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Corresponding author's contact information: Department of Psychology, University of Haifa, Mount Carmel, Haifa 31905, Israel, Telephone: 972-4-8249047, 972-52-3385944.
Corresponding author's: Department of Epidemiology, Biostatistics and Community Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
The hippocampus plays an important role in the pathophysiology of posttraumatic stress disorder (PTSD) and its prognosis. Accumulating findings suggest that individuals with larger pre-treatment hippocampal volume are more likely to benefit from PTSD treatment, but the mechanism underlying this effect is unknown. We investigated whether further increase in hippocampal volume during treatment explains the better prognosis of individuals with greater pre-treatment hippocampal volume.
Method
We collected structural magnetic resonance images (MRI) from patients with PTSD before and after treatment. We examined whether larger hippocampal volume moderates the effect of increased hippocampal volume during treatment on symptom reduction. Given the relatively small sample sizes of treatment studies with pre- and post-treatment MRI, we focused on effect sizes and sought to replicate findings in an external sample. We tested our hypothesis in Study 1 (N=38; Prolonged Exposure Therapy), then tested whether results can be externally replicated in Study 2 (N=20; Ketamine Infusion followed by Exposure Therapy).
Results
Findings from Study 1 revealed that increased right hippocampal volume during treatment was associated with greater PTSD symptom reduction only in patients with greater pre-treatment right hippocampal volume (p=.03; Eta2=.13, a large effect). Findings were partially replicated in Study 2 for depressive symptoms (p=.034; Eta2=.25, a very large effect) and for PTSD symptoms (p=.15; Eta2=.15, a large effect).
Conclusions
Elucidating increased hippocampal volume as one of the neural mechanisms predictive of therapeutic outcome for individuals with larger pre-treatment hippocampal volume may help identify clinical targets for this subgroup.
Habetha S, Bleich S, Weidenhammer J & Fegert JM. (2012): A prevalence-based approach to societal costs occurring in consequence of child abuse and neglect. Child and adolescent psychiatry and mental health 6: 1-10.
), but the mechanisms underlying this effect remain to be discovered.
Hippocampal volume in PTSD has been the focus of much research because of the central role it plays in regulating stress hormones and responses through the hypothalamic-pituitary-adrenal axis (
). A large-scale study conducted by the Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium suggested that of all eight subcortical structures examined (nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, and lateral ventricle), the most robust difference between individuals with PTSD and trauma-exposed healthy controls (TEHCs) was hippocampal volume, with individuals with PTSD showing significantly lower hippocampal volume compared to TEHCs (
). These findings are consistent with the neurobiological model of PTSD, according to which the hippocampus subserves extinction memory recall and context-encoding during a traumatic event, and it is therefore likely to play an important role in context differentiation between cues that signal safety and those that signal threat (
Studies of PTSD treatment support the putative role the hippocampus plays in PTSD, and suggest that individuals with larger hippocampal volume are more likely to benefit from treatment (
). Although the accumulating findings suggest that larger hippocampal volume may be key to successful treatment, the neural mechanism underlying this effect, namely which neural alterations occur during treatment in individuals with larger pre-treatment hippocampal volume, is not clear.
In the current investigation, we hypothesized that the mechanism underlying the greater response to PTSD treatment of individuals with larger pre-treatment hippocampal volume is an additional increase in hippocampal volume during treatment. This hypothesis is based on theories arguing for the benefit of capitalizing on strengths — the “rich get richer” phenomenon (
): individuals with already larger pre-treatment hippocampal volume may benefit most from leveraging this strength, gaining further increase in hippocampal volume during treatment for showing better treatment outcomes. The underlying mechanism may be extinction learning, which is key to successful PTSD treatment (
Meaney MJ & Szyf M. (2022): Environmental programming of stress responses through DNA methylation: life at the interface between a dynamic environment and a fixed genome. Dialogues in clinical neuroscience.
) via brain regions involved in autobiographical memory. During the process of extinction recall, new learning is attained, which can be translated into therapeutic gains, potentially reversing the adverse effect of PTSD on hippocampal volume. Accumulated findings suggest that an increase in hippocampal volume may be associated, at least for some patients, with greater treatment efficacy. Significant post-treatment volume increases were reported in the bilateral hippocampus (
Association among clinical response, hippocampal volume, and FKBP5 gene expression in individuals with posttraumatic stress disorder receiving cognitive behavioral therapy.
Association among clinical response, hippocampal volume, and FKBP5 gene expression in individuals with posttraumatic stress disorder receiving cognitive behavioral therapy.
) given the mixed findings in the literature, there is no robust evidence, to date, of therapy-induced changes in the hippocampus at the group level, and much heterogeneity may exist between patients. Given the better prognosis of individuals with larger hippocampal volume pre-treatment as well as the beneficial effect of increased hippocampal volume during treatment for a subset of the patients, we hypothesized that only individuals with already larger pre-treatment hippocampal volume are able to benefit from further increased hippocampal volume during treatment to achieve symptom reduction. The present study tested this hypothesis. We investigated whether a further increase in hippocampal volume during treatment is the mechanism underlying the better prognosis of individuals with larger pre-treatment hippocampal volume (Figure 1).
Figure 1On the left: The proposed conceptual model according to which an increase in hippocampal volume during treatment explains the better prognosis of individuals with greater pre-treatment hippocampal volume. In the middle: Study 1 (Prolonged Exposure Therapy). On the right: Study 2 (ketamine and exposure therapy).
), especially in small treatment samples with repeated MRI scans, we resorted to an external validation design. Specifically, we tested our hypothesis on one sample in which PE was administered, then tested its potential replication in an independent sample, in which both PE and ketamine were administered. The two treatment samples differ in treatment, methodology, and sample characteristics, representing a rigorous test of the validity and generalizability of the findings. We focused on both PTSD and depressive symptoms because of their centrality in PE (
Study 1. Individuals with PTSD and trauma-exposed, medically healthy controls (TEHC) matched on gender, age at exposure to trauma, trauma type (interpersonal vs. non-interpersonal) and duration, race, and ethnicity were recruited through advertisement and fliers. All participants met DSM-IV (
) PTSD criterion A1 for adult traumatic events, including vehicular accidents, sexual or physical assaults, and witnessing serious injuries or deaths. Medical history, review of systems, physical examination, and laboratory tests determined the health status of all participants.
Individuals with PTSD were included in the study only following clinician diagnosis of PTSD and a Clinician-Administered PTSD Scale (CAPS) (
) score of ≥50. Full inclusion and exclusion criteria for individuals with PTSD appear in Table S1 in the online supplements. TEHC exclusion criteria were: any current or past Axis I disorder, and a CAPS score >19, which is considered symptomatic (
). The New York State Psychiatric Institute Institutional Review Board approved all procedures, and all participants provided written informed consent for the trial, which was registered at clinicaltrials.gov (identifier NCT01576510). Eighty-five participants consented. A total of 43 individuals did not drop out and had both pre- and post-treatment MRI scans (24 of them receiving treatment), and therefore were included in the analyses. To enlarge variability in hippocampal volume pre-treatment and in changes in hippocampal volume during treatment, we used the data of both individuals with PTSD receiving PE and of TEHC individuals not receiving treatment. Thus, the TEHCs served as a “control” to expand heterogeneity in hippocampal volume variance, enabling the capture of potential associations, if they indeed exist. The sample of Study 1 overlaps with Rubin et al. (
Study 2. Individuals with PTSD were recruited to participate in the study. PTSD diagnosis was established using the Clinician-Administered PTSD Scale (CAPS-5) (
). Patients were excluded for acute medical illness based on medical history, physical examination, and screening laboratory test values. Possible cardiac issues were screened using EKG. The Yale University School of Medicine Institutional Review Board approved all procedures, and all participants provided written informed consent for the trial, which was registered at clinicaltrials.gov (identifier NCT02727998).
Twenty-eight individuals suffering from PTSD consented. A total of 20 individuals (9 receiving ketamine; 11 receiving midazolam) did not drop out and had both pre- and post-treatment MRI scans, and were therefore included in the analyses.
Treatments
Study 1. Individuals with PTSD started treatment with one of two trained therapists who adhered to the 10-week standard PE protocol (
Randomized trial of prolonged exposure for posttraumatic stress disorder with and without cognitive restructuring: outcome at academic and community clinics.
Journal of consulting and clinical psychology.2005; 73: 953
). According to the protocol, patients are required to (a) repeatedly recount the traumatic experience by describing the event in detail in the present tense with guidance from the therapist (imaginal exposure), and (b) identify and confront a range of previously avoided trauma reminders, such as specific stimuli and situations, to extinguish fear responses (in vivo exposure). Before the start of the study, therapists treated two pilot cases under supervision to confirm their expertise. In the course of the study, they were continuously monitored and supervised by PE experts for adherence and competence. The independent assessors used the PE integrity measure (
Study 2. While the trauma memory was reactivated into a labile state, either ketamine, a non-competitive Nmethyl-D-aspartate glutamate receptor (NMDAR) antagonist (0.5mg/kg), or benzodiazepine midazolam, a positive allosteric modulator of GABAA receptors (0.045mg/kg), infusion was administered inside the MRI scanner for 40 minutes. Twenty-four hours post-infusion, participants began daily exposure-based therapy (
) that included imaginal and in vivo exposure. The PE protocol was administered by one of two trained therapists and was identical in its goals and therapeutic techniques with that used in Study 1, but with differences in the time frame. The complete study procedure, including imaging sessions, lasted 7 days. For a detailed description of the design and procedure, see Duek et al. (
) to assess PTSD symptoms and BDI to assess depressive symptoms, pre- and post-treatment. Given that treatments lasted for 7 days, we used the 1-month post-treatment assessment of outcome in all analyses.
MRI Data Acquisition. See online supplements.
Overview of statistical analyses
To test the study hypothesis, we examined whether larger hippocampal volume moderates the effect of increased hippocampal volume during treatment on symptom reduction, so that increased hippocampal volume during treatment is associated with greater symptom reduction only for individuals with larger pre-treatment hippocampal volume. We focused on the interaction between the baseline level of hippocampal volume and changes in hippocampal volume over the course of treatment in predicting outcome. Such an interaction between the baseline value of a given variable and changes during treatment in that variable was designed to identify the process of change in treatment associated with best outcomes for individuals holding a given pre-treatment characteristic (
Association among clinical response, hippocampal volume, and FKBP5 gene expression in individuals with posttraumatic stress disorder receiving cognitive behavioral therapy.
); therefore, we conducted separate analyses for right and left hippocampal volume. We conducted a set of linear regressions to adjust pre- and post-treatment left and right hippocampal volume for the relevant estimated intracranial volume (eTIV). Positive values of adjusted features mean higher scores than what can be anticipated based on eTIV. We then used the residual scores in two multiple regressions: the first tested the interaction between pre-treatment and changes (from pre- to post-treatment) in left hippocampal volume in predicting pre- to post-treatment symptom changes, accounting for all main effects; the second repeated the analysis focusing on the right hippocampus.
Given the small sample sizes, we focused on effect sizes, with eta square of .01 meaning a small effect size, .06 a medium effect size, and .14 a large effect size (
). We first tested the study hypothesis on the sample of Study 1. If confirmed (namely, showing medium-to-large effect sizes), we tested the validity of the findings externally, based on the sample of Study 2.
Results
The pre-treatment demographics and clinical characteristics of the two samples appear in Table S2 in the online supplements.
Study 1. The interaction between pre-treatment right hippocampal volume and changes in right hippocampal volume during treatment showed a large effect size in predicting treatment outcome, as measured by CAPS (B=-0.006, S.E.=0.02, t=-0.35, p=.03; Eta2=.13), and a medium effect size in predicting treatment outcome using BDI (B=-0.00002, S.E.=0.00002, t=-1.41, p=.16; Eta2=.0.06). Simple slope analysis of the CAPS suggested that for those with large right hippocampal volume, there was a significant association between increased right hippocampal volume and greater reduction in PTSD symptoms (B=-0.05. S.E.=0.05, t=-1.0, p=.04). By contrast, for those with low right hippocampal volume, there was an insignificant association between increased right hippocampal volume and less reduction in PTSD symptoms (B=0.04, S.E.=0.03, t=1.33, p=.19). As shown in Figure 2, an increase in right hippocampal volume during treatment was associated with greater PTSD symptom reduction for those with greater pre-treatment right hippocampal volume.
Figure 2The interaction between pre-treatment right hippocampal volume and changes in its volume in predicting CAPS changes in Study 1. Note. Low vs. high pre-treatment hippocampal volume refers to 1 standard deviation above and below the mean, respectively. This categorization is for visualization only, and hippocampal volume was used as a continuous variable in all analyses.
The interaction between pre-treatment left hippocampal volume and changes in left hippocampal volume during treatment showed only a low-to-medium effect size in predicting treatment outcome, as measured by CAPS (B=-0.00002, S.E.=0.00002, t=-0.72, p=.19; Eta2=.05) and BDI (B=-0.00006, S.E.=0.00004, t=-1.31, p=.48; Eta2=.01).
Study 2. The interaction between pre-treatment right hippocampal volume and changes in right hippocampal volume during treatment showed a very large effect size in predicting treatment outcome as measured by BDI (B=-0.003, S.E.=0.001, t=-2.31, p=.034; Eta2=.25), and a large effect size, as measured by PCL (B=-0.002, S.E.=0.001, t=-1.50, p=.15; Eta2=.15). Simple slope analysis of the BDI suggested that for those with large right hippocampal volume, there was a significant association between increased right hippocampal volume and greater reduction in depressive symptoms (B=-0.57, S.E.=0.25, t=-2.24, p=.04). By contrast, for those with low right hippocampal volume, there was an insignificant association between increased right hippocampal volume and less reduction in depressive symptoms (B=0.04, S.E.=0.21, t=1.70, p=.11). As shown in Figure 3, increase in right hippocampal volume during treatment was associated with greater depressive symptom reduction for those with greater pre-treatment right hippocampal volume.
Figure 3The interaction between pre-treatment right hippocampal volume and changes in its volume in predicting BDI changes in Study 2. Note. Low vs. high pre-treatment hippocampal volume refers to 1 standard deviation above and below the mean, respectively. This categorization is for visualization only, and hippocampal volume was used as a continuous variable in all analyses. The differences in the changes from pre-treatment to post-treatment within each study (Figure 2 vs. Figure 3) may be due to the specific pipeline used. For example, Study 2 used a longitudinal protocol whereas Study 1 did not.
The interaction between pre-treatment left hippocampal volume and changes in left hippocampal volume during treatment did not predict treatment outcome, using either PCL (B=0.0003, S.E.=0.0004, t=0.67, p=.51; Eta2=.03) or BDI (B=0.0001, S.E.=0.0003, t=0.29, p=.77; Eta2=.005).
Sensitivity analyses. (a) Given that findings in Study 2 replicated those of Study 1 mainly for depressive and less for PTSD symptoms, and because of potential differences between the CAPS and PCL (
) in evaluating re-experiencing, which is a core characteristic of PTSD psychopathology, and a main mechanism underlying PE effects, we tested whether the re-experiencing subscale of PCL yielded larger effects. Findings reveal that the interactions for the right and left hippocampus were insignificant (B=-0.0007, S.E.=0.0005, t=-1.43, p=.17; Eta2=.11), and moderately significant (B=-0.0001, S.E.=0.000006, t=-1.83, p=.08; Eta2=.17, a large effect size), respectively. (b) We tested whether findings were replicated when controlling for age and gender. For Study 1, the effect size of the relevant interaction remained similar (B=-0.00008, S.E.=0.00003, t=-2.43, p=.02; Eta2=.15, a large effect size). For Study 2, the effect sizes of the relevant interaction remained relatively similar for both PCL (B=-0.001, S.E.=0.002, t=-0.85, p=.41; Eta2=.05, a medium effect size) and BDI (B=-0.002, S.E.=0.002 , t=-1.77, p=.09; Eta2=.16, a very large effect size). (c) Reanalyzing the data from Study 2 separately for the ketamine (n=11) and midazolam (n=9) revealed a significant effect for ketamine. The findings for ketamine suggest that the interaction between pre-treatment right hippocampal volume and changes in right hippocampal volume during treatment showed a very large effect size in predicting treatment outcome as measured by BDI (B=-0.004, S.E.=0.001; t=-2.75; p=.002; Eta2=0.52). By contrast, the findings for midazolam (n=9) yielded a non-significant interaction (B=-0.0008, S.E.=0.001; t=-0.58; p=.58; Eta2=0.06). A simple slope analysis of the BDI for ketamine suggested that for those with large right hippocampal volume, there was a significant association between increased right hippocampal volume and greater reduction in depressive symptoms (B=-0.61, S.E.=.20, t=-3.02, p=0.02), whereas for those with low right hippocampal volume, there was an insignificant association between increased right hippocampal volume and less reduction in depressive symptoms (B=0.19, S.E.=0.17, t=1.07, p=0.32).
Discussion
The findings suggest that one possible mechanism underlying the ability of individuals with greater pre-treatment right hippocampal volume to show better prognosis is increased hippocampal volume during treatment. The findings of Study 1 indicated that an increase in right hippocampal volume during treatment was significantly and meaningfully associated with greater PTSD and depressive symptom reduction only for patients with greater pre-treatment right hippocampal volume. The findings were partially replicated in a separate external sample, for both depressive symptom reduction and reduced PTSD symptoms. Based on the findings, it can be suggested that for individuals with a relatively larger hippocampus, successful treatment for PTSD may compensate for PTSD-related neural aberrations, potentially enabling better extinction of memory recall and facilitating context differentiation. The replication of the findings in an external sample that received a different treatment composition is an important strength of the current work.
The hippocampus is considered to play an important role in PTSD pathophysiology and treatment through its involvement in memory functions (
). The findings suggest that over the course of treatment, hippocampal volume may increase through neurogenesis or show greater density, which potentially can lead to greater functional connectivity to other brain areas (
). This process may point to the potential of hippocampus plasticity in humans, which may have some similarities with hippocampal neurogenesis processes that were documented in mice (
). Therefore, critical aspects of impaired hippocampal function, associated with PTSD, may potentially be reversed as a result of successful treatment, particularly for individuals with large pre-treatment hippocampal volume. This may also explain how effective treatment for PTSD produces the therapeutic response by causing new cell growth in an area of the brain known to suffer cell death and atrophy as a result of trauma. Future studies should examine whether the larger hippocampal volume may result in less activation of the amygdala during the process of reconsolidation of the traumatic memory.
Both Study 1 and Study 2 included exposure to trauma as part of the treatment, therefore it is not possible to determine whether the mechanism underpinning the good prognosis for patients with larger hippocampal volume is common across other types of effective treatments for PTSD or a characteristic of exposure treatment only. One possibility is that the documented neural changes in the hippocampus in individuals with large pre-treatment hippocampal volume are central to any process of recovery from PTSD. Such a conclusion is consistent with previous findings suggesting that changes were observed in the activation of brain regions considered implicated in PTSD (such as the medial prefrontal cortex, the rostral anterior cingulate cortex, and the amygdala) following various forms of treatment (e.g., imaginal exposure and cognitive restructuring therapy, exposure and cognitive restructuring therapy, PE and virtual reality exposure therapy, group MBET, and individual and group CBT) (
). Alternatively, because both treatments in the present study contained an exposure component, the observed brain alterations may be conceptualized as neural correlates of extinction learning (
). Future studies testing whether the current findings can be replicated in non-exposure treatment are needed to determine which of the two alternative conclusions is valid.
It is not entirely clear why the CAPS findings of Study 1 were replicated in Study 2 mainly for depressive symptoms. The many differences between the studies may account of the slightly different results: the different characteristics of the patients’ population (including different inclusion and exclusion criteria, demographic differences), differences in treatment duration, and differences in the type of treatments provided. For example, regarding the treatment provided, the original findings of the Study 2 trial suggest greater sensitivity to changes during treatment of depression than of PTSD symptoms (
), possibly because half of the patients in Study 2 received ketamine. Accumulating findings support the potential therapeutic role of ketamine in reducing depressive symptoms (
). This post hoc explanation receives support from the large effects that appeared when the ketamine condition was analyzed separately (see sensitivity analyses). Another possible reason for the differences between the studies may have to do with the different measures used. Study 1 used CAPS to assess PTSD symptoms, whereas Study 2 used PCL. The literature suggests that although PCL and CAPS are highly correlated in cross-sectional designs, their sensitivity to change differs, with CAPS being more sensitive to symptom reduction (
). Previous literature suggests that the correlation between reduction in symptoms using CAPS and BDI was higher (r=.9) than the correlation between PCL and BDI (r=.8) (
). This literature may provide some explanation why the findings based on CAPS in Study 1 were replicated in Study 2 mainly using BDI. This post hoc reasoning received only partial support when we focused on a core PTSD characteristic, the reexperiencing scale (rather than the full PCL scale) in Study 2 (see sensitivity analyses).
The most important limitation of the present work is the small sample size that forced us to focus mainly on effect sizes. It should be noted that the sample sizes of the RCTs we used in the present study are within the range of 8 to 39 (mean = 18.25), typically published in the literature on brain changes as a result of PTSD treatments (
). To mitigate this limitation, we conducted external validation, strengthening the potential validity of the findings. Yet, additional replications in large samples are needed. Such replications would also enable testing the potential effects of trauma type (
), resources activated during trauma exposure, distress experienced during the therapy session, general activity level, comorbidities with major depressive disorder, and pharmacotherapy. Such replication would also enable quantifying the size of the hippocampus (relative to the individual’s eTIV) that may indicate a better treatment prognosis, as well as the individual’s characteristics that may affect such an estimate. It may also shed further light on the mechanisms underlying the present findings, answering questions like whether resources activated during trauma exposure may explain why increased hippocampal volume for those with already large hippocampal volume results in a greater reduction in symptoms. We did not use a prospective pre-trauma design, enrolling individuals before exposure to the trauma, therefore causal inferences should be made with caution. A previous study found a specific effect of the volume of the anterior hippocampus for non-exposure treatments (
). Therefore, future studies should further investigate whether certain subregions of the hippocampus are driving the findings reported here, and whether the pattern of results differs between exposure and non-exposure treatments.
The findings shed light on the potential mechanism underlying the better prognosis for individuals with larger pre-treatment hippocampal volume in the treatment of PTSD, and point to the role that an increase in hippocampal volume during treatment may play in driving better outcomes. The findings suggest a potential merit of classical theories of treatment personalization, such as the theory of capitalizing on strengths (
), in the field of neuroscience. Specifically, those individuals who may be most able to benefit from an increase in hippocampal volume are those who have a larger volume even before the start of treatment, suggesting that the “rich get richer” phenomenon may be at play regarding hippocampal volume. This raises potential hypotheses about the different capabilities of individuals to benefit from curative processes such as neurogenesis. Elucidating neural biomarkers predictive of therapeutic outcome for subgroups of individuals with PTSD, in this case, individuals with larger hippocampal volume, may assist in identifying clinical targets for treatment selection and improve treatments for this subgroup of individuals (
). The finding that the main results were replicated despite the many differences between the two studies further supports the validity and generalizability of the findings and their robustness for replication.
The authors report no biomedical financial interests or potential conflicts of interest. This paper has not been previously presented.
Habetha S, Bleich S, Weidenhammer J & Fegert JM. (2012): A prevalence-based approach to societal costs occurring in consequence of child abuse and neglect. Child and adolescent psychiatry and mental health 6: 1-10.
Meaney MJ & Szyf M. (2022): Environmental programming of stress responses through DNA methylation: life at the interface between a dynamic environment and a fixed genome. Dialogues in clinical neuroscience.
Association among clinical response, hippocampal volume, and FKBP5 gene expression in individuals with posttraumatic stress disorder receiving cognitive behavioral therapy.
Randomized trial of prolonged exposure for posttraumatic stress disorder with and without cognitive restructuring: outcome at academic and community clinics.
Journal of consulting and clinical psychology.2005; 73: 953
Financial Disclosures and acknowledgements: Work on this paper was supported by NIMH grant R01MH105355 (Dr. Neria), and R01MH072833 (Dr. Neria). Independent Investigator Grant from the Brain and Behavior Research Foundation (Dr. Harpaz-Rotem); by the Clinical Neurosciences Division of the National Center for PTSD (Dr. Harpaz-Rotem); a donation from the American Brain Society (Dr. Harpaz-Rotem), and the Yale Center for Clinical Investigation (YCCI; Dr. Harpaz-Rotem) supported by CTSA Grant from the National Center for Advancing Translational Science (NCATS; Dr. Harpaz-Rotem), a component of the National Institutes of Health (NIH).
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