Identification of Physiological Sleep Indices That Reflect Clinical Improvement and Reduction in Stress Biomarkers After Stellate Ganglion Block in Patients With Posttraumatic Stress Disorder (PTSD)

Plain-language summary

Post-traumatic stress disorder (PTSD) is a chronic disorder that develops following exposure to trauma, and is characterized by intrusive experiences, avoidance, cognitive-emotional changes, and hyperarousal. It is based on a complex noradrenergic dysregulation. The amygdala activates the hypothalamus to release excessive corticotropin releasing factor (CRF), which activates the hypothalamic-pituitary-adrenal (HPA) axis and leads to high nocturnal cortisol levels with EEG changes and increased arousals. At the same time, the Locus Coeruleus (LC) releases excess norepinephrine (NE), which interferes with the transition to Non-REM sleep and suppresses the stability of REM sleep, a stage essential for emotional processing and the extinction of conditioned fear. Sleep disturbances occur in 70-90% of PTSD patients, leading to fragmented sleep that impairs conditioned fear extinction, reinforces hyperarousal, and perpetuates the disorder as a protective-morbidity mechanism \[1,2\]. Beyond the clinical implications, sleep disturbances mediate the relationship between PTSD and functional disability and occupational disability, with 74% of the economic burden of PTSD in Israel attributed to loss of employment and productivity (3,4). The Stellate Ganglion (SG), located between the C6-C7 vertebrae, is a central sympathetic junction between the central nervous system and the periphery. This connection is expressed in descending pathways from the amygdala and prefrontal cortex (PFC) and ascending pathways from the periphery through the SG that feed the LC, which in turn secretes NE to the amygdala and other limbic areas and affects fear and memory processing. Subganglionic ganglion block (SGB) using local anesthetic injection reduces sympathetic tone, reduces Nerve Growth Factor (NGF) and NE levels, and "breaks" the pathological feedback loop. This effect was found to reduce conditioned fear memory and was accompanied by a significant decrease in NE concentration in the amygdala (5,6). A multicenter RCT showed that SGB led to an improvement in PTSD symptoms, with sleep disturbances and hyperarousal being the most responsive symptoms \[7\]. This finding was supported by a recent meta-analysis that confirmed a significant improvement in key sleep measures, including total sleep time and overall sleep quality (8). A RCT that included a sleep laboratory and neurotransmitter measurements in anxiety patients with sleep disorders found that SGB led to a decrease in NE and an increase in Serotonin- and NPY-, along with an objective improvement in quality and time of wakefulness \[9\]. Initial findings in primary insomnia patients without PTSD also showed significant improvement, and combining SGB with CBT-I (cognitive-behavioral therapy) yielded stable results over time \[10\]. These findings strengthen the rationale for using SGB as a treatment for disorders resulting from sympathetic overactivity and HPA axis dysregulation. Despite this promising evidence, there is a knowledge gap: the effect of SGB on objective and continuous sleep measures in a natural setting has not yet been examined, and cortisol levels have not been measured concurrently with changes in sleep. Polysomnography (PSG)-the standard test for diagnosing sleep disorders-is not suitable for continuous monitoring due to discomfort. Wearable devices, in particular the Oura Ring Gen3, have been shown to be a valid alternative to PSG for sleep monitoring in a natural setting. The ring, which demonstrated the highest PSG compliance among consumer monitoring devices, combines accelerometry and photoplethysmography (PPG) to continuously measure WASO (Wake After Sleep Onset), Sleep efficiency (SE), Heart rate variability (HRV), sleep stages, and nocturnal heart rate (11,12). The proposed study aims to bridge this gap, to monitor for the first time objective physiological sleep measures and cortisol levels over time in PTSD patients after SGB. In addition to its contribution to understanding the mechanism of action of SGB, this study will isolate the physiological measures associated with clinical improvement and may serve as a gateway for further research and treatments in the field and for therapeutic success in PTSD and autonomic dysregulation.

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