Major depressive disorder (MDD) is often marked by impaired motivation and reward processing, known as anhedonia. Many patients do not respond to first-line treatments, and improvements in motivation ...can be slow, creating an urgent need for rapid interventions. Recently, we demonstrated that transcutaneous auricular vagus nerve stimulation (taVNS) acutely boosts effort invigoration in healthy participants, but its effects on depression remain unclear.
To assess the impact of taVNS on effort invigoration and maintenance in a sample that includes patients with MDD, evaluating the generalizability of our findings.
We used a single-blind, randomized crossover design in 30 patients with MDD and 29 matched (age, sex, and BMI) healthy control participants (HCP).
Consistent with prior findings, taVNS increased effort invigoration for rewards in both groups during Session 1 (p = .040), particularly for less wanted rewards in HCP (pboot < 0.001). However, invigoration remained elevated in all participants, and no acute changes were observed in Session 2 (Δinvigoration = 3.3, p = .12). Crucially, throughout Session 1, we found taVNS-induced increases in effort invigoration (pboot = 0.008) and wanting (pboot = 0.010) in patients with MDD, with gains in wanting maintained across sessions (Δwanting = 0.06, p = .97).
Our study replicates the invigorating effects of taVNS in Session 1 and reveals its generalizability to depression. Furthermore, we expand upon previous research by showing taVNS-induced conditioning effects on invigoration and wanting within Session 1 in patients that were largely sustained. While enduring motivational improvements present challenges for crossover designs, they are highly desirable in interventions and warrant further follow-up research.
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•Anhedonia is a core symptom of major depressive disorder that is hard to treat.•Vagus nerve stimulation (VNS) has increased motivation in healthy participants.•We extend this work using non-invasive VNS (tVNS) in participants with depression.•tVNS increases wanting and invigoration in Session 1 over trials in depression.•Gains in motivation from Session 1 are maintained until Session 2.
In cost-benefit decision-making, women and men often show different trade-offs. However, surprisingly little is known about sex differences in instrumental tasks, where physical effort is exerted to ...gain rewards. To this end, we tested 81 individuals (47 women) with an effort allocation task, where participants had to repeatedly press a button to collect food and money tokens. We analyzed the motivational phases of invigoration and effort maintenance with varying reward magnitude, difficulty, and reward type. Whereas women and men did not differ in invigoration, we found that women showed higher effort maintenance as well as higher subjective wanting and exertion ratings for small rewards compared with men. Notably, men increased their effort more than women for higher rewards to match women's levels of performance. Crucially, we found no sex differences depending on reward type or difficulty, indicating that sex differences were specific to the encoding of the magnitude of benefits, not costs. To summarize, women exerted higher physical effort for small rewards, which corresponded with an elevated subjective value in women compared with men. Therefore, sex differences in perceived reward magnitude may contribute to differential behavioral preferences highlighting the potential of cost-benefit decision-making to provide insights about potential mechanisms.
Youth with attention-deficit/hyperactivity disorder (ADHD) exhibit increased effort aversion, likely due to deficits in anticipatory dopamine firing. Previous research has shown that transcranial ...direct current stimulation (tDCS) targeting the right prefrontal cortex can enhance activity in dopaminergic meso-striatal regions. However, the extent to which this specific tDCS configuration effectively modulates effort behavior in anticipation of rewards in ADHD remains uncertain.
We expected an increase of effort maintenance and invigoration during and following our tDCS set-up compared to sham in subjects with ADHD.
Twenty-four children and adolescents with ADHD (mean age: 11.6 years; 95 % CI 10.7, 12.4) received 2 mA and sham tDCS for 20 min each. The anode was positioned over the ventromedial prefrontal cortex (PFC), while the cathode was placed over the right dorsolateral PFC, generating an electrical field with maximal strength in the right PFC. During and after the tDCS sessions, participants performed a button-pressing task aimed at earning delayed monetary rewards. Primary outcomes were effort maintenance (frequency of button presses) and invigoration (slopes of button presses), measuring motor task performance.
We observed a significant increase in effort maintenance both during (b = 2.66; p < 0.001) and after tDCS (b = 2.04; p= .007) compared to sham. No significant difference was found for invigoration during stimulation, while after bonferroni correction (p = 0.025) a non-significant decrease was found after tDCS compared to sham (b = −5.18; p = 0.041).
tDCS targeting the ventromedial PFC (anodal) and right dorsolateral PFC (cathodal) increases effort maintenance in children and adolescents with ADHD.
•In ADHD an increased effort aversion is linked to deficits in dopamine firing.•TDCS over the right prefrontal cortex may enhance meso-striatal dopaminergic activity.•Youth with ADHD performed an effort aversion task during and after tDCS/sham over the right prefrontal cortex.•During and following tDCS we found an increased effort maintenance.
Maladaptive stress responses are important risk factors in the etiology of mood and anxiety disorders, but exact pathomechanisms remain to be understood. Mapping individual differences of acute ...stress-induced neurophysiological changes, especially on the level of neural activation and functional connectivity (FC), could provide important insights in how variation in the individual stress response is linked to disease risk.
Using an established psychosocial stress task flanked by two resting states, we measured subjective, physiological, and brain responses to acute stress and recovery in 217 participants with and without mood and anxiety disorders. To estimate blockwise changes in stress-induced activation and FC, we used hierarchical mixed-effects models based on denoised time series within predefined stress-related regions. We predicted inter- and intraindividual differences in stress phases (anticipation vs. stress vs. recovery) and transdiagnostic dimensions of stress reactivity using elastic net and support vector machines.
We identified four subnetworks showing distinct changes in FC over time. FC but not activation trajectories predicted the stress phase (accuracy = 70%, pperm < .001) and increases in heart rate (R2 = 0.075, pperm < .001). Critically, individual spatiotemporal trajectories of changes across networks also predicted negative affectivity (ΔR2 = 0.075, pperm = .030) but not the presence or absence of a mood and anxiety disorder.
Spatiotemporal dynamics of brain network reconfiguration induced by stress reflect individual differences in the psychopathology dimension of negative affectivity. These results support the idea that vulnerability for mood and anxiety disorders can be conceptualized best at the level of network dynamics, which may pave the way for improved prediction of individual risk.
A major research finding in the field of Biological Psychiatry is that symptom-based categories of mental disorders map poorly onto dysfunctions in brain circuits or neurobiological pathways. Many of ...the identified (neuro) biological dysfunctions are "transdiagnostic", meaning that they do not reflect diagnostic boundaries but are shared by different ICD/DSM diagnoses. The compromised biological validity of the current classification system for mental disorders impedes rather than supports the development of treatments that not only target symptoms but also the underlying pathophysiological mechanisms. The Biological Classification of Mental Disorders (BeCOME) study aims to identify biology-based classes of mental disorders that improve the translation of novel biomedical findings into tailored clinical applications.
BeCOME intends to include at least 1000 individuals with a broad spectrum of affective, anxiety and stress-related mental disorders as well as 500 individuals unaffected by mental disorders. After a screening visit, all participants undergo in-depth phenotyping procedures and omics assessments on two consecutive days. Several validated paradigms (e.g., fear conditioning, reward anticipation, imaging stress test, social reward learning task) are applied to stimulate a response in a basic system of human functioning (e.g., acute threat response, reward processing, stress response or social reward learning) that plays a key role in the development of affective, anxiety and stress-related mental disorders. The response to this stimulation is then read out across multiple levels. Assessments comprise genetic, molecular, cellular, physiological, neuroimaging, neurocognitive, psychophysiological and psychometric measurements. The multilevel information collected in BeCOME will be used to identify data-driven biologically-informed categories of mental disorders using cluster analytical techniques.
The novelty of BeCOME lies in the dynamic in-depth phenotyping and omics characterization of individuals with mental disorders from the depression and anxiety spectrum of varying severity. We believe that such biology-based subclasses of mental disorders will serve as better treatment targets than purely symptom-based disease entities, and help in tailoring the right treatment to the individual patient suffering from a mental disorder. BeCOME has the potential to contribute to a novel taxonomy of mental disorders that integrates the underlying pathomechanisms into diagnoses.
Retrospectively registered on June 12, 2019 on ClinicalTrials.gov (TRN: NCT03984084).
Reinforcement learning is a core facet of motivation and alterations have been associated with various mental disorders. To build better models of individual learning, repeated measurement of ...value-based decision-making is crucial. However, the focus on lab-based assessment of reward learning has limited the number of measurements and the test-retest reliability of many decision-related parameters is therefore unknown. In this paper, we present an open-source cross-platform application Influenca that provides a novel reward learning task complemented by ecological momentary assessment (EMA) of current mental and physiological states for repeated assessment over weeks. In this task, players have to identify the most effective medication by integrating reward values with changing probabilities to win (according to random Gaussian walks). Participants can complete up to 31 runs with 150 trials each. To encourage replay, in-game screens provide feedback on the progress. Using an initial validation sample of 384 players (9729 runs), we found that reinforcement learning parameters such as the learning rate and reward sensitivity show poor to fair intra-class correlations (ICC: 0.22–0.53), indicating substantial within- and between-subject variance. Notably, items assessing the psychological state showed comparable ICCs as reinforcement learning parameters. To conclude, our innovative and openly customizable app framework provides a gamified task that optimizes repeated assessments of reward learning to better quantify intra- and inter-individual differences in value-based decision-making over time.
High childhood emotional maltreatment (CM-EMO) is reported in mood and anxiety disorders. The associations with an increased risk for psychopathology are not fully understood. One potential factor ...may be through alterations in gamma-Aminobutyric acid (GABA). The pregenual anterior cingulate cortex (pgACC) is an important brain region for emotion processing and its’ GABA levels were previously implicated in mood and anxiety disorders pathophysiology. We examined the association between the self-reported CM-EMO in adulthood and GABA + levels in the pgACC and in a control region, anterior mid cingulate cortex. GABA+ and total creatine (tCr) were measured in the pgACC and aMCC voxels in seventy-four healthy volunteers (32 (43%) women, ages 19–54, age standard deviation = 27.1 6.5) using proton magnetic resonance spectroscopy at 7 T. Childhood Trauma Questionnaire was completed by adult participants to measure retrospective self-reported experience of emotional neglect (CM-EMO-NEG) and emotional abuse (CM-EMO-AB) during childhood. Linear mixed models tested the interaction between the region and the two subscales, and GABA+/tCr ratios, with an adjusted alpha = 0.025. Following, linear models, including with covariates were tested. There was an interaction effect between region and CM-EMO-NEG (B = −0.007, p = 0.009), driven by a negative relationship between CM-EMO-NEG and GABA+/tCr in the pgACC (B = −0.004, p = 0.013). Results for CM-EMO-NEG were robust to inclusion of different covariates (ps < 0.035). There was no interaction effect for the CM-EMO-AB (B = 0.007, p = 0.4). Limitations include cross-sectional measurement and retrospective nature of the CTQ. The findings indicate preliminary importance of inhibitory neurometabolite concentrations in the pgACC for retrospective reporting of CM-EMO-NEG.
•Childhood emotional maltreatment (CM-EMO) may increase risks for psychopathology through brain alterations.•Gamma-Aminobutyric acid (GABA) is a potential pathway connecting CM-EMO and psychopathology.•We examined association between CM-EMO and GABA in pregenual anterior cingulate cortex.•Emotional neglect but not abuse was negatively associated with GABA in healthy participants.•Results highlight importance of distinguishing types of CM-EMO.
Non‐invasive brain stimulation techniques, such as transcutaneous auricular vagus nerve stimulation (taVNS), have considerable potential for clinical use. Beneficial effects of taVNS have been ...demonstrated on symptoms in patients with mental or neurological disorders as well as transdiagnostic dimensions, including mood and motivation. However, since taVNS research is still an emerging field, the underlying neurophysiological processes are not yet fully understood, and the replicability of findings on biomarkers of taVNS effects has been questioned. The objective of this analysis was to synthesize the current evidence concerning the effects of taVNS on vagally mediated heart rate variability (vmHRV), a candidate biomarker that has, so far, received most attention in the field. We performed a living Bayesian random effects meta‐analysis. To keep the synthesis of evidence transparent and up to date as new studies are being published, we developed a Shiny web app that regularly incorporates new results and enables users to modify study selection criteria to evaluate the robustness of the inference across potential confounds. Our analysis focuses on 16 single‐blind studies comparing taVNS versus sham in healthy participants. The meta‐analysis provides strong evidence for the null hypothesis (g = 0.014, CIshortest = −0.103, 0.132, BF01 = 24.678), indicating that acute taVNS does not alter vmHRV compared to sham. To conclude, there is no support for the hypothesis that vmHRV is a robust biomarker for acute taVNS. By increasing transparency and timeliness, the concept of living meta‐analyses can lead to transformational benefits in emerging fields such as non‐invasive brain stimulation.
Although vagally mediated heart rate variability has often been proposed as a biomarker for transcutaneous auricular vagus nerve stimulation, previous results are inconsistent and variable, leading to conflicting conclusions. Using a Bayesian random‐effects meta‐analysis that allows for continuous updates, we show that there is conclusive evidence for an absence of robust modulatory effects across a wide range of inclusion criteria for studies.
Abstract
Overweight and obesity are associated with altered stress reactivity and increased inflammation. However, it is not known whether stress-induced changes in brain function scale with BMI and ...if such associations are driven by peripheral cytokines. Here, we investigate multimodal stress responses in a large transdiagnostic sample using predictive modeling based on spatio-temporal profiles of stress-induced changes in activation and functional connectivity. BMI is associated with increased brain responses as well as greater negative affect after stress and individual response profiles are associated with BMI in females (
p
perm
< 0.001), but not males. Although stress-induced changes reflecting BMI are associated with baseline cortisol, there is no robust association with peripheral cytokines. To conclude, alterations in body weight and energy metabolism might scale acute brain responses to stress more strongly in females compared to males, echoing observational studies. Our findings highlight sex-dependent associations of stress with differences in endocrine markers, largely independent of peripheral inflammation.
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