Jindra Bakker

Therapygenetics in mindfulness-based cognitive therapy: do genes have an impact on therapy-induced change in real-life positive affective experiences?

Positive affect (PA) has an important role in resilience against depression and has been shown to increase with mindfulness-based cognitive therapy (MBCT). To elucidate the underlying mechanisms of change in PA as well as develop insights that may benefit personalized medicine, the current study examined the contribution of genetic variation to individual differences in change in PA in response to MBCT. Individuals (n=126) with residual depressive symptoms were randomized to either an MBCT group or treatment as usual. PA was assessed using experience sampling methodology (ESM). Single-nucleotide polymorphisms (SNPs) in genes known to be involved in reward functioning were selected. SNPs in the genes for brain-derived neurotrophic factor (BDNF), the muscarinic acetylcholine receptor M2 (CHRM2), the dopamine receptor D4 (DRD4) and the μ1 opioid receptor (OPRM1) significantly moderated the impact of treatment condition over time on PA. Genetic variation in the genes for CHRM2 and OPRM1 specifically had an impact on the level of PA following MBCT. The current study shows that variation in response to MBCT may be contingent on genetic factors associated with the regulation of PA. These findings contribute to our understanding of the processes moderating response to treatment and prediction of treatment outcome.

Acceptance and Commitment Therapy in Daily Life Training: A Feasibility Study of an mHealth Intervention

Background With the development of mHealth, it is possible to treat patients in their natural environment. Mobile technology helps to bridge the gap between the therapist’s office and the “real world.” The ACT in Daily Life training (ACT-DL) was designed as an add-on intervention to help patients practice with acceptance and commitment therapy in their daily lives. The ACT-DL consists of two main components: daily monitoring using experience sampling and ACT training in daily life. Objectives To assess the acceptability and feasibility of the ACT-DL in a general outpatient population. A secondary objective was to conduct a preliminary examination of the effectiveness of the ACT-DL. Methods An observational comparative study was conducted. The experimental group consisted of 49 patients who volunteered for ACT-DL, and the control group consisted of 112 patients who did not volunteer. As part of an inpatient treatment program, both groups received a 6-week ACT training. Participants went home to continue their treatment on an outpatient basis, during which time the experimental group received the 4-week add-on ACT-DL. Acceptability and feasibility of the ACT-DL was assessed weekly by telephone survey. Effectiveness of the ACT-DL was evaluated with several self-report questionnaires ( Flexibility Index Test (FIT-60): psychological flexibility, Brief Symptom Inventory: symptoms, Utrechtse Coping List: coping, and Quality of life visual analog scale (QoL-VAS): quality of life). Results More than three-quarters of the participants (76%) completed the full 4-week training. User evaluations showed that ACT-DL stimulated the use of ACT in daily life: participants practiced over an hour a week (mean 78.8 minutes, standard deviation 54.4), doing 10.4 exercises (standard deviation 6.0) on average. Both ACT exercises and metaphors were experienced as useful components of the training (rated 5 out of 7). Repeated measures ANCOVA did not show significant effects of the ACT-DL on psychological flexibility (P=.88), symptoms (P=.39), avoidant coping (P=.28), or quality of life (P=.15). Conclusions This is the first study that uses experience sampling to foster awareness in daily life in combination with acceptance and commitment therapy to foster skill building. Adherence to the ACT-DL was high for an intensive mHealth intervention. ACT-DL appears to be an acceptable and feasible mHealth intervention, suitable for a broad range of mental health problems. However, short-term effectiveness could not be demonstrated. Additional clinical trials are needed to examine both short-term and long-term effects.

Behavioral pattern separation and its link to the neural mechanisms of fear generalization

Abstract Fear generalization is a prominent feature of anxiety disorders and post-traumatic stress disorder (PTSD). It is defined as enhanced fear responding to a stimulus that bears similarities, but is not identical to a threatening stimulus. Pattern separation, a hippocampal-dependent process, is critical for stimulus discrimination; it transforms similar experiences or events into non-overlapping representations. This study is the first in humans to investigate the extent to which fear generalization relies on behavioral pattern separation abilities. Participants (N = 46) completed a behavioral task taxing pattern separation, and a neuroimaging fear conditioning and generalization paradigm. Results show an association between lower behavioral pattern separation performance and increased generalization in shock expectancy scores, but not in fear ratings. Furthermore, lower behavioral pattern separation was associated with diminished recruitment of the subcallosal cortex during presentation of generalization stimuli. This region showed functional connectivity with the orbitofrontal cortex and ventromedial prefrontal cortex. Together, the data provide novel experimental evidence that pattern separation is related to generalization of threat expectancies, and reduced fear inhibition processes in frontal regions. Deficient pattern separation may be critical in overgeneralization and therefore may contribute to the pathophysiology of anxiety disorders and PTSD.

Real-Life Validation of Reduced Reward Processing in Emerging Adults With Depressive Symptoms

Subclinical symptoms of depression are common in emerging adults. Anhedonia is one such symptom that specifically puts one at risk for developing clinical depression. Recently, important progress has been made in elucidating the underlying neurobiology of anhedonia. This progress rests on many experimental studies examining how subjects with depressive symptoms respond to anticipating and consuming rewarding stimuli. Translating these findings to real-life reward processing dynamics is an important next step in order to guide fine-tuning of preventive treatments. We propose that the Experience Sampling Methodology (ESM) represents a useful tool in addressing this issue. ESM requires individuals to carry a device that beeps at semirandom moments, inviting them to fill out a short questionnaire on mood, context, and behavior. Using this methodology, we aimed to decompose the construct of reward processing into its daily life dynamics, by investigating how positive affect (PA), reward anticipation and active behavior influence each other over time. A group of emerging adults (aged 16–25) was included, of which two-thirds presented with subclinical depressive symptoms. Associations between PA, reward anticipation and active behavior manifested in the flow of daily life. Depressive symptoms were significantly associated with reduced time-lagged associations between reward anticipation and active behavior (&bgr; = −.005, p = .006) and active behavior and reward anticipation (&bgr; = −.002, p = .027). The moderating effect of depressive symptoms on the time-lagged association between reward anticipation and PA approached significance (&bgr; = −.002, p = .051). These findings represent an important step in translating experimental knowledge on reward processing into daily life processes.

The Two-Sided. Face of Antidepressants: The Impact of Their Use on Real-Life Affective Change during Mindfulness-Based Cognitive Therapy

Neuroimaging research has shown that ADs can diminish the neural processing of both rewarding and aversive stimuli in healthy controls when investigating the placebo-controlled effect [6] . This could account for the experience of emotional blunting described by some patients during selective serotonin reuptake inhibitor treatment [7] . Hence it seems that some ADs can suppress the brain system that is important for the generation of positive emotions (reward system) in addition to the one generating negative emotions (stress system). It was therefore hypothesized that AD and MBCT have a synergistic effect on NA but that AD inhibits the positive effect of MBCT on PA. In the trial, individuals (n = 129) with residual depressive symptoms (score ≥ 7 on the 17-item Hamilton Depression Rating Scale after at least 1 prior episode of MDD) were randomized to either MBCT or WLCG [for details on the procedures, see 4 ]. One of the exclusion criteria for participation was recent (in the past 4 weeks) or upcoming changes in ongoing psychological or pharmacological treatment. PA (mean of items: I feel ‘happy’, ‘satisfied’, ‘strong’, enthusiastic’, ‘curious’, cheerful’ and ‘inspired’) and NA (mean of items: I feel ‘down’, ‘anxious’, ‘lonely’, ‘suspicious’, ‘disappointed’, ‘insecure’ and ‘guilty’) were assessed using experience sampling methodology before and after the treatment (or waiting list) period. Analyses were executed with the XTMIXED command when they concerned multilevel data and LOGIT and REGRESS commands for, respectively, dichotomous and quantitative unilevel data in STATA 12.1. Since AD use was not randomized within treatment groups, potential confounder variables were examined. It was investigated whether (a) treatment groups (MBCT and WLCG) differed in their AD use, and (b) participants taking ADs (AD+) differed from participants not taking ADs (AD–) with regard to the outcome measures at baseline (PA, NA) or potential confounding variables ( table 1 ) both overall as well as within treatment groups (MBCT and WLCG). Based on these analyses only antipsychotic use was found to be a potential confounder. Significant three-way interaction [MBCT/WLCG × time (pre/ post) × AD (yes/no)] effects were found for both NA (b = –0.208, p = 0.001) and PA (b = –0.171, p = 0.031) and these effects remained significant after controlling for the interaction of antipsychotic use with time and group (NA: b = –0.207, p = 0.002; PA: b = –0.187, p = 0.023). NA: When stratifying the analysis by use of ADs (i.e., two-way interaction: MBCT/WLCG × time), the impact of MBCT (compared to WLCG) on decrease in NA was stronger in AD+ (b = –0.424, p < 0.001) than in AD– (b = –0.216, p < 0.001). The results of the three-way interaction analysis (see above) indicated that this difference was statistically significant. PA: When stratifying the Antidepressant medication (AD) is the most often used treatment for major depressive disorder (MDD), prescribed to an estimated 73.8% of the MDD patients in care in 2007 [1] . However, many patients with MDD who experience full symptomatic remission after AD treatment still have residual depressive symptoms, which have been associated with continued impaired functioning [2] . The sequential addition of psychotherapy to pharmacotherapy has therefore been considered, and shown, to offer a better possibility of improving long-term outcome in terms of reduced relapse/recurrence [3] . Since positive emotions play a crucial role in the development of long-term personal skills and resources through broadening awareness and behavioural repertoires [4] , it is of interest to examine whether adding psychotherapy to AD treatment has beneficial effects on positive emotional experiences. We explored this question in a randomized controlled trial of mindfulness-based cognitive therapy (MBCT) versus a waiting list control group (WLCG), based upon which it was previously shown that MBCT increases positive affect (PA) in people with residual depressive symptoms [5] . Participants in this randomized controlled trial were asked to continue any pharmacological treatment during participation in the study, hence providing us with a subgroup of people taking ADs. It was investigated whether this subgroup responded differently to MBCT treatment in terms of both PA and negative affect (NA). Received: August 27, 2015 Accepted after revision: December 14, 2015 Published online: April 5, 2016

Functional neuroimaging of associative learning and generalization in specific phobia

Background: Theoretical models have implicated classical fear conditioning, fear generalization, and extinction learning in the development of anxiety disorders. To date, it is largely unknown to what extent these mechanisms and the underlying neurobiology may be altered in specific phobia, a disorder characterized by focal fears. The current study systematically examined fear conditioning, fear generalization, extinction learning, and extinction recall in a sample of individuals with a specific phobia. Methods: Participants with a specific phobia (SP) of spiders (n=46) and healthy controls (HC) (n=48) underwent a 3‐day fMRI cue‐conditioning protocol, including a fear acquisition and a fear generalization phase (day 1), an extinction learning phase (day 2), and an extinction recall phase (day 3). Stimuli were phobia‐irrelevant, as geometrical shapes served as conditioned threat (CS+) and safety stimuli (CS‐), and an electrical shock as the unconditioned stimulus (US). Self‐reported fear, US expectancy, and blood‐oxygen‐level dependent responses were measured. Results: Behavioral results only revealed enhanced CS+/CS‐differentiation in fear scores during acquisition retention in SP. Some neural differences were observed during other task phases. During early fear acquisition, SP showed enhanced differential activation in the angular gyrus and lateral occipital cortex, and during extinction recall, more precuneus deactivation was found in SP compared to HC. There were no clear indications of altered neural fear generalization or extinction learning mechanisms in the SP group. Conclusions: Results indicate that spider phobia may be characterized by enhanced differential fear retention and altered brain activation patterns during fear acquisition and extinction recall. The findings provide insight into the nature of fear learning alterations in specific phobia, and how these may differ from those found in disorders characterized by broad anxious distress. HIGHLIGHTSSpecific phobia was characterized by stronger fear acquisition retention.No clear alterations in fear generalization and extinction learning.Minor changes in neural circuitry involved in fear learning and extinction recall.