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

Lay Summary

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

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.