The Neurochemistry and Neurocircuitry of Panic Disorder: PET Imaging of 5-HT1A Receptor Distribution and the Neural Correlates of Panic

Gregory Sullivan, M.D.

Columbia University

Funded in June, 2004: $100000 for 4 years
LAY SUMMARY . ABSTRACT . HYPOTHESIS . SELECTED PUBLICATIONS .

LAY SUMMARY

back to top

Neural Correlates of Panic Disorder

The investigators will use PET imaging to determine whether the onset of panic disorder is associated with abnormal secretion of the neurotransmitter serotonin in specific brain cell circuits.  If so, this improved understanding of panic disorder could lead to development of better preventative therapies.

Prior animal and clinical studies suggest that people who suffer from panic disorder have overactive brain fear circuits, coupled with underactive cortical breaks that otherwise would serve to lessen anxiety.  Therapies being used with modest effectiveness regulate serotonin transmission levels, suggesting that this neurotransmitter plays a role in calming excessive anxiety.

The investigators will induce panic in consenting patients who suffer from the disease.  Researchers then will image patients with PET to identify “fear circuits,” determining how much serotonin is binding to patients’ brain cells, and where the excess blood flow is occurring in the brain.  These PET imaging findings will be compared to those obtained in healthy controls and in patients with a related anxiety disorder.  This comparison may allow investigators to characterize the specific neuronal and chemical factors involved in panic disorder.

Significance:  Determining specific dysfunctions that occur in the transmission of serotonin in nerve networks in patients who suffer from panic disorder would provide an understanding of why existing pharmaceutical treatments are able to confer modest benefit.  Moreover, developing an understanding of the problems in brain circuitry and neurotransmission in these patients can lead to development of more effective therapies that address the specific problems found.  

ABSTRACT

back to top

The Neurochemistry and Neurocircuitry of Panic Disorder: PET Imaging of 5-HT1A Receptor Distribution and the Neural Correlates of Panic

Panic disorder (PD) is an anxiety disorder which affects about 2-8% of the population. It is characterized by recurrent panic attacks and severe, progressive disability, in large part related to inter-panic anxiety and avoidance. Preclinical work and neuroimaging studies suggest that pathological dysregulation of fear neurocircuitry may be fundamental to the etiology. Panic responses in PD are hypothetically mediated by overactivity in subcortical and paleocortical fear circuits and underactivity in frontal cortical processing that would otherwise serve to moderate anxiety. Efficacy of serotonergic (5-HT) therapies, reactivity to 5-HT compounds in PD and in preclinical anxiety models, and work in the 5-HT1A knockout mouse all point to a role for the 5-HT system in modulating pathological anxiety.

This project is aimed at elucidating the neural circuitry involved in the panic response in PD and defining a neurochemical deficiency that may be involved, if not etiological. Symptomatic patients with PD will be compared with a healthy volunteer group. Two forms of positron emission tomography (PET) imaging will be utilized to compare these subject groups: 1) quantitative neuroreceptor mapping of regional 5-5-HT1A  binding potential utilizing the radioligand [11C]-WAY 100635; and 2) regional cerebral blood flow (rCBF) response to a panicogen, pentagastrin, using [15O]-H2O. Defining key neurocircuitry by rCBF change during laboratory-induced anxiety is considered a crucial first step in the effort to characterize the regional neurochemical mediators of pathological anxiety circuits using PET, beginning with the serotonergic system. The relationships will be established between dysfunctional neurociruitry and abnormal serotonergic neurochemistry, and these biological parameters will be correlated with vulnerability to panic and symptomatic expression of the disorder.

This work is intended to provide a heretofore unavailable in vivo characterization of the neural substrates of pathological panic responses in those suffering from the disorder, promising significant contribution to the understanding of the etiology of PD. It is proposed that only through establishment of the functional and chemical mediators of PD, utilizing advanced imaging technology, can a rational scientific approach proceed in the development of novel and improved therapeutics for this devastating brain disorder.

HYPOTHESIS

back to top

Hypothesis:
1. During panic there is engagement of a circuit involving deficient prefrontal cortex activity and hyperactive paleocortical and amygdala activity.

2. Pathology in the raphe-based serotonin(5-HT) system is permissive to this pathological activity pattern and therefore panic; and preclinical evidence suggests a role for the 5-HT1A receptor in this modulatory function of the 5-HT system in anxiety. 

Goals:
1. To measure in panic disorder subjects and healthy volunteer subjects change in regional cerebral blood flow(rCBF) in orbital prefrontal cortex (OPFC) and amygdala upon acute administration of a panicogen using [15O]-H2O positron emission tomography (PET).

2. To measure in PD patients and controls 5-HT1A binding potential (BP) in OPFC and amygdala using [carbonyl-11C]-WAY 100635 and PET.

3. To explore the relationships between change in rCBF and regional 5-HT1A BP, and to explore the relationships between components of psychopathology and the two biological outcome measures.

Methods:
Medication-naïve panic disorder patients (n=14) and healthy volunteers (n=14) will have a PET scan with [11C]-WAY 100635 to measure regional 5-HT1A BP. Arterial samples will allow quantitative kinetic modeling. Next, subjects will have a series of four [15O]-H2O PET scans to measure rCBF. Before the final [15O]-H2O scan, subjects will receive a bolus challenge of i.v. pentagastrin, a polypeptide that induces a panic attack in most panic disorder subjects, and rCBF change relative to a resting scan will be measured. Anxiety scales will be administered. An MRI is acquired for coregistration. Patients will receive treatment.

SELECTED PUBLICATIONS

back to top

Sullivan G.M. and LeDoux J.E.  Synaptic Self: conditioned fear, developmental adversity, and the anxious individual.  In Fear and Anxiety: Benefits of Translational Research, edited by JM Gorman. Washington, DC, American Psychiatric Press, Inc., 2004.

Gorman J.M., Kent J.M., Sullivan G.M., and Coplan J.D.  A neuroanatomical hypothesis of panic disorder, revised.  Am J Psychiatry. 2000 Apr;157(4):493-505.