Efficacy and acceptability of third-wave psychotherapies in the treatment of depression: a network meta-analysis of controlled trials.

Introduction: In recent decades, various new psychotherapy approaches have been developed in an effort to overcome issues of non-response, referred to as "third-wave psychotherapies." How third-wave therapies perform in comparison to each other, to classical CBT, or other common comparators in the treatment of depression has not yet been systematically assessed. Methods: We firstly determined the scope of the term "third-wave" by conducting a systematic search. The identified approaches were then used as search terms for the systematic review and network meta-analysis (NMA). We searched MEDLINE, CENTRAL, PsychINFO and Web of Science from inception until 31 July 2022. We assessed randomized controlled trials comparing third-wave psychotherapies to each other, CBT, treatment as usual (TAU), medication management, active control conditions, or waitlist (WL) in adult populations with depressive disorders. The treatments included were acceptance and commitment therapy, behavioral activation, cognitive behavioral analysis system of psychotherapy, dialectical behavioral therapy, mindfulness-based cognitive therapy, meta-cognitive therapy, positive psychotherapy and schema therapy. The primary outcome was depression severity (efficacy) at study endpoint, and the secondary outcome was all-cause discontinuation (acceptability). This review was registered in PROSPERO, identifier CRD42020147535. Results: Of 7,971 search results, 55 trials were included in our NMA (5,827 patients). None of the third-wave therapies were more efficacious than CBT but most were superior to TAU [standardized mean differences (SMD) ranging between 0.42 (95% CI -0.37; 1.19) and 1.25 (0.48; 2.04)]. Meta-cognitive therapy (MCT) was more efficacious than three other third-wave therapy approaches. None of the third-wave treatments were more acceptable than WL or CBT. Twenty-seven percent of the trials were rated as low risk of bias. Confidence in the evidence was largely low according to GRADE. Inconsistency emerged for a small number of comparisons. Interpretations: Third-wave therapies are largely efficacious and acceptable alternatives to CBT when compared to TAU, with few differences between them. The evidence so far does not point toward superiority or inferiority over CBT. Patient-level research may offer possibilities for tailoring individual psychotherapies to the needs of individual patients and future trials should make this data available. The evidence base needs to be broadened by sufficiently powered trials.

[Inpatient psychotherapy of depressive disorders: options and challenges]. / Stationäre Psychotherapie depressiver Störungen: Möglichkeiten und Herausforderungen.

BACKGROUND: The psychotherapy of depressive disorders has become established as a central component of inpatient treatment in psychiatric and psychosomatic hospitals and furthermore constitutes an important component of the residency training in Germany; however, the number of studies examining the effectiveness and efficacy is limited. METHODS: This narrative review summarizes the current state of research on inpatient psychotherapy for depressive disorders. The results of meta-analyses as well as practice-based observational studies from routine treatment in Germany, disorder-specific special programs, and side effects of inpatient psychotherapy are summarized. RESULTS: The number of studies on the efficacy of inpatient psychotherapy of depressive disorders is overall low. The main finding of the largest recent meta-analysis indicates that psychotherapy in clinics and other facilities has a significant effect on depressive symptoms, with small to moderate effect sizes in randomized controlled studies. The effects are mostly maintained even after 9-15 months follow-up. An observational study from routine treatment with a very large sample size reported large pre-post and pre-follow-up effect sizes. It additionally revealed factors that appear to be difficult to change during inpatient psychotherapy, negatively affect treatment success and could be specifically addressed in future trials. Special programs, such as inpatient Interpersonal Psychotherapy (IPT) and the inpatient Cognitive Behavioral Analysis System of Psychotherapy (CBASP) indicate acceptance and efficacy/effectiveness in an initial randomized controlled (IPT) study and in observational (CBASP) studies. Side effects of inpatient psychotherapy were reported by 60-94% of patients with depressive disorders, whereby a perceived dependence on the therapist or the therapeutic setting was identified as a frequent side effect. CONCLUSION: Overall, the results of the narrative review reveal that inpatient psychotherapy appears to be meaningful and effective for many patients with depressive disorders. Specific side effects, cost-effectiveness, and the question of differential indications (what works for whom?) should be further investigated.

Impaired empathic functioning in chronic depression: Behavioral evidence for the Cognitive Behavioral Analysis System of Psychotherapy (CBASP) model.

The Cognitive Behavioral Analysis System of Psychotherapy (CBASP) model proposes preoperational functioning as a core feature of persistent depressive disorders (PDD). Empathy deficits comprise one aspect. Resulting from childhood maltreatment, empathy deficits may aggravate social isolation, a key factor in the maintenance of depression. CBASP targets empathy by teaching patients to disengage from past experiences and to engage successfully in present social interactions. However, behavioral evidence for empathy deficits in PDD has remained elusive. We reasoned that deficits become apparent only under stress and that these deficits improve after CBASP-treatment. Twenty-two patients and 21 controls performed two parallel versions of the Multifaceted Empathy Test. For stress induction, a negative autobiographical event was presented before performing the task. A neutral event served as control. Fifteen patients performed the experiment twice, before and after a 12-week inpatient CBASP-treatment. Supporting our hypotheses, patients showed reduced empathy under stress, while no group difference was found in the absence of stress. Reduced empathy correlated with the level of re-experiencing negative memories. Pre-post-treatment comparison revealed that the stress-induced empathy deficit improved in patients over time. Post-treatment empathic capacity correlated positively with clinical improvement. Our findings provide empirical support for the CBASP model, but highlight an important new aspect: Empathy is not generally deficient in PDD but becomes impaired under stress. In real-life situations, stress-induced empathy impairments may exacerbate interpersonal conflicts. CBASP's interpersonal focus improved empathy, accompanied by clinical improvement as the model predicts.

Autobiographical Script-Driven Imagery Has No Detectable Effect on Emotion Regulation in Healthy Individuals.

INTRODUCTION: Emotion regulation (ER), the ability to actively modulate one's own emotion reactions, likely depends on the individual's current emotional state. Here, we investigated whether negative emotions induced by an interpersonal autobiographic script affect the neuronal processes underlying ER. METHODS: Twenty healthy participants were recruited and underwent functional magnetic resonance imaging (fMRI) during performance of distancing, a specific ER strategy, while viewing emotionally arousing pictures. Participants were instructed to either naturally experience ("permit" condition) or to actively downregulate ("regulate" condition) their emotional responses to the presented stimuli. Before each of the 4 runs in total, a neutral or negative autobiographical audio script was presented. The negative script comprised an emotionally negative event from childhood or adolescence that represented either emotional abuse or emotional neglect. The second event comprised an everyday neutral situation. We aimed at identifying the neural correlates of ER and their modulation by script-driven imagery. RESULTS: fMRI analyses testing for greater responses in the "regulate" than the "permit" condition replicated previously reported neural correlates of ER in the right dorsolateral prefrontal cortex and the right inferior parietal lobule. A significant ER effect was also observed in the left orbitofrontal cortex. In the amygdala, we found greater responses in the "permit" compared to the "regulate" condition. We did not observe a significant modulation of the ER effects in any of these regions by the negative emotional state induced by autobiographical scripts. Bayesian statistics confirmed the absence of such modulations by providing marginal evidence for null effects. DISCUSSION: While we replicated previously reported neural correlates of ER, we found no evidence for an effect of mood induction with individualized autobiographical scripts on the neural processes underlying ER in healthy participants.

Interpersonal Change During Inpatient CBASP Treatment: Focus on Group Therapy.

Background: The Cognitive Behavioral Analysis System of Psychotherapy (CBASP) has been tailored specifically to the demands of patients with persistent depressive disorder (PDD). According to the CBASP model, PDD patients are supposed to live perceptually disconnected from their social environment, which consequently maintains depression. While initially developed as an individual treatment modality, the adaptation for group therapy yields an important interpersonal space. However, little is known about the specific factors that contribute to patients' benefit from the CBASP group modality. Methods: The analyzed sample comprised N = 87 PDD patients who completed a 12 week multimodal inpatient treatment including 2 weekly CBASP-specific individual and group sessions, respectively, as well as CBASP-unspecific medical contacts, pharmacotherapy and complementary therapies. Group sessions included trainings in situational analysis and interpersonal skills. Interpersonal change over therapy was examined based on the patients' self-perceived interpersonal problems (IIP) and the impact messages as perceived by their individual therapists (IMI). Pre and post-treatment data were compared using within-sample t-tests. Additionally, patients evaluated CBASP group therapy on a feedback form. They were invited to reflect on individual benefits and its helpful and unhelpful aspects. Qualitative content analysis with inductive category development was used to analyze feedback. Inter-rater reliability was computed to confirm categories before summarizing the frequencies of reported factors. Results: Self-perceived interpersonal distress significantly decreased over therapy. Patients reported reduced interpersonal problems and therapists reported more friendly and dominant impact messages. Interestingly, patients who showed a significant depressive symptom reduction described higher change scores. Regarding qualitative data, patients reported five main benefits from group therapy: Gain in social competence, self-confidence, self-reflection, interpersonal dynamics, and optimism/universality. Patients responding to CBASP identified significantly more factors than non-responders. Conclusions: Compared to studies with individual CBASP only, the present findings suggest that CBASP group therapy may contribute to the improvement of interpersonal behavior. Group therapy is discussed as a potential boosting effect for individual CBASP. However, as the present data were collected in a multimodal inpatient setting without competitor, randomized controlled trials are warranted that investigate the specific benefits of the group modality or the combined individual and group therapy over individual CBASP only.

Cognitive Behavioral Analysis System of Psychotherapy for inpatients with persistent depressive disorder: a naturalistic trial on a general acute psychiatric unit.

The Cognitive Behavioral Analysis System of Psychotherapy (CBASP) was originally developed for outpatients with persistent depressive disorder (PDD). We adapted CBASP as inpatient treatment on a general acute psychiatric ward and evaluated its outcome and feasibility. Sixty PDD patients received a 12-week multidisciplinary CBASP program. Hamilton Depression Rating Scale (HAMD24) and Beck Depression Inventory (BDI-II) served as primary and secondary outcome measures. Childhood maltreatment at baseline and change in interpersonal distress from pre to post were investigated as predictors of treatment outcome. A 6-month follow-up assessment was conducted. Feasibility was assessed through dropouts and satisfaction with the program. Fifty patients completed the program (16.7% dropouts). An ANOVA with three repeated measurements (pre, post, FU) in the ITT sample revealed a main effect of time. For the primary outcome, depressive symptoms decreased from pre (28.3) to post (11.5, response rate: 72.7%, d = 1.8), and from pre to FU (13.9, d = 1.2). Four patients relapsed. The secondary outcome confirmed the results; however, the response rate was lower (BDI-II: 31.7%, pre to post: d = 0.8, pre to FU: d = 0.3), and ten patients relapsed at FU. Reduction in interpersonal distress, but not childhood maltreatment, predicted BDI-II response. Key limitations of this naturalistic open trial are the lack of a comparison group and non-blinded HAMD24 ratings. Inpatient CBASP for PDD appears feasible on a general acute psychiatric ward with effect sizes comparable to specialized psychotherapy wards and to the outpatient setting.

Understanding versus feeling the emotions of others: How persistent and recurrent depression affect empathy.

Empathy refers to the ability to understand the emotions of others. It encompasses a cognitive component of decoding a mental state, and an affective component that relates to an emotional response. Deficits in empathy have been associated with social dysfunction in depression. It is further assumed that impairments are aggravated when depression takes a chronic course. Existing evidence in the literature, however, is scarce and heterogeneous. The present study investigated empathy in patients with persistent and recurrent depression as well as in healthy controls (N = 102). Empathy measurements included both self-report (Interpersonal Reactivity Index, IRI) as well as a laboratory task (Multifaceted Empathy Task, MET). A mixed model analyses of covariance, which accounted for differences in executive functioning, found no evidence for impaired cognitive empathy in depression. All three groups performed equally well in understanding mental states. However, both IRI and MET confirmed the hypothesis of significant deficits in affective empathy. Patients reported higher personal distress than controls, and showed lower affective responses towards positive emotions in others. There was no difference between patient groups. Childhood maltreatment was further related to reduced affective empathy. The present results contribute to our understanding of social dysfunction in depression, since loss of emotional reactivity to the feelings of others is considered to reduce the desire to engage in social interaction, thus leading to isolation and aggravation of depression.

Persistent depressive disorder across the adult lifespan: results from clinical and population-based surveys in Germany.

BACKGROUND: Although the individual and economic disease burden of depression is particularly high for long-term symptoms, little is known of the lifetime course of chronic depression. Most evidence derives from clinical samples, and the diagnostic distinction between persistent depressive disorder (PDD) and non-chronic major depression (NCMDD) is still debated. Thus, we examined characteristics of PDD among clinical vs. non-clinical cases, and the associated disease burden at a population level. METHODS: Data were drawn from the mental health module of the German Health Interview and Examination Survey for Adults (DEGS1-MH, 2009-2012, n = 4483) and a clinical sample of PDD inpatients at Charité - Universitätsmedizin Berlin (2018-2019, n = 45). The DSM-5 definition of PDD was operationalized a priori to the study using interview-based DSM-IV diagnoses of dysthymia and major depression lasting at least 2 years in both surveys. Additional depression characteristics (depression onset, self-classified course, suicidality, comorbid mental disorders, treatment history and current depressive symptoms [Patient Health Questionnaire-9]) were assessed. In the DEGS1-MH, health-related quality of life (Short Form Health Survey-36, SF-36), chronic somatic conditions, number of sick days (past 12 months) or days with limitations in normal daily life activities (past 4 weeks), and health service utilization (past 12 months) were compared for PDD vs. NCMDD. RESULTS: PDD cases from the clinical sample had a significantly earlier depression onset, a higher proportion of self-classification as persistent course, and treatment resistance than PDD and NCMDD cases in DEGS1-MH. At a population level, PDD cases showed worse outcomes compared with NCMDD cases in terms of somatic comorbidity, SF-36 mental component score, and activity limitations owing to mental health problems, as well as a higher risk for outpatient mental health care contact. CONCLUSIONS: The distinction between PDD and NCMDD proposed for DSM-5 seems warranted. Early onset depression, self-classification as persistent depressive course, and treatment resistance are suggested as markers of more severe and chronic depression courses. At a population level, PDD is associated with remarkably higher individual and economic disease burden than NCMDD, highlighting the need to improve medical recognition of chronic courses and establish specific treatment concepts for chronic depression.

Correction: Negative mood induction: Affective reactivity in recurrent, but not persistent depression.

[This corrects the article DOI: 10.1371/journal.pone.0208616.].

Negative mood induction: Affective reactivity in recurrent, but not persistent depression.

BACKGROUND: Despite the high clinical and epidemiological relevance of persistent depression, little is known about its specific psychopathology and whether it is distinct from recurrent depression. Depression in general has been associated with blunted affective reactivity but the evidence from previous studies is inconsistent. Here, we asked whether affective reactivity might differ between persistent and recurrent depression. METHODS: Twenty patients with persistent depression, 20 patients with recurrent depression and 20 healthy controls (HC) were recruited. Both patient groups showed moderate symptom severity. All participants underwent a sad mood induction procedure. Affective reactivity was assessed with the Positive and Negative Affect Schedule (PANAS) before and after mood induction. RESULTS: We found a striking difference in affective reactivity between patient groups. While the persistent group showed blunted reactivity to mood induction, the recurrent group demonstrated an affective response that was comparable to HC, with an increase in negative and a decrease in positive affect. Blunted affective reactivity was thus specifically associated with persistent in contrast to recurrent depression. CONCLUSIONS: These results highlight affective reactivity as an important psychopathological feature that differs between the two patient groups. Preserved affective reactivity to emotional stimuli in the recurrent group might reflect a resilience factor against persistence of depression.

Differences between chronic and nonchronic depression: Systematic review and implications for treatment.

BACKGROUND: There is still uncertainty if and to what extent chronic depression (CD) presents with specific features especially in contrast to the nonchronic course of major depressive disorder (non-CD). This systematic review aims to summarize the existing literature regarding sociodemographic factors, psychopathology, and course of disease in patients with CD in comparison to patients with non-CD. METHODS: A structured database search (MEDLINE, PsycINFO, Web of Science, CENTRAL) was performed. All studies comparing CD with non-CD patients were included. Twenty-eight studies, including cohort studies, cross-sectional studies, and observational studies, were identified in which both subgroups were diagnosed according to DSM-IV or DSM-5, respectively. Primary outcome were group comparisons focused on sociodemographic factors, childhood adversity, onset of the disorder, comorbidities, severity and course of the depressive symptoms, and specific psychopathology. RESULTS: Patients with CD had an earlier onset of depressive symptoms, higher rates of psychiatric comorbidities, and a complicated treatment course (e.g., higher rates of suicidality) compared to non-CD. We also found some evidence for specific features in the psychopathology of CD patients (submissive and hostile interpersonal styles) in contrast to non-CD patients. Results were inconsistent with regard to childhood maltreatment. No differences were found regarding the severity of depressive symptoms and most sociodemographic factors. CONCLUSION: Despite some inconsistencies, the results of this review verified important differences between CD and non-CD. However, future research is needed to characterize especially the specific psychopathology of CD in comparison to non-CD patients to develop more tailored treatment strategies.

Effects of Cognitive Behavioral Therapy on Neural Processing of Agoraphobia-Specific Stimuli in Panic Disorder and Agoraphobia.

BACKGROUND: Patients suffering from panic disorder and agoraphobia are significantly impaired in daily life due to anxiety about getting into a situation due to apprehension about experiencing a panic attack, especially if escape may be difficult. Dysfunctional beliefs and behavior can be changed with cognitive behavioral therapy; however, the neurobiological effects of such an intervention on the anticipation and observation of agoraphobia-specific stimuli are unknown. METHODS: We compared changes in neural activation by measuring the blood oxygen level-dependent signal of 51 patients and 51 healthy controls between scans before and those after treatment (group by time interaction) during anticipation and observation of agoraphobia-specific compared to neutral pictures using 3-T fMRI. RESULTS: A significant group by time interaction was observed in the ventral striatum during anticipation and in the right amygdala during observation of agoraphobia-specific pictures; the patients displayed a decrease in ventral striatal activation during anticipation from pre- to posttreatment scans, which correlated with clinical improvement measured with the Mobility Inventory. During observation, the patients displayed decreased activation in the amygdala. These activational changes were not observed in the matched healthy controls. CONCLUSIONS: For the first time, neural effects of cognitive behavioral therapy were shown in patients suffering from panic disorder and agoraphobia using disorder-specific stimuli. The decrease in activation in the ventral striatum indicates that cognitive behavioral therapy modifies anticipatory anxiety and may ameliorate abnormally heightened salience attribution to expected threatening stimuli. The decreased amygdala activation in response to agoraphobia-specific stimuli indicates that cognitive behavioral therapy can alter the basal processing of agoraphobia-specific stimuli in a core region of the fear network.

Affective and cognitive reactivity to mood induction in chronic depression.

BACKGROUND: Chronic depression (CD) is strongly associated with childhood maltreatment, which has been proposed to lead to inefficient coping styles that are characterized by abnormal affective responsiveness and dysfunctional cognitive attitudes. However, while this notion forms an important basis for psychotherapeutic strategies in the treatment of CD, there is still little direct empirical evidence for a role of altered affective and cognitive reactivity in CD. The present study therefore experimentally investigated affective and cognitive reactivity to two forms of negative mood induction in CD patients versus a healthy control sample (HC). METHODS: For the general mood induction procedure, a combination of sad pictures and sad music was used, while for individualized mood induction, negative mood was induced by individualized scripts with autobiographical content. Both experiments included n = 15 CD patients versus n = 15 HC, respectively. Interactions between affective or cognitive reactivity and group were analyzed by repeated measurements ANOVAs. RESULTS: General mood induction neither revealed affective nor cognitive reactivity in the patient group while the control group reported the expected decrease of positive affect [interaction (IA) affective reactivity x group: p = .011, cognitive reactivity x group: n.s.]. In contrast, individualized mood induction specifically increased affective reactivity (IA: p = .037) as well as the amount of dysfunctional cognitions in patients versus controls (IA: p = .014). LIMITATIONS: The experiments were not balanced in a crossover design, causal conclusions are thus limited. Additionally, the differences to non-chronic forms of depression are still outstanding. CONCLUSIONS: The results suggest that in patients with CD, specific emotional activation through autobiographical memories is a key factor in dysfunctional coping styles. Psychotherapeutic interventions aimed at modifying affective and cognitive reactivity are thus of high relevance in the treatment of CD.

Therapeutic Self-Disclosure within DBT, Schema Therapy, and CBASP: Opportunities and Challenges.

In recent years, various therapeutic interventions have been established that extended behavior and cognitive behavior therapy (CBT) by so-called "third-wave" strategies. In order to address specific therapeutic challenges in certain subgroups of patients who do not sufficiently respond to "classical CBT," some of these third-wave strategies put particular emphasis on therapist self-disclosure. This article highlights therapeutic self-disclosure as a means to address interpersonal problems by comparing three third-wave strategies: (a) acceptance and change strategies as used in Dialectical Behavioral Therapy (DBT), (b) the concept of "limited reparenting" as used in Schema Therapy (ST), and (c) disciplined personal involvement as used in the Cognitive Behavioral Analysis System of Psychotherapy (CBASP). On the basis of a critical discussion on opportunities and challenges within these three concepts, self-disclosure is proposed to be a promising therapeutic tool that is worth to be investigated in more depth in future studies.

Phasic and sustained brain responses in the amygdala and the bed nucleus of the stria terminalis during threat anticipation.

Several lines of evidence suggest that the amygdala and the bed nucleus of the stria terminalis (BNST) are differentially involved in phasic and sustained fear. Even though, results from neuroimaging studies support this distinction, a specific effect of a temporal dissociation with phasic responses to onset versus sustained responses during prolonged states of threat anticipation has not been shown yet. To explore this issue, we investigated brain activation during anticipation of threat in 38 healthy participants by means of functional magnetic resonance imaging. Participants were presented different visual cues indicated the temporally unpredictable occurrence of a subsequent aversive or neutral stimulus. During the onset of aversive versus neutral anticipatory cues, results showed a differential phasic activation of amygdala, anterior cingulate cortex (ACC), and ventrolateral prefrontal cortex (PFC). In contrast, activation in the BNST and other brain regions, including insula, dorsolateral PFC, ACC, cuneus, posterior cingulate cortex, and periaqueductal grey was characterized by a sustained response during the threat versus neutral anticipation period. Analyses of functional connectivity showed phasic amygdala response as positively associated with activation, mainly in sensory cortex areas whereas sustained BNST activation was negatively associated with activation in visual cortex and positively correlated with activation in the insula and thalamus. These findings suggest that the amygdala is responsive to the onset of cues signaling the unpredictable occurrence of a potential threat while the BNST in concert with other areas is involved in sustained anxiety. Furthermore, the amygdala and BNST are characterized by distinctive connectivity patterns during threat anticipation.

Neuropeptide S receptor gene variation and neural correlates of cognitive emotion regulation.

The neuropeptide S (NPS) and its receptor NPSR have captured attention in the pathogenesis of anxiety disorders. Here, a functional polymorphism in the NPSR1 gene has been linked to deviant cortico-limbic interactions in response to negative stimuli. While healthy T allele carriers exhibited increased amygdala and prefrontal cortex activity, panic disorder patients carrying the T risk allele displayed hypofrontality possibly reflecting insufficient prefrontal inhibition of limbic reactivity. In order to study multi-level effects of genotype and anxiety, prefrontal cortex activity during an emotional n-back task was measured in 66 volunteers genotyped for the NPSR1 rs324981 A/T variant (AA homozygotes vs. T allele carriers) by means of functional near-infrared spectroscopy. For a high working memory load (3-back), T allele carriers showed a signal increase to negative pictures in the dorsolateral and medial prefrontal cortex while AA homozygotes displayed a signal decrease. Since groups did not differ on skin conductance level and behavioral parameters, this effect in the risk group in line with results from fMRI studies is speculated to represent an adaptive mechanism to compensate for presumably increased subcortical activity driven by an overactive NPS system. However, anxiety sensitivity correlated negatively with prefrontal activity in T allele carriers possibly suggesting a decompensation of the adaptive compensatory upregulation.

Does adult ADHD interact with COMT val (158) met genotype to influence working memory performance?

Both attention-deficit/hyperactivity disorder (ADHD) and catechol-O-methyltransferase (COMT) genotype have been linked to altered dopaminergic transmission and possible impairment in frontal lobe functioning. This study offers an investigation of a possible interaction between ADHD diagnosis and COMT genotype on measures of working memory and executive function. Thirty-five adults with ADHD, who were recruited from the ADHD outpatient clinic at the Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, and thirty-five matched healthy controls completed the Digit Span test and the Stroop Color Word Test. While there were no main effects of ADHD or COMT, the two factors interacted on both Digit Span subtests with the two groups' met/met carriers showing significantly different performance on the Digit Span Forward subtest and the val/val carriers showing significantly different performance on the Digit Span Backward subtest. Findings provide preliminary support for a differential impact of COMT genotype on working memory measures in adult patients with ADHD compared to healthy controls.

Medial prefrontal cortex stimulation modulates the processing of conditioned fear.

The extinction of conditioned fear depends on an efficient interplay between the amygdala and the medial prefrontal cortex (mPFC). In rats, high-frequency electrical mPFC stimulation has been shown to improve extinction by means of a reduction of amygdala activity. However, so far it is unclear whether stimulation of homologues regions in humans might have similar beneficial effects. Healthy volunteers received one session of either active or sham repetitive transcranial magnetic stimulation (rTMS) covering the mPFC while undergoing a 2-day fear conditioning and extinction paradigm. Repetitive TMS was applied offline after fear acquisition in which one of two faces (CS+ but not CS-) was associated with an aversive scream (UCS). Immediate extinction learning (day 1) and extinction recall (day 2) were conducted without UCS delivery. Conditioned responses (CR) were assessed in a multimodal approach using fear-potentiated startle (FPS), skin conductance responses (SCR), functional near-infrared spectroscopy (fNIRS), and self-report scales. Consistent with the hypothesis of a modulated processing of conditioned fear after high-frequency rTMS, the active group showed a reduced CS+/CS- discrimination during extinction learning as evident in FPS as well as in SCR and arousal ratings. FPS responses to CS+ further showed a linear decrement throughout both extinction sessions. This study describes the first experimental approach of influencing conditioned fear by using rTMS and can thus be a basis for future studies investigating a complementation of mPFC stimulation to cognitive behavioral therapy (CBT).

Neural correlates of a standardized version of the trail making test in young and elderly adults: a functional near-infrared spectroscopy study.

The trail making test (TMT) is a widely applied diagnostic tool measuring executive functioning in order to discriminate between healthy and pathological aging processes. However, due to its paper-and-pencil nature it is difficult to adapt for functional brain imaging. Related neural underpinnings even in healthy aging are mostly unknown since no consistent administration for imaging is available. In this study a standardized implementation of the TMT for functional near-infrared spectroscopy (fNIRS) is proposed to investigate associated frontal cortex activation in healthy young (mean age 25.7 ± 3.02 years) and elderly adults (mean age 70.95 ± 3.55 years). The TMT consisted of a number condition (TMT-A), an alternating number and letter condition (TMT-B) as well as a control task. Behavioral results demonstrated that elderly participants performed slower but committed a similar number of errors compared to younger adults. The fNIRS results showed that particularly the TMT-B provoked bilateral activation in the ventro- and dorsolateral prefrontal cortex (vlPFC and dlPFC) as well as in premotor regions. Elderly participants displayed more significantly activated channels and a different activation pattern compared to younger participants especially manifesting in more bilateral dlPFC activation. In line with the hemispheric asymmetry reduction in elderly adults (HAROLD) model, the results were interpreted as an additional need for cognitive control resources in elderly participants. This study succeeded in implementing an appropriate version of the TMT for fNIRS and helps elucidating neural aging effects associated with this task.