demonstrated no change,37· 89 a decrease, 144 or an increase 108 in frontal cortical activity during phobic exposure. As suggested previously, the data support the hypothesis that the prefrontal cortex is involved in regulation of anticipatory anxiety states. Also, the ability of different phobic states to induce all levels of prefrontal cortical activation would argue against a specific relationship between prefrontal cortical

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activity and phobic anxiety. Interestingly, both lactate- and yohimbineinduced panic attacks have been associated with a decrease in frontal activity in patients who panic, but have been shown to actually cause an increase in frontal cortex activity in subjects who do not panic. 128• 149 It is possible that this increased frontal activation might be initiated by signals sent from the brain stem to the frontal cortex through the cortical reticular tract described earlier. This increased frontal activity might reflect the enhanced cognitive processing associated with increased states of arousal whereas the decrease in frontal activity seen during panic attacks might reflect the relative inhibition of anticipatory cognitive activity during a fight-or-flight response with a preferential activation of circuits involved in more reflexive attack or escape responses as proposed by Gray. In summary, neuroanatomic models derived from animal and human studies of anxiety have postulated important roles for numerous cortical, limbic, and brain stem structures in the physiology of normal and pathologic anxiety states. Gray51 has proposed that anticipatory anxiety is comparable to a state of behavioral inhibition, which is derived from animal studies of stress and anxiety. The state of behavioral inhibition is associated with increased vigilance and suppression of ongoing motor programs. This state theoretically is initiated by activation of the septohippocampal areas by serotonergic and noradrenergic inputs from the raphe nucleus and the locus coeruleus. The prefrontal cortex also may play an important role in modulating septohippocampal activity during states of anticipatory anxiety. Evidence of reduced basal ganglia activity and enhanced limbic activity associated with states of moderate anxiety support this model. Gray proposed the existence of a separate anatomic system for modulation of panic anxiety, which he named the "fight-or-flight" system. He identified the amygdala, the medial hypothalamus, and the dorsal periaqueductal gray matter as the major components of this system. Imaging data that support activation of this system during panic attacks currently are limited. Hsiao and Potter58 have proposed that the nPGi located in the lateral medulla is a key relay station involved in processing sensory information from brain stem chemoreceptors, the peripheral autonomic nervous system, and neocortical areas. They also have proposed that under certain conditions, the nPGi plays a role in initiating a panic attack by activation of the locus coeruleus, the periaqueductal gray matter, and the sympathetic nervous system. Although imaging data are not available to assess this hypothesis, it is consistent with data from clinical and neuroendocrine studies of the anxiety disorders. Gorman and colleagues48 proposed a three-part neuroanatomic model of panic disorder that hypothesized that panic attacks are initiated in the brain stem, that anticipatory anxiety is modulated by limbic structures, and that phobic anxiety is modulated by centers in the prefrontal cortex. They used data from studies of lactate and C02 sensitivity in panic patients to present a model in which brain stem centers normally activate panic anxiety during states of physiologic mismatch,

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which normally would be linked to dangerous physiologic conditions. Pathologic panic would be caused by over sensitivity of this system. The additional possibility that panic attacks can be initiated by activity in the limbic system is supported by data reviewed by George and Ballenger,42 which connected panic attacks to abnormal functional activity in the right parahippocampal area. CONCLUSIONS Summary of Available Data

An extensive data base from biochemical and neuroimaging studies of patients with anxiety disorders supports the notion that these disorders are associated with abnormal function in various neurotransmitter systems and that multiple brain structures are involved in the modulation of normal and pathologic anxiety states. Panic disorder has been associated with abnormal function of noradrenergic, serotonergic, and GABAergic receptor function as well as with abnormal sensitivity of brain stem chemoreceptors. Structural brain imaging studies have demonstrated abnormalities in the temporal lobes and limbic structures of many panic patients. Functional brain imaging studies have demonstrated abnormal activation of the parahippocampal area and the prefrontal cortex in panic patients at rest. Panic anxiety also has been associated with activation of brain stem and basal ganglia areas along with suppression of activity in the prefrontal cortex. The medullary nucleus paragigantocellularis, the dorsal periaqueductal gray matter, the locus coeruleus, the raphe nucleus, the medial hypothalamus, and the amygdala all have been proposed to play important roles in the pathophysiology of panic attacks. Panic attacks have been linked theoretically to dysfunction of the brain stem system for monitoring metabolic states that normally would initiate panic anxiety only under physiologically dangerous conditions. A second mechanism for the initiation of panic attacks may involve dysfunction in the parahippocampal area, which normally functions to regulate the monitoring of threat-related stimuli and normally would initiate a panic attack only under conditions of severe environmental threat. Structural abnormalities in this area as well as abnormal right parahippocampal blood flow may be related specifically to panic disorder. Limited data have supported the presence of abnormal serotonergic and GABAergic function in many patients with GAD. Functional imaging data have demonstrated abnormally increased cortical activity and decreased activity in the basal ganglia of patients with GAD. After treatment there appears to be an increase in basal ganglia activity and a reciprocal decrease in cortical activity. Limbic function has been found to be normal or somewhat decreased in patients with GAD but improvement in anxiety symptoms has been associated with decreased limbic activity in this patient group. The fact that the anxiolytic actions of

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benzodiazepines are likely related, in part, to their ability to decrease hippocampal activity also suggests that certain limbic structures play a role in the pathophysiology of GAD. The biochemical mechanisms involved in social phobia are unclear but there are limited data identifying an abnormality in serotonergic function and possibly abnormal dopaminergic activity. Data from one imaging study of social phobic patients suggest that these patients may have abnormally decreased activity in the caudate nucleus and thalamus. Data from functional brain imaging studies of simple/specific phobic patients undergoing exposure are complicated by differences in experimental technique between studies. Increased and decreased cortical activity have both been demonstrated during phobic exposure. It is likely that the nature of the phobic stimulus (e.g., imaginal vs. in vivo) as well as the severity of the anxiety response both play significant roles in the pattern of cortical activity during phobic exposure. Implications for Future Research

Despite the extensive data available on the physiologic and neuroanatomic aspects of pathologic anxiety, it is possible to discern only a vague image of how anxiety states are modulated within the vastly complex neural network of the brain. Functional imaging studies have enhanced significantly the clarity of this image but further clarification is needed and will require many more studies using current technologies as well as further improvements in the available imaging technology. Biologic challenges of relevant neurotransmitter systems and functional imaging studies of cerebral activity associated with anxiety have been the most useful tools available to study the biochemical aspects of anxiety. Some of the seemingly contradictory results from biologic challenge studies will need to be accounted for in future studies using these methods. The use of more receptor specific challenges (particularly in the serotonin system) may lend some clarity to these data. It is likely that the GABA/benzodiazepine system is involved in the pathophysiology of anxiety, and many more studies using available challenge agents active at the benzodiazepine site likely would yield particularly valuable information. Although there is an extensive data base available on biologic challenges in panic disorder, there is a striking lack of this type of data on patients with GAD and social phobia. Studies comparing and contrasting the effects of different biologic challenges in patients with these different disorders will be very useful in understanding the unique pathophysiology associated with each disorder. In a related fashion, future studies will need to control carefully for the presence of comorbid conditions that may alter significantly the nature of the response to certain biologic challenges. Within each disorder it is likely that there are distinct biologic subgroups that might be identified by differential responses to challenge agents. Within-subject challenges of multiple receptor systems would be helpful in identifying these subgroups. It

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will be important to determine whether patients with specific biologic subtypes respond differentially to different pharmacologic and psychological treatments. Functional imaging studies of patients with anxiety disorders during different states of arousal and under different conditions of anxiety provocation likely will be most useful in developing an understanding of the neuroanatomy of anxiety. The current data base is complicated by differences between studies in the imaging technology used as well as in the technique of data preparation used (e.g., the use of relative vs. absolute measures of rCBF). More standardization of procedures will be helpful in comparing results from different studies. Additionally, because many of the changes in cerebral activity during anxiety states appear to be affected by sometimes subtle differences in the context of the anxiety condition (e.g., imaginal vs. in vivo exposure), future studies will need to consider carefully the effects of different experimental conditions on the study results and to limit conclusions to these conditions. Moreover, because patterns of cerebral activation appear to be so state dependent, changes in data analysis that will be helpful would include careful measurement of subjective anxiety during scans and the combining of data from patients with comparable anxiety responses rather than simply combining data from patients with the same diagnosis. Longitudinal studies of cerebral activity in individual anxiety patients under different anxiety conditions and after effective treatment (particularly after nonpharmacologic treatment) likely would decrease significantly the intersubject variability, which complicates interpretation of results from studies using multiple subjects under a single condition. Improvements in imaging technology that allow better imaging of brain stem structures as well as the ability to examine functional activity within specific receptor systems are likely to advance further our understanding of the neuroanatomy and pathophysiology of the anxiety disorders. References 1. Abelson J, Glitz D, Cameron 0, et al: Blunted growth hormone response to clonidine in patients with generalized anxiety disorder. Arch Gen Psychiatry 48:157-162, 1991 2. Abelson JL, Glitz D, Cameron OG, et al: Endocrine, cardiovascular, and behavioral responses to clonidine in patients with panic disorder. Biol Psychiatry 32:18-25, 1992 3. Apostolopoulos M, Judd FK, Burrows GD, et al: Prolactin response to dl-fenfluramine in panic disorder. Psychoneuroendocrinology 18:337-342, 1993 4. Aronson T, Carasiti I, McBane D, e t al: Biological correlates of lactate sensitivity in panic disorder. Biol Psychiatry 26:463-477, 1989 5. Balon R, Pohl R, Yeragani VK, et al: Lactate- and isoproterenol-induced panic attacks in panic disorder patients and controls. Psychiatry Res 23:153-160, 1988 6. Baxter LJ: Neuroimaging studies of obsessive compulsive disorder. Psychiatr Clin North Am 15:871-84, 1992 7. Black B, Uhde T, Tancer M: Fluoxetine for the treatment of social phobia [letter]. J Clin Psychopharmacol 12:293-295, 1992 8. Bradwejn J: Neurobiological investigations into the role of cholecystokinin in panic disorder. J Psychiatry Neurosci 18:178-188, 1993

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