Altered cerebral benzodiazepine receptor binding in post-traumatic stress disorder

Inbal Reuveni,Wayne C Drevets,Meena Vythilingam,Allison C Nugent,Paul J Carlson,Alexander Neumeister,Jessica Gill,Omer Bonne,Alicja Lerner,Dennis S Charney

doi:10.1038/s41398-018-0257-9

Abstract

Agonists of the γ-aminobutyric acid (GABA) type A benzodiazepine (BZD) receptor exert anxiolytic effects in anxiety disorders, raising the possibility that altered GABA-ergic function may play a role in the pathophysiology of anxiety disorders, such as post-traumatic stress disorder (PTSD). However, few neuroimaging studies have assessed the function or binding potential of the central GABAA BZD receptor system in PTSD. Therefore, our aim was to compare the BZD receptor binding potential between PTSD patients and healthy controls. Twelve medication-free participants with a current diagnosis of PTSD and 15 matched healthy controls underwent positron emission tomography (PET) imaging using [11C] flumazenil. Structural magnetic resonance imaging (MRI) scans were obtained and co-registered to the PET images to permit co-location of neuroanatomical structures in the lower resolution PET image data. Compared to healthy controls, PTSD patients exhibited increased BZD binding in the caudal anterior cingulate cortex and precuneus (p’s < 0.05). Severity of PTSD symptoms positively correlated with BZD binding in the left mid- and anterior insular cortices. This study extends previous findings by suggesting that central BZD receptor system involvement in PTSD includes portions of the default mode and salience networks, along with insular regions that support interoception and autonomic arousal.

Highlights

Introduction γAminobutyric acid (GABA) is the principle inhibitory neurotransmitter in the brain
The mean [11C]-flumazenil binding potential (BP) was significantly higher in patients with post-traumatic stress disorder (PTSD) than in healthy controls in a contiguous cluster comprising the medial and superior portion of the caudal anterior cingulate cortex (ACC) and precuneus
We further report a positive correlation between PTSD symptom severity and BZD BP in the left anterior and mid-insula, which are key regions of the salience network (SN) and cerebral targets of the afferent projections of the vagus nerve, as reviewed below

Summary

Introduction

Aminobutyric acid (GABA) is the principle inhibitory neurotransmitter in the brain. Agonists of the GABAsubtype A benzodiazepine (BZD) receptor complex constitute one of the major classes of compounds used to treat anxiety disorders, including post-traumatic stress disorder (PTSD). Only a few studies have examined cerebral BZD receptor binding and/or GABA concentrations in PTSD, were limited to combat exposed males, and proved ambiguous in their findings. Reduced BZD receptor binding potential (BP) in the prefrontal cortex was initially reported in combat-trauma. Other measures examined have implicated altered central GABA-ergic function in PTSD. In civilians with PTSD, greater cortical excitability was observed after transcranial magnetic stimulation, suggesting widespread impairment of GABAergic function[4]. Magnetic resonance spectroscopy (MRS) studies of cerebral GABA concentrations showed lower levels of GABA in PTSD

Methods

Results

Conclusion