Laura Nawijn

Intranasal oxytocin as strategy for medication-enhanced psychotherapy of PTSD: Salience processing and fear inhibition processes

About ten percent of people experiencing a traumatic event will subsequently develop post-traumatic stress disorder (PTSD). PTSD is characterized by an exaggerated fear response which fails to extinguish over time and cannot be inhibited in safe contexts. The neurobiological correlates of PTSD involve enhanced salience processing (i.e. amygdala, dorsal anterior cingulate cortex (dACC) and anterior insula (AI) hyperactivity), and reduced top-down inhibitory control over this fear response (i.e. dorsal and ventromedial prefrontal cortex (vmPFC) hypoactivity and diminished structural and functional connectivity between the vmPFC, hippocampus and amygdala). Therefore, dampening the exaggerated fear response (i.e. by reducing amygdala hyperactivity) and enhancing top-down inhibitory control (i.e. by promoting prefrontal control over the amygdala) during psychotherapy is an important target for medication-enhanced psychotherapy (MEP) in PTSD patients. Since the neuropeptide oxytocin (OT) has been found to act on these two processes, we propose that OT is a promising pharmacological agent to boost treatment response in PTSD. Human fMRI studies indicate that intranasal OT attenuates amygdala (hyper)activity and enhances connectivity of the amygdala with the vmPFC and hippocampus, resulting in increased top-down control over the fear response. In addition, intranasal OT was found to attenuate amygdala-brainstem connectivity and to change activity and connectivity in nodes of the salience network (i.e. AI and dACC). Furthermore, OT administration may modulate hypothalamus-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) function and may enhance social behaviour, which could be beneficial in the therapeutic alliance. We also discuss contextual and interindividual factors (e.g. gender and social context) which may influence the effectiveness of OT in MEP. In all, we propose that intranasal OT given prior to each psychotherapy session may be an effective additive treatment to boost treatment response in PTSD.

ABERRANT RESTING-STATE BRAIN ACTIVITY IN POSTTRAUMATIC STRESS DISORDER: A META-ANALYSIS AND SYSTEMATIC REVIEW.

About 10% of trauma‐exposed individuals develop PTSD. Although a growing number of studies have investigated resting‐state abnormalities in PTSD, inconsistent results suggest a need for a meta‐analysis and a systematic review.

Intranasal Oxytocin Normalizes Amygdala Functional Connectivity in Posttraumatic Stress Disorder.

The neuropeptide oxytocin (OT) has been suggested as a promising pharmacological agent for medication-enhanced psychotherapy in posttraumatic stress disorder (PTSD) because of its anxiolytic and prosocial properties. We therefore investigated the behavioral and neurobiological effects of a single intranasal OT administration (40 IU) in PTSD patients. We conducted a randomized, placebo-controlled, cross-over resting-state fMRI study in male and female police officers with (n=37, 21 males) and without PTSD (n=40, 20 males). We investigated OT administration effects on subjective anxiety and functional connectivity of basolateral (BLA) and centromedial (CeM) amygdala subregions with prefrontal and salience processing areas. In PTSD patients, OT administration resulted in decreased subjective anxiety and nervousness. Under placebo, male PTSD patients showed diminished right CeM to left ventromedial prefrontal cortex (vmPFC) connectivity compared with male trauma-exposed controls, which was reinstated after OT administration. Additionally, female PTSD patients showed enhanced right BLA to bilateral dorsal anterior cingulate cortex (dACC) connectivity compared with female trauma-exposed controls, which was dampened after OT administration. Although caution is warranted, our findings tentatively suggest that OT has the potential to diminish anxiety and fear expression of the amygdala in PTSD, either via increased control of the vmPFC over the CeM (males) or via decreased salience processing of the dACC and BLA (females). Our findings add to accumulating evidence that OT administration could potentially enhance treatment response in PTSD.

Intranasal Oxytocin Administration Dampens Amygdala Reactivity towards Emotional Faces in Male and Female PTSD Patients

Post-traumatic stress disorder (PTSD) is a disabling psychiatric disorder. As a substantial part of PTSD patients responds poorly to currently available psychotherapies, pharmacological interventions boosting treatment response are needed. Because of its anxiolytic and pro-social properties, the neuropeptide oxytocin (OT) has been proposed as promising strategy for treatment augmentation in PTSD. As a first step to investigate the therapeutic potential of OT in PTSD, we conducted a double-blind, placebo-controlled, cross-over functional MRI study examining OT administration effects (40 IU) on amygdala reactivity toward emotional faces in unmedicated male and female police officers with (n=37, 21 males) and without (n=40, 20 males) PTSD. Trauma-exposed controls were matched to PTSD patients based on age, sex, years of service and educational level. Under placebo, the expected valence-dependent amygdala reactivity (ie, greater activity toward fearful-angry faces compared with happy-neutral faces) was absent in PTSD patients. OT administration dampened amygdala reactivity toward all emotional faces in male and female PTSD patients, but enhanced amygdala reactivity in healthy male and female trauma-exposed controls, independent of sex and stimulus valence. In PTSD patients, greater anxiety prior to scanning and amygdala reactivity during the placebo session were associated with greater reduction of amygdala reactivity after OT administration. Taken together, our results indicate presumably beneficial neurobiological effects of OT administration in male and female PTSD patients. Future studies should investigate OT administration in clinical settings to fully appreciate its therapeutic potential.

Social support, oxytocin and PTSD

Background A lack of social support and recognition by the environment is one of the most consistent risk factors for posttraumatic stress disorder (PTSD), and PTSD patients will recover faster with proper social support. The oxytocin system has been proposed to underlie beneficial effects of social support as it is implicated in both social bonding behavior and reducing stress responsivity, notably amygdala reactivity (Koch et al., 2014; Olff et al., 2010; Olff, 2012). The amygdala is found to be hypersensitive in people with PTSD. Method In order to investigate neurobiological mechanisms underlying potential preventive and therapeutic effects of intranasal oxytocin, we performed a series of fMRI studies (funded with a prestigious NWO TOP grant): BONDS standing for “Boosting Oxytocin after trauma: Neurobiology and the Development of Stress-related psychopathology” in acutely traumatized persons admitted to the emergency department (Frijling et al., 2014); BOOSTER “Boosting oxytocin after trauma: the effects of intranasal oxytocin administration on emotional and motivational processing and neural activity in PTSD” in police officers with and without PTSD. Results In this presentation, we present the BOOSTER results on the effects of a single oxytocin administration on amygdala reactivity in response to emotional faces in PTSD patients versus traumatized controls. We found significantly decreased bilateral amygdala reactivity towards emotional faces in PTSD patients compared to traumatized controls. Conclusions These promising results call for intervention studies such as studying the effects of medication (oxytocin) enhanced psychotherapy in PTSD patients.

Effects of intranasal oxytocin on amygdala reactivity to emotional faces in recently trauma-exposed individuals

UNLABELLED There is a need for effective, early post-trauma preventive interventions for post-traumatic stress disorder (PTSD). Attenuating amygdala hyperreactivity early post-trauma, a likely PTSD vulnerability factor, may decrease PTSD risk. Since oxytocin modulates amygdala reactivity to emotional stimuli, oxytocin administration early post-trauma may be a promising candidate for PTSD prevention. In a randomized double-blind placebo-controlled fMRI study, we investigated effects of a single intranasal oxytocin administration (40 IU) on amygdala reactivity to happy, neutral and fearful faces in 41 recently trauma-exposed men and women showing moderate to high distress after initial post-trauma screening. We explored treatment interactions with sex. Participants were scanned within 11 days post-trauma. Compared with placebo, oxytocin significantly increased right amygdala reactivity to fearful faces. There was a significant treatment by sex interaction on amygdala reactivity to neutral faces, with women showing increased left amygdala reactivity after oxytocin. These findings indicate that a single oxytocin administration may enhance fearful faces processing in recently trauma-exposed individuals and neutral faces processing in recently trauma-exposed women. These observations may be explained by oxytocin-induced increased salience processing. Clinical implications of these findings for PTSD prevention should be further investigated. TRIAL REGISTER Netherlands Trial Registry; Boosting Oxytocin after trauma: Neurobiology and the Development of Stress-related psychopathology (BONDS); NTR3190; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC = 3190.

Intranasal oxytocin enhances neural processing of monetary reward and loss in post-traumatic stress disorder and traumatized controls.

BACKGROUND Anhedonia is a significant clinical problem in post-traumatic stress disorder (PTSD). PTSD patients show reduced motivational approach behavior, which may underlie anhedonic symptoms. Oxytocin administration is known to increase reward sensitivity and approach behavior. We therefore investigated whether oxytocin administration affected neural responses during motivational processing in PTSD patients and trauma-exposed controls. METHODS 35 police officers with PTSD (21 males) and 37 trauma-exposed police officers without PTSD (19 males) were included in a within-subjects, randomized, placebo-controlled fMRI study. Neural responses during anticipation of monetary reward and loss were investigated with a monetary incentive delay task (MID) after placebo and oxytocin (40 IU) administration. RESULTS Oxytocin increased neural responses during reward and loss anticipation in PTSD patients and controls in the striatum, dorsal anterior cingulate cortex and insula, key regions in the reward pathway. Although PTSD patients did not differ from controls in motivational processing under placebo, anhedonia severity in PTSD patients was negatively related to reward responsiveness in the ventral striatum. Furthermore, oxytocin effects on reward processing in the ventral striatum were positively associated with anhedonia. CONCLUSIONS Oxytocin administration increased reward pathway sensitivity during reward and loss anticipation in PTSD patients and trauma-exposed controls. Thus, oxytocin administration may increase motivation for goal-directed approach behavior in PTSD patients and controls, providing evidence for a neurobiological pathway through which oxytocin could potentially increase motivation and reward sensitivity in PTSD patients.

Intranasal Oxytocin Affects Amygdala Functional Connectivity after Trauma Script-Driven Imagery in Distressed Recently Trauma-Exposed Individuals.

Approximately 10% of trauma-exposed individuals go on to develop post-traumatic stress disorder (PTSD). Neural emotion regulation may be etiologically involved in PTSD development. Oxytocin administration early post-trauma may be a promising avenue for PTSD prevention, as intranasal oxytocin has previously been found to affect emotion regulation networks in healthy individuals and psychiatric patients. In a randomized double-blind placebo-controlled between-subjects functional magnetic resonance (fMRI) study, we assessed the effects of a single intranasal oxytocin administration (40 IU) on seed-based amygdala resting-state FC with emotion regulation areas (ventromedial prefrontal cortex (vmPFC), ventrolateral prefrontal cortex (vlPFC)), and salience processing areas (insula, dorsal anterior cingulate cortex (dACC)) in 37 individuals within 11 days post trauma. Two resting-state scans were acquired; one after neutral- and one after trauma-script-driven imagery. We found that oxytocin administration reduced amygdala-left vlPFC FC after trauma script-driven imagery, compared with neutral script-driven imagery, whereas in PL-treated participants enhanced amygdala-left vlPFC FC was observed following trauma script-driven imagery. Irrespective of script condition, oxytocin increased amygdala–insula FC and decreased amygdala–vmPFC FC. These neural effects were accompanied by lower levels of sleepiness and higher flashback intensity in the oxytocin group after the trauma script. Together, our findings show that oxytocin administration may impede emotion regulation network functioning in response to trauma reminders in recently trauma-exposed individuals. Therefore, caution may be warranted in administering oxytocin to prevent PTSD in distressed, recently trauma-exposed individuals.

Intranasal oxytocin increases neural responses to social reward in post-traumatic stress disorder

Abstract Therapeutic alliance and perceived social support are important predictors of treatment response for post-traumatic stress disorder (PTSD). Intranasal oxytocin administration may enhance treatment response by increasing sensitivity for social reward and thereby therapeutic alliance and perceived social support. As a first step to investigate this therapeutical potential, we investigated whether intranasal oxytocin enhances neural sensitivity to social reward in PTSD patients. Male and female police officers with (n = 35) and without PTSD (n = 37) were included in a double-blind, randomized, placebo-controlled cross-over fMRI study. After intranasal oxytocin (40 IU) and placebo administration, a social incentive delay task was conducted to investigate neural responses during social reward and punishment anticipation and feedback. Under placebo, PTSD patients showed reduced left anterior insula (AI) responses to social rewards (i.e. happy faces) compared with controls. Oxytocin administration increased left AI responses during social reward in PTSD patients, such that PTSD patients no longer differed from controls under placebo. Furthermore, in PTSD patients, oxytocin increased responses to social reward in the right putamen. By normalizing abberant insula responses and increasing putamen responses to social reward, oxytocin administration may enhance sensitivity for social support and therapeutic alliance in PTSD patients. Future studies are needed to investigate clinical effects of oxytocin.

Decreased uncinate fasciculus tract integrity in male and female patients with PTSD: a diffusion tensor imaging study

Background Posttraumatic stress disorder (PTSD) is a disabling psychiatric disorder that has been associated with lower white matter integrity of tracts connecting the prefrontal cortex with limbic regions. However, previous diffusion tensor imaging (DTI) findings have been inconsistent, showing high variability in the exact location and direction of effects. Methods We performed probabilistic tractography of the bilateral uncinate fasciculus, cingulum and superior longitudinal fasciculus (both temporal and parietal projections) in male and female police officers with and without PTSD. Results We included 38 (21 men) police officers with and 39 (20 men) without PTSD in our analyses. Compared with trauma-exposed controls, patients with PTSD showed significantly higher mean diffusivity of the right uncinate fasciculus, the major white matter tract connecting the amygdala to the prefrontal cortex (p = 0.012). No other significant between-group or group × sex differences were observed. Mean diffusivity of the right uncinate fasciculus was positively associated with anxiety symptoms (r = 0.410, p = 0.013) in patients with PTSD as well as with amygdala activity (r = 0.247, p = 0.038) and ventromedial prefrontal cortex (vmPFC) activity (r = 0.283, p = 0.016) in all participants in response to happy and neutral faces. Limitations Our specific sample of trauma-exposed police officers limits the generalizability of our findings to other PTSD patient groups (e.g., civilian trauma). Conclusion Patients with PTSD showed diminished structural connectivity between the amygdala and vmPFC, which was correlated with higher anxiety symptoms and increased functional activity of these brain regions. Our findings provide additional evidence for the prevailing neurocircuitry model of PTSD, postulating that ineffective communication between the amygdala and vmPFC underlies decreased top–down control over fear responses.