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.

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.

Research Objectives Evaluation of the effect of Stellate Ganglion Block (SGB) on physiological sleep indices and biological indices of stress in patients suffering from PTSD (post-traumatic stress disorder). We will examine the following indices: 1. Primary objective - changes in REM sleep - percentage of REM sleep and total REM sleep time. 2. Continuous objective sleep indices: SE, WASO,, HRV - by continuous wearable monitoring in the natural environment. 3. Post-traumatic stress disorder symptoms (PCL-5). 4. Sleep indices as measured by questionnaires (PSQI, RBD1Q) 5. Biological indices of stress - hair cortisol as an index of chronic HPA axis dysregulation and inflammatory markers: CRP, IL-6 -hs. Recruitment and study population Approximately 60 patients over the age of 18 who are treated in a pain clinic, psychiatric and community medicine referrals, a call for applications, contact with non-profit organizations, and targeted advertising. It should be noted that although SGB treatment is not included in the health basket, our clinic provides it to patients. It should be clarified that participation in the study is not a condition for receiving the treatment. Inclusion criteria The study will include adults (age ≥18) with a confirmed diagnosis of post-traumatic stress disorder (PCL-5), who are capable of providing informed consent, and who are willing to continuously wear a smart device (ring and/or watch) throughout the study period. Exclusion criteria Allergy to local anesthetics, psychosis (active or past), active suicidality in the last 2 months, treatment with anticoagulants or P2Y12 antiplatelet agents, significant arrhythmias, pregnancy, clinical contraindication to SGB (such as infection limiting the procedure), as well as inability to wear a monitoring device or baldness preventing hair sampling. Patients who report data equal to 25% of what is expected for the follow-up period will be excluded from the study. Study course Recruitment and Baseline Phase: After recruitment and signing of informed consent, a one-month baseline phase will begin, which includes continuous monitoring using a smart ring under natural living conditions. At the end of this period, an initial assessment visit will be performed, which includes measuring the severity of post-traumatic stress disorder using a questionnaire (PCL-5), sleep quality assessment (PSQI RBD1Q questionnaires), and blood tests for biological markers of stress and inflammation - IL-6, CRP, and a cortisol test in hair from the scalp to assess chronic exposure to stress in the three months preceding the intervention. Intervention phase: Each participant will undergo two Stellate Ganglion Blocks (SGB) on the right side, two weeks apart. The operation will be performed under ultrasound guidance at the C6-C7 level using an in-plane approach while identifying the relevant anatomical structures, performing negative suction and injecting a 6-8 ml 0.5% bupivacaine solution into the longus coeli muscle fascia. The distribution of the anesthetic will be confirmed in real time sonographically. After the operation, clinical monitoring will be performed to identify complications and side effects. If Horner's syndrome is not observed, another injection will be considered (on the left side or again on the right side). Follow-up phase: Continuous monitoring using the smart ring will continue throughout the study period. Three months after performing both barriers, a summary follow-up visit will be performed that includes collecting sleep data and physiological indicators from the wearable device, along with repeating all questionnaires and tests (PCL-5, PSQI, RBD1Q), blood tests and a repeat hair cortisol test.

Methods and Materials Statistical Analysis All analyses will be performed using SPSS version 32, and the significance level will be set at α=0.05 two-sided. The normality of the distribution of the variables will be tested using the Shapiro-Wilk test before choosing the appropriate test. Primary Outcome-Percentage and total REM sleep Comparison of REM% before and after the intervention will be performed using Paired t-test or Wilcoxon signed-rank if necessary). To reduce the effect of confounding variables (baseline PTSD severity, psychiatric medication use, age), a Repeated Measures ANCOVA will be applied, with the baseline value used as the covariate. Subjective secondary outcomes (PCL-5 Posttraumatic Stress Disorder Severity Questionnaire, PSQI Subjective Sleep Quality Questionnaire, and RBD1Q (parasomnia measure) will be subjected to the same analysis-Paired t-test or Wilcoxon by distribution-with comparison at time points: baseline, 4 weeks, and 12 weeks. For multiple time points, a Linear Mixed Effects (LME) model with Bonferroni correction for multiple comparisons will be applied. Effect sizes will be reported as Cohen's d for each outcome. Stress and inflammation indices Hair cortisol (reflecting cumulative secretion over 3 months) and inflammatory markers (such as (CRP, IL-6) will be adjusted for non-parametric analysis (Wilcoxon signed-rank) due to the expected right-skewed distribution, or after logarithmic transformation to the extent that this normalizes the distribution. Spearman's coefficient will be calculated to examine the correlation between changes in markers and changes in REM and PCL-5. Objective sleep indices from the ring , WASO, SE (sleep efficiency) will be analyzed as exploratory secondary outcomes using the RMSSD model and will be analyzed separately as an autonomous measure - with a before-and-after comparison, and examination of its correlations with changes in PCL-5 and inflammatory markers using Pearson or Spearman according to distribution. Sensitivity analysis Per-Protocol analysis will include only participants in whom Horner's syndrome was documented after the injection, and will be presented as an upper estimate for the biological effect of the intervention, without change in α. Dropout and missing data Missing data will be handled using Multiple Imputation (MI) assuming Missing At Random (MAR), and Complete Case Analysis will be presented as a comparison. The question of whether there is a systematic difference between dropouts and completers (dropout analysis) based on baseline characteristics will also be examined. Ethical considerations The study will be approved by the Institutional Helsinki Committee (Meir Medical Center). All participants will sign an informed consent and it will be emphasized to them that receiving the treatment does not entail participation in the study. All data will be anonymized and patients' confidentiality will be maintained. Primary outcome The primary outcome is the change in relative and total REM sleep time between the baseline period and three months after the intervention. A reduction of 10 minutes or more in WASO (Wakefulness After Sleep Onset. Secondary outcomes The secondary outcomes will examine a change of more than 10 in the PCL-5 index, an improvement of more than 3 points Subjective sleep quality questionnaires PSQI and RBD1Q, changes in biological stress indices (hair cortisol and inflammatory markers), and the difference between the cortisol values of PTSD patients before and after treatment compared to the reference values of healthy controls, in order to quantify the degree of biological normalization.

Sample Size Assuming a medium effect (Cohen's d≈0.5) on objective sleep measures, a minimum sample of approximately 48 supplemental participants is required to achieve 80% power (α=0.05). Considering an expected dropout rate of ~20%, 60 participants will be recruited for the study. Anticipated Challenges 1. Participant dropout and poor compliance - expected in the PTSD population, therefore approximately 60 participants will be recruited to compensate for an expected decrease to ~48 supplemental participants. Use of continuous wearable tracking is intended to improve and monitor compliance. 2. Reliability of wearable measures - Although not the standard in sleep research, wearable devices show high accuracy in key sleep measures (sleep time), WASO, HRV, especially in long-term monitoring and not as a point measurement. 3. Selection bias - patients who apply to participate in the study tend to be motivated to recover and do not reflect the entire patient population. In addition, there is a difference in comorbidity. An exploratory subgroup analysis will be performed 4. Dropout bias - the study is designed to characterize improvement measures, therefore information obtained from dropouts without clinical improvement will be calculated accordingly. 5. Regression to the mean - the baseline period allows for the establishment of a starting point and its analysis reduces the effect of regression to the mean on the statistical analysis. 6. Follow-up bias - patients will not be exposed to the data obtained from the measurement device. 7. Treatment heterogeneity - participants will receive background treatment according to clinical judgment; treatment will be documented and will be entered as a variable in the statistical models. Exploratory subgroup analysis will be performed. 8. Absence of a PTSD control group - This is a single-arm study before and after intervention. The use of prolonged baseline measurements and longitudinal models is intended to reduce bias and strengthen inferences about within-subject change. 9. Nerve block failure - injection in an abnormal position or sympathetic system at thoracic rather than cervical level. If no expected change in the indices is observed (Horner syndrome), the patient will be called for SGB on the left side. 10. Treatment changes during the study - the study attempts to simulate clinical conditions. Treatment changes are part of reality and from an ethical perspective, restrictions or changes to current treatment are avoided. Criteria for exclusion from the study: 1. Patient refusal to continue in one of the phases of the study 2. Failure to perform the block 3. Low patient compliance to use the ring/discontinuation of use of the ring. Products and continuity 1. This study will allow for the characterization of the physiological patterns measured using the wearable device, which correspond to clinical improvement in questionnaires and a decrease in cortisol levels. Identifying these relationships will lay the foundation for the future use of wearable technologies as an objective, accessible, and reliable tool for validating and proving a positive response to treatment for post-traumatic stress disorder. 2. Economic savings - improving the patients' functioning and returning them to the workforce may save the Ministry of Defense and the National Insurance Institute compensation payments and supportive treatments over the years. 3. Inclusion of this treatment in the Rehabilitation Department's treatment basket as a first or second line for patients suffering from severe arousal symptoms and sleep disorders. 4. Possible future uses - the methodology of wearable monitoring with cortisol measurement may be used for a broader platform: monitoring response to other treatments (drugs, psychology, electromagnetic stimulation), integration into wearable products, expanding indications For other disorders resulting from HPA dysregulation. 5. Preventive treatment - If the study is successful, we will consider an option for early treatment close to the triggering event (within weeks of exposure) in order to reduce the chances of it becoming chronic. 6. Reducing medication use - reducing the use of psychiatric medications, sleep medications - reducing side effects (fatigue, obesity), saving medical costs, improving quality of life and occupational functioning.

Inclusion Criteria:The study will include adults (age ≥18) with a confirmed diagnosis of post-traumatic stress disorder (PCL-5), who are capable of providing informed consent and are willing to continuously wear a smart device (ring and/or watch) throughout the study period.

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Exclusion Criteria:Allergy to local anesthetics, psychosis (active or past), active suicidality in the past 2 months, treatment with anticoagulants or P2Y12 antiplatelet agents, significant arrhythmias, pregnancy, clinical contraindication to SGB (such as infection limiting the procedure), as well as inability to wear a monitoring device or baldness preventing hair sampling. Patients who report data equal to 25% of what is expected for the follow-up period will be excluded from the study.

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