Corrigendum to "Cross-sectional study of retrospective self-reported childhood emotional neglect and inhibitory neurometabolite levels in the pregenual anterior cingulate cortex in adult humans" [Neurobiol. Stress, 25 (July 2023), 100556].

[This corrects the article DOI: 10.1016/j.ynstr.2023.100556.].

Association among childhood adversity and susceptibility to interference during varying salience: two studies in healthy males.

Childhood adversity, a prevalent experience, is related to a higher risk for externalizing and internalizing psychopathology. Alterations in the development of cognitive processes, for example in the attention-interference domain may link childhood adversity and psychopathology. Interfering stimuli can vary in their salience, i.e. ability to capture attentional focus, and valence. However, it is not known if interference by salience or valence is associated with self-reported adversity. In two independent study samples of healthy men (Study 1: n = 44; mean age [standard deviation (SD)] = 25.9 [3.4] years; Study 2: n = 37; 43.5 [9.7] years) we used the attention modulation task (AMT) that probed interference by two attention-modulating conditions, salience and valence separately across repeated target stimuli. The AMT measures the effects of visual distractors (pictures) on the performance of auditory discrimination tasks (target stimuli). We hypothesized that participants reporting higher levels of childhood adversity, measured with the childhood trauma questionnaire, would show sustained interference in trials with lower salience. Due to conflicting reports on the valence-modulation, we tested the valence condition in an exploratory manner. Linear mixed models revealed an interaction between reported childhood adversity and the salience condition across tone presentations in both study samples (Sample 1: p = .03; Sample 2: p = .04), while there were no effects for the valence condition across both studies. Our study suggests that higher self-reported childhood adversity is related to faster processing of target cues during high salience, but slower during low salience conditions. These results hint to the mechanisms linking childhood adversity and psychopathological symptoms in the attentional domain.

Cross-sectional study of retrospective self-reported childhood emotional neglect and inhibitory neurometabolite levels in the pregenual anterior cingulate cortex in adult humans.

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.

Trait anxiety is related to Nx4's efficacy on stress-induced changes in amygdala-centered resting state functional connectivity: a placebo-controlled cross-over trial in mildly to moderately stressed healthy volunteers.

BACKGROUND: The multicomponent drug Neurexan (Nx4) was shown to reduce the neural stress network activation. We now investigated its effects on stress-induced resting state functional connectivity (RSFC) in dependence of trait anxiety (TA), an acknowledged vulnerability factor for stress-induced psychopathologies. METHODS: Nx4 was tested in a randomized placebo-controlled crossover trial. Resting state fMRI scans were performed before and after a psychosocial stress task and exploratively analyzed for amygdala centered RSFC. Effects of Nx4 on stress-induced RSFC changes were evaluated and correlated to TA levels. A subgroup analysis based on TA scores was performed. RESULTS: Multiple linear regression analysis revealed a significant correlation between TA and Nx4 effect on stress-induced RSFC changes between right amygdala and pregenual anterior cingulate cortex (pgACC) and ventro-medial prefrontal cortex (vmPFC). For participants with above average TA, a significant amelioration of the stress-induced RSFC changes was observed. CONCLUSIONS: The data add evidence to the hypothesis that Nx4's clinical efficacy is based on a dampened activation of the neural stress network, with a greater neural response in subjects with anxious personality traits. Further studies assessing clinically relevant outcome measures in parallel to fMRI are encouraged to evaluate the real-world benefit of Nx4. Trial registration NCT02602275.

Nx4 Modulated Resting-State Functional Connectivity Between Amygdala and Prefrontal Cortex in a Placebo-Controlled, Crossover Trial.

Background: The basic functional organization of the resting brain, assessed as resting-state functional connectivity (rsFC), can be affected by previous stress experience and it represents the basis on which subsequent stress experience develops. Notably, the rsFC between the amygdala and the cortical regions associated with emotion regulation and anxiety are affected during stress. The multicomponent drug Neurexan® (Nx4) has previously demonstrated a reduction in amygdala activation in an emotional face matching task and it ameliorated stress-related symptoms. We, thus, investigated the effect of Nx4 on rsFC of the amygdala before stress induction compared with baseline in mildly to moderately stressed participants. Methods: In a randomized, placebo-controlled, double-blind, crossover trial 39 participants received a single dose of placebo or Nx4. Resting-state functional magnetic resonance imaging scans were performed pre-dose and 40 to 60 min post-dose, before any stress induction. First, highly connected functional hubs were identified by global functional connectivity density (gFCD) analysis. Second, by using a seed-based approach, rsFC maps of the left centromedial amygdala (CeMA) were created. The effect of Nx4 on both was evaluated. Results: The medial prefrontal cortex was identified as a relevant functional hub affected by Nx4 in an explorative whole brain gFCD analysis. Using the seed-based approach, we then demonstrated that Nx4 significantly enhanced the negative connectivity between the left CeMA and two cortical regions: the dorsolateral and medial prefrontal cortices. Conclusions: In a resting-state condition, Nx4 reduced the prefrontal cortex gFCD and strengthened the functional coupling between the amygdala and the prefrontal cortex that is relevant for emotion regulation and the stress response. Further studies should elaborate whether this mechanism represents enhanced regulatory control of the amygdala at rest and, consequently, to a diminished susceptibility to stress. ClinicalTrials.gov ID: NCT02602275.

Nx4 attenuated stress-induced activity of the anterior cingulate cortex-A post-hoc analysis of a randomized placebo-controlled crossover trial.

OBJECTIVE: Stress-related symptoms are associated with significant health and economic burden. Several studies suggest Nx4 for the pharmacological management of the stress response and investigated the underlying neural processes. Here we hypothesized that Nx4 can directly affect the stress response in a predefined stress network, including the anterior cingulate cortex (ACC), which is linked to various stress-related symptoms in patients. METHODS: In a randomized, placebo-controlled, double-blind, crossover trial, 39 healthy males took a single dose of placebo or Nx4. Psychosocial stress was induced by the ScanSTRESS paradigm inside an MRI scanner, and stress network activation was analyzed in brain regions defined a priori. RESULTS: Using the placebo data only, we could validate the activation of a distinct neural stress pattern by the ScanSTRESS paradigm. For Nx4, we provide evidence of an attenuating effect on this stress response. A statistically significant reduction in differential stress-induced activation in the right supracallosal ACC was observed for the rotation stress task of the ScanSTRESS paradigm. The results add to previously published results of Nx4 effects on emotion regulation. CONCLUSIONS: Our results strengthen the hypothesis that Nx4 modulates the stress response by reducing the activation in parts of the neural stress network, particularly in the ACC. TRIAL REGISTRATION: NCT02602275; ClinicalTrials.gov.

Corrigendum to "EEG revealed improved vigilance regulation after stress exposure under Nx4 - A randomized, placebo-controlled, double-blind, cross-over trial" [IBRO Neurosci. Rep. 11C (2021) 175-182].

[This corrects the article DOI: 10.1016/j.ibneur.2021.09.002.].

EEG revealed improved vigilance regulation after stress exposure under Nx4 - A randomized, placebo-controlled, double-blind, cross-over trial.

OBJECTIVES: Vigilance is characterized by alertness and sustained attention. The hyper-vigilance states are indicators of stress experience in the resting brain. Neurexan (Nx4) has been shown to modulate the neuroendocrine stress response. Here, we hypothesized that the intake of Nx4 would alter brain vigilance states at rest. METHOD: In this post-hoc analysis of the NEURIM study, EEG recordings of three, 12 min resting-state conditions in 39 healthy male volunteers were examined in a randomized, placebo-controlled, double-blind, cross-over clinical trial. EEG was recorded at three resting-state sessions: at baseline (RS0), after single-dose treatment with Nx4 or placebo (RS1), and subsequently after a psychosocial stress task (RS2). During each resting-state session, each 2-s segment of the consecutive EEG epochs was classified into one of seven different brain states along a wake-sleep continuum using the VIGALL 2.1 algorithm. RESULTS: In the post-stress resting-state, subjects exhibited a hyper-stable vigilance regulation characterized by an increase in the mean vigilance level and by more rigidity in the higher vigilance states for a longer period of time. Importantly, Nx4-treated participants exhibited significantly lower mean vigilance level compared to placebo-treated ones. Also, Nx4- compared to placebo-treated participants spent comparably less time in higher vigilance states and more time in lower vigilance states in the post-stress resting-state. CONCLUSION: Study participants showed a significantly lower mean vigilance level in the post-stress resting-state condition and tended to stay longer in lower vigilance states after treatment with Nx4. These findings support the known stress attenuation effect of Nx4.

Met carriers of the BDNF Val66Met polymorphism show reduced Glx/NAA in the pregenual ACC in two independent cohorts.

The Met allele of the Val66Met SNP of the BDNF gene (rs6265) is associated with impaired activity-dependent release of brain-derived neurotrophic factor (BDNF), resulting in reduced synaptic plasticity, impaired glutamatergic neurotransmission, and morphological changes. While previous work has demonstrated Val66Met effects on magnetic resonance spectroscopy (MRS) markers of either glutamatergic metabolism (Glx) or neuronal integrity (NAA), no study has investigated Val66Met effects on these related processes simultaneously. As these metabolites share a metabolic pathway, the Glx/NAA ratio may be a more sensitive marker of changes associated with the Val66Met SNP. This ratio is increased in psychiatric disorders linked to decreased functioning in the anterior cingulate cortex (ACC). In this study, we investigated the correlation of the Val66Met polymorphism of the BDNF gene with Glx/NAA in the pregenual anterior cingulate cortex (pgACC) using MRS at 3 Tesla (T) (n = 30, all males) and 7 T (n = 98, 40 females). In both cohorts, Met carriers had lower Glx/NAA compared to Val homozygotes. Follow-up analyses using absolute quantification revealed that the Met carriers do not show decreased pgACC glutamate or glutamine levels, but instead show increased NAA compared to the Val homozygotes. This finding may in part explain conflicting evidence for Val66Met as a risk factor for developing psychiatric illnesses.

Heart Rate Variability as an Index of Differential Brain Dynamics at Rest and After Acute Stress Induction.

The brain continuously receives input from the internal and external environment. Using this information, the brain exerts its influence on both itself and the body to facilitate an appropriate response. The dynamic interplay between the brain and the heart and how external conditions modulate this relationship deserves attention. In high-stress situations, synchrony between various brain regions such as the prefrontal cortex and the heart may alter. This flexibility is believed to facilitate transitions between functional states related to cognitive, emotional, and especially autonomic activity. This study examined the dynamic temporal functional association of heart rate variability (HRV) with the interaction between three main canonical brain networks in 38 healthy male subjects at rest and directly after a psychosocial stress task. A sliding window approach was used to estimate the functional connectivity (FC) among the salience network (SN), central executive network (CEN), and default mode network (DMN) in 60-s windows on time series of blood-oxygen-level dependent (BOLD) signal. FC between brain networks was calculated by Pearson correlation. A multilevel linear mixed model was conducted to examine the window-by-window association between the root mean square of successive differences between normal heartbeats (RMSSD) and FC of network-pairs across sessions. Our findings showed that the minute-by-minute correlation between the FC and RMSSD was significantly stronger between DMN and CEN than for SN and CEN in the baseline session [b = 4.36, t(5025) = 3.20, p = 0.006]. Additionally, this differential relationship between network pairs and RMSSD disappeared after the stress task; FC between DMN and CEN showed a weaker correlation with RMSSD in comparison to baseline [b = -3.35, t(5025) = -3.47, p = 0.006]. These results suggest a dynamic functional interplay between HRV and the functional association between brain networks that varies depending on the needs created by changing conditions.

fMRI Revealed Reduced Amygdala Activation after Nx4 in Mildly to Moderately Stressed Healthy Volunteers in a Randomized, Placebo-Controlled, Cross-Over Trial.

Social stress contributes to major societal health burdens, such as anxiety disorders and nervousness. Nx4 has been found to modulate stress responses. We investigated whether dampening of such responses is associated with neuronal correlates in brain regions involved in stress and anxiety. In a randomized, placebo-controlled, double-blind, cross-over trial, 39 healthy males took a single dose (three tablets) of either placebo or Nx4, 40 to 60 minutes before an fMRI scan session. We here report on drug effects on amygdala responses during a face-matching task, which was performed during a complex test battery further including resting-state brain connectivity and a social stress experiment. The first of the Primary Outcomes, defined in a hierarchical order, concerned reduced amygdala effects after intake of verum compared to placebo. We found a statistically significant reduction in differential activations in the left amygdala for the contrast negative faces versus forms during verum versus placebo condition. Our results indicate that effects of Nx4 can be monitored in the brain. Previously noted effects on stress responses may thus be modulated by affective brain regions including the amygdala.

The anterior insula channels prefrontal expectancy signals during affective processing.

Expectancy shapes our perception of impending events. Although such an interplay between cognitive and affective processes is often impaired in mental disorders, it is not well understood how top-down expectancy signals modulate future affect. We therefore track the information flow in the brain during cognitive and affective processing segregated in time using task-specific cross-correlations. Participants in two independent fMRI studies (N1 = 37 & N2 = 55) were instructed to imagine a situation with affective content as indicated by a cue, which was then followed by an emotional picture congruent with expectancy. To correct for intrinsic covariance of brain function, we calculate resting-state cross-correlations analogous to the task. First, using factorial modeling of delta cross-correlations (task-rest) of the first study, we find that the magnitude of expectancy signals in the anterior insula cortex (AIC) modulates the BOLD response to emotional pictures in the anterior cingulate and dorsomedial prefrontal cortex in opposite directions. Second, using hierarchical linear modeling of lagged connectivity, we demonstrate that expectancy signals in the AIC indeed foreshadow this opposing pattern in the prefrontal cortex. Third, we replicate the results in the second study using a higher temporal resolution, showing that our task-specific cross-correlation approach robustly uncovers the dynamics of information flow. We conclude that the AIC arbitrates the recruitment of distinct prefrontal networks during cued picture processing according to triggered expectations. Taken together, our study provides new insights into neuronal pathways channeling cognition and affect within well-defined brain networks. Better understanding of such dynamics could lead to new applications tracking aberrant information processing in mental disorders.