PET Mapping of Neurofunctional Changes in a Posttraumatic Stress Disorder Model

Abstract

Posttraumatic stress disorder (PTSD) is an anxiety disorder that occurs after exposure to a traumatic event. This study aimed to investigate the neurobiologic changes before and after exposure-based therapy by PET in a rat model of PTSD. Methods: Serial 18 F-FDG PET imaging studies were performed under the control (tone presentation), fear-conditioning, and extinction retrieval phases. Neuroactivity marker c-Fos protein was used for immunostaining. Results: Increased glucose metabolism was observed in the bilateral amygdala after fearconditioning (P , 0.001) and in the right posterior insular cortex under extinction retrieval (P , 0.001) compared with the control phase. Increased c-Fos expression in the posterior insular cortex under extinction retrieval was positively correlated to the glucose metabolism (P , 0.01). Conclusion: Our results indicated that the amygdala plays a key role in fear memory formation and, most importantly, the insular cortex is related to the retrieval of extinction memory. 18 F-FDG PET may provide a promising in vivo approach for evaluating exposurebased therapy of PTSD. Post traumatic stress disorder (PTSD) is the most costly psychiatric disorder, affecting up to 40% of individuals over lifetime exposure to traumatic events (1,2). Over the past decades, considerable studies have explored how fear memories are encoded in the brain. A neurocircuitry model of PTSD emphasized the importance of the amygdala, as well as its interactions with the ventral/ medial prefrontal cortex (PFC) and hippocampus (3). In accord with this model, initial neuroimaging studies of PTSD provided evidence for exaggerated amygdala responses and attenuated ventral/ medial PFC responses during exposure to reminders of the traumatic event (3). In addition, Pavlovian fear-conditioning studies highlighted the key role of the amygdala in the acquisition and storage of conditioned fear memories (4,5). Electrophysiologic recording and inactivation studies in rats suggest that fear extinction depended on increased neuroactivity in the medial PFC under extinction training (6,7). Furthermore, the amygdala has been found activated during fear acquisition (8) and positively correlated with the severity of PTSD symptoms (9). Failure to recall fear extinction memory is associated with lower activation in the hippocampus and ventral/medial PFC in PTSD patients relative to trauma-exposed healthy subjects (10).Although exposure-based therapy (conceptually based on fear extinction) has been widely used in the treatment of PTSD (1), its underlying mechanism has not been completely elucidated. Because PET has been increasingly used to characterize neural activities, we hypothesized that 18 F-FDG PET could be applied for evaluating cerebral glucose metabolism before and after exposure-based therapy and could provide a potential translational tool for future clinical applications. Thus, the present study aimed to investigate the neurobiologic changes by 18 F-FDG PET in a rat model of PTSD. MATERIALS AND METHODS AnimalsMale Sprague-Da...

Relation between resting amygdalar activity and cardiovascular events: a longitudinal and cohort study

“…Amygdalar activity was corrected for background cerebral (amygdala c , as mean temporal lobe SUV) and cerebellar (amygdala cbl , as mean cerebellar SUV) activity. 26 Bone-marrow activity, splenic activity, and arterial infl ammation were measured according to previously validated methods 12,20 by deriving SUVs from the target tissue (bone marrow, spleen, or aortic and carotid walls) and correcting them for venous blood background activity to calculate target-to-background ratios. Arterial ¹⁸F-FDG uptake is a well validated measure of arterial infl ammation that relates to atherosclerotic macrophages 22 and predicts subsequent cardiovascular disease events.…”

“…15,16 Amygdalar activity is upregulated in conditions marked by stress, such as post-traumatic stress disorder, anxiety, and depression. [16][17][18][19][20] By showing cellular glycolysis, ¹⁸F-FDG PET/CT can be used to simultaneously quantify not only regional brain metabolism (activity), [16][17][18][19]21 but also haemopoietic tissue activity and large vessel arterial infl ammation, 12,22 thereby making it uniquely suitable for investigation of linked activity among these systems and the pathogenesis of atherosclerosis. Accordingly, we used ¹⁸F-FDG-PET/CT to test the hypotheses that amygdalar activity is associated with haemopoietic activity and arterial infl ammation, and predicts the development of future cardiovascular disease events.…”

The neurobiology of emotion regulation in posttraumatic stress disorder: Amygdala downregulation via real‐time fMRI neurofeedback

“…It has been well documented that dysregulation of amygdala neural circuitry-a brain region associated with the generation and processing of emotions [Duvarci and Pare, 2014;Frank et al, 2014;LeDoux, 2007]-is central to the development and maintenance of symptoms experienced by patients with posttraumatic stress disorder (PTSD) [Aghajani et al, 2016;Birn et al, 2014;Etkin and Wager, 2007;Lanius et al 2010Lanius et al , 2015Mickleborough et al, 2011;Patel et al, 2012;Pitman et al, 2012;Shin and Liberzon, 2010;Stevens et al, 2013;Weston, 2014;Yehuda et al, 2015]. The amygdala, along with the prefrontal cortex (PFC), a region central to emotion regulation [Etkin et al, 2011[Etkin et al, , 2015, displays unique activation patterns among PTSD patients across a number of modalities, including symptom provocation [Frewen et al, 2011;Hayes et al, 2012;Hopper et al, 2007], fear processing [Bruce et al, 2013;Bryant et al, 2008;Williams et al, 2006;Wolf and Herringa, 2016;Zhu et al, 2016], and resting state [Brown et al, 2014;Huang et al, 2014;Koch et al, 2016;Nicholson et al, 2015]. Critically, during rest, the amygdala also displays altered connectivity to the cingulate cortex [Brown et al, 2014;Nicholson et al, 2015;Sripada et al, 2012], insula [Fonzo et al, 2010;Nicholson et al, 2016a;Rabinak et al, 2011;…”

Eye Movement Desensitization and Reprocessing and Slow Wave Sleep: A Putative Mechanism of Action

“…The neurobiological correlates of PTSD have been increasingly investigated by neuroimaging studies showing changes in cerebral blood flow ( Bonne et al, 2003 ; Pagani et al, 2005 ; Lindauer et al, 2008 ; Nardo et al, 2011 , 2015 ; for review see Bremner, 2007 ), metabolism ( Pissiota et al, 2002 ; Osuch et al, 2008 ; Kim et al, 2012 ; Zhu et al, 2016 ), neuronal volume and density ( Lindauer et al, 2004 ; Looi et al, 2009 ; Nardo et al, 2010 , 2013 ; O’Doherty et al, 2015 , 2017 ) and more recently in brain electric signal ( Lee et al, 2014 ; Lobo et al, 2015 ), concordant with an involvement of the limbic system in the hyperarousal responsible for clinical symptoms. When reliving the traumatic events, the reduced control of the prefrontal cortex over hyperreactive amygdala and hippocampus is thought to be the core functional mechanisms of PTSD ( Shin et al, 2006 ; Etkin and Wager, 2007 ).…”