Neuroscience Informed Prolonged Exposure Practice: Increasing Efficiency and Efficacy Through Mechanisms

Prolonged exposure (PE) is an empirically supported efficacious treatment for posttraumatic stress disorder (PTSD). In this focused review, we briefly review the neurobiological networks in PTSD relevant to PE, discuss the theoretical basis of PE, review the neurobiological mechanisms underlying the effectiveness of PE and identify the enhancements that can be applied to increase treatment response and retention. Based on the reviewed studies, it is clear that PTSD results in disrupted network of interconnected regions, and PE has been shown to increase the connectivity within and between these regions. Successful extinction recall in PE is related to increased functional coherence between the ventromedial prefrontal cortex (vmPFC), amygdala and the hippocampus. Increased connectivity within the dorsolateral PFC (dlPFC) following PE is associated with more effective downregulation of emotional responses in stressful situations. Pre-existing neural connectivity also in some cases predicts response to exposure treatment. We consider various enhancements that have been used with PE, including serotonin reuptake inhibitors (SSRIs), D-cycloserine (DCS), allopregnanolone (ALLO) and propranolol, repetitive transcranial magnetic stimulation (rTMS), oxytocin and MDMA. Given that neural connectivity appears to be crucial in mechanisms of action of PE, rTMS is a logical target for further research as an enhancement of PE. Additionally, exploring the effectiveness and mechanisms of action of oxytocin and MDMA in conjunction with PE may lead to improvement in treatment engagement and retention

Change in posttraumatic stress disorder–related thoughts during treatment: Do thoughts drive change when pills are involved?

Posttraumatic negative thoughts about one's self and the world are related to posttraumatic stress disorder (PTSD) symptom severity and change in cognitive behavioral treatment (CBT), but little is known about this association when CBT is delivered with medication. The current study presents a planned comparison of changes in negative posttraumatic thoughts during (a) prolonged exposure (PE) plus pill placebo (PE+PLB), (b) sertraline plus enhanced medication management (SERT+EMM), and (c) PE plus sertraline (PE+SERT) as part of a randomized clinical trial in a sample of 176 veterans. Lagged regression modeling revealed that change in posttraumatic negative thoughts was associated with PTSD symptom change in the conditions in which participants received sertraline, ds = 0.14-0.25, ps = 0.04-.001). However, contrary to previous research, the models that started with symptom change were also statistically significant, d = 0.23, p < .001, for the lagged effect of symptoms on negative thoughts about self in the SERT+EMM condition, indicating a bidirectional association between such thoughts and PTSD symptoms. In the PE+PLB condition, no significant association between posttraumatic thoughts and PTSD symptoms emerged in either direction. These results suggest that the previously demonstrated role of change in posttraumatic thoughts leading to PTSD symptom reduction in PE may be altered when combined with pill administration, either active or placebo

Change in posttraumatic stress disorder–related thoughts during treatment: Do thoughts drive change when pills are involved?

Posttraumatic negative thoughts about one’s self and the world are related to posttraumatic stress disorder (PTSD) symptom severity and change in cognitive behavioral treatment (CBT), but little is known about this association when CBT is delivered with medication. The current study presents a planned comparison of changes in negative posttraumatic thoughts during (a) prolonged exposure (PE) plus pill placebo (PE+PLB), (b) sertraline plus enhanced medication management (SERT+EMM), and (c) PE plus sertraline (PE+SERT) as part of a randomized clinical trial in a sample of 176 veterans. Lagged regression modeling revealed that change in posttraumatic negative thoughts was associated with PTSD symptom change in the conditions in which participants received sertraline, ds = 0.14–0.25, ps = 0.04–.001). However, contrary to previous research, the models that started with symptom change were also statistically significant, d = 0.23, p < .001, for the lagged effect of symptoms on negative thoughts about self in the SERT+EMM condition, indicating a bidirectional association between such thoughts and PTSD symptoms. In the PE+PLB condition, no significant association between posttraumatic thoughts and PTSD symptoms emerged in either direction. These results suggest that the previously demonstrated role of change in posttraumatic thoughts leading to PTSD symptom reduction in PE may be altered when combined with pill administration, either active or placebo.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/172308/1/jts22762_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/172308/2/jts22762.pd

DNA sensor associated type I Interferon signalling is increased in ulcerative colitis and induces JAK-dependent inflammatory cell death in colonic organoids

DNA sensor pathways can initiate inflammasome, cell death and type I interferon (IFN) signalling in immune-mediated inflammatory diseases (IMIDs); including type I interferonopathies. We investigated the involvement of these pathways in the pathogenesis of ulcerative colitis (UC); by analysing expression of DNA sensor, inflammasome, and type I IFN biomarker genes in colonic mucosal biopsy tissue from control (n=31), inactive UC (n=31), active UC (n=33) and a UC single cell RNA-Seq dataset. The effects of type I IFN (IFN-β), IFN-γ and TNF-α on gene expression, cytokine production and cell death were investigated in human colonic organoids. In organoids treated with cytokines alone, or in combination with NLRP3, caspase or JAK inhibitors, cell death was measured, and supernatants were assayed for IL-1β/IL-18/CXCL10. The expression of DNA sensor pathway genes - PYHIN family members (AIM2, IFI16, MNDA, PYHIN1), as well as ZBP1, cGAS and DDX41 were increased in active UC and expressed in a cell type restricted pattern. Inflammasome genes (CASP1, IL1B, IL18), type I IFN inducers (STING, TBK1, IRF3), IFNB1 and type I IFN biomarker genes (OAS2, IFIT2, MX2) were also increased in active UC. Co-treatment of organoids with IFN-β or IFN-γ and TNFα increased expression of IFI16, ZBP1, CASP1, cGAS and STING, induced cell death and IL-1β/IL-18 secretion. This inflammatory cell death was blocked by the JAK inhibitor tofacitinib but not by inflammasome or caspase inhibitors. Increased type I IFN activity may drive elevated expression of DNA sensor genes and JAK-dependent but inflammasome-independent inflammatory cell death of colonic epithelial cells in UC