Prediction of Panic Response to a Respiratory Stimulant by Reduced Orbitofrontal Cerebral Blood Flow in Panic Disorder

Although much is now known about the pathophysiology of panic disorder, the neurocircuitry central to panic is still being delineated. The role of inhibitory cortical inputs on amygdalofugal pathways in the development of panic anxiety is especially poorly understood.

Although the results are not completely consistent, the majority of functional imaging studies in panic disorder support frontal cortical deactivation during panic anxiety provoked by pharmacological challenges (1–3) and during spontaneous panic attacks (4). Because the medial and orbitofrontal regions of the prefrontal cortex are known to have extensive connections with the amygdala, exerting a primarily inhibitory influence on its activity (5), they are of prime interest as areas of potentially aberrant functioning in panic disorder.

The aims of this study were to use quantitative water method ([¹⁵O]H₂O) positron emission tomography (PET) to test the following hypotheses: 1) Subjects with panic disorder demonstrate greater activation of the amygdala than healthy comparison subjects in response to an anxiety-provoking challenge. 2) Subjects with panic disorder demonstrate less cortical restraint than healthy comparison subjects over subcortical fear pathway structures, as manifest by hypoactivity in medial and orbitofrontal cortical regions.

Method

Five subjects with a DSM-IV diagnosis of panic disorder (four female, one male; mean age=27.2 years, SD=3.2) and five healthy comparison subjects (three female, two male; mean age=31.6 years, SD=6.8) participated in the study. All subjects participated in a psychiatric interview and the Structured Clinical Interview for DSM-IV Axis I Disorders (6), and all were determined to be in good physical health after a complete medical evaluation. Subjects with panic disorder were included if they met DSM-IV criteria for panic disorder; no other current axis I diagnoses were allowed except dysthymia. Subjects with panic disorder were excluded if they had a lifetime history of schizophrenia or bipolar disorder. Healthy comparison subjects did not meet criteria for any current or lifetime history of an axis I disorder. All subjects were required to be free of psychotropic medications for 6 weeks before scanning. The study was approved by the institutional review boards of New York State Psychiatric Institute and Columbia University. After complete description of the study to the subjects, written informed consent was obtained from all who participated.

Subjects were scanned with [¹⁵O]H₂O PET on an ECAT EXACT HR+ PET scanner (Siemens CTI, Knoxville, Tenn.); input function was measured with arterial blood samples. The respiratory stimulant doxapram was used to induce anxiety in subjects (7). The pharmacological action of doxapram hydrochloride is mediated through the peripheral carotid chemoreceptors, producing respiratory stimulation within 20–40 seconds of injection, with a peak effect at 1–2 minutes and a total duration of action of approximately 5 minutes. Because the effects of doxapram preclude a double-blind randomized study design, a single-blind nonrandomized design was used.

All subjects underwent five activations (scans), each consisting of an intravenous bolus injection of 20 mCi [¹⁵O]H₂O. Scans were acquired 15 minutes apart in a fixed order: resting baseline, repeat resting baseline, placebo injection, placebo injection, doxapram injection (0.5 mg/kg). Scanning began 30 seconds after placebo and doxapram injections. Throughout the scanning session, repeated anxiety assessments were made with three scales: 1) Acute Panic Inventory (8), 2) 10-point Anxiety Scale (8), and 3) 10-point Borg Breathlessness Scale (9). Occurrence of panic was judged on the basis of DSM-IV criteria of a crescendo of fear/anxiety with four or more associated symptoms (rated on the Acute Panic Inventory).

Dynamic PET imaging data were summed and coregistered with magnetic resonance imaging (MRI). Data were fitted to the integrated form of the Kety-Schmidt equation (10) according to a lookup table. Summed PET data (from 30 seconds to 2 minutes after injection) were matched to flow values from a lookup table generated by fitting the equations to a range of possible summed activity values. The delay between the time of measurement of arterial tracer concentration and the time of brain exposure was incorporated by fitting whole brain data to the dynamic form of the equations and including delay time as a fitted parameter. Parametric maps were generated, with one flow value for each voxel. Regions of interest were drawn on individual patients’ MRIs and transferred to the blood flow maps, generating regional mean flow values. Subcortical regions of interest included the midbrain, hippocampus, amygdala, thalamus, and striatum. The prefrontal cortex was divided into the following regions of interest: anterior cingulate, medial, dorsolateral, orbitofrontal, and subgenual.

Change in cerebral blood flow (CBF) over time (scans 1–5) was analyzed by using repeated-measures analysis of variance. Behavioral data were compared with regional CBF (rCBF) values from the scans by using correlational analyses based on the a priori hypotheses described above.

Results

All five of the subjects with panic disorder panicked in response to doxapram, compared with one of the five healthy subjects, a significant difference (χ²=5.76, df=1, p<0.02). One of the subjects with panic disorder was dropped from the PET data analysis because of a technical problem with processing her PET data (this subject was 22 years old). There were no significant differences in rCBF in the amygdala in response to placebo or doxapram injections between the subjects with panic disorder and the comparison subjects. Similarly, there were no significant differences between the groups in global (weighted average) subcortical or cortical blood flow in response to placebo or doxapram injections and no significant differences between the groups when regions of interest were analyzed individually (Bonferroni correction for multiple comparisons).

When all subjects were considered together (N=9), baseline orbitofrontal CBF distinguished subjects who panicked (N=5) from those who did not panic (N=4) in response to doxapram injection (t=2.82, df=7, p<0.05). Additionally, baseline orbitofrontal CBF was negatively correlated with anxiety scores on the Acute Panic Inventory (r=–0.83, N=9, p<0.05) (Figure 1), the 10-point Anxiety Scale (r=–0.77, N=9, p<0.05), and the Borg Breathlessness Scale (r=–0.75, N=9, p<0.05) in response to doxapram injection.

Conclusions

Perfusion of the orbitofrontal prefrontal cortex at baseline predicted panic vulnerability to respiratory challenge across subjects, suggesting that input from this cortical region may be important in suppressing fear responding. In addition, orbitofrontal blood flow at baseline correlated negatively with scores on the Acute Panic Inventory, 10-point Anxiety Scale, and Borg Breathlessness Scale in response to doxapram challenge: higher levels of CBF in the orbitofrontal region was associated with lower anxiety scores and less breathlessness.

These data should be viewed cautiously given the small number of subjects and the high risk of a type II error. This may account for our inability to demonstrate a relationship between panic anxiety and amygdala activation. Lack of differentiation between the panic and comparison groups in rCBF response to the anxiogenic challenge was perhaps due to a “floor” effect, in which the respiratory response to doxapram, resulting in hyperventilation, hypocapnia, and resultant physiological vasoconstriction, overshadowed potential differences between groups. This potential confound of hypocapnia-induced vasoconstriction could be controlled for by measuring Pco₂ with serial blood gases in future studies. Hypocapnia-induced vasoconstriction, however, is likely to be a global effect that would not account for the regional difference identified in the orbitofrontal cortex at baseline. Despite the limitations of this study, these results may stimulate more studies focusing on the orbitofrontal cortex and directed at determining the nature of inhibitory cortical input to the amygdala in the development of panic vulnerability.

Received Oct. 23, 2003; revision received June 15, 2004; accepted July 7, 2004. From the Department of Psychiatry and Department of Radiology, Columbia University College of Physicians & Surgeons; New York State Psychiatric Institute, New York; State University of New York-Downstate, Brooklyn, N.Y.; and Mount Sinai School of Medicine, New York. Address correspondence and reprint requests to Dr. Kent, Department of Psychiatry, Unit 41, Columbia University, 1051 Riverside Dr., New York, NY 10032; [email protected] (e-mail). Supported by Eli Lilly & Co.