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The prefrontal cortex plays a crucial role in cognitive processes, both during anticipatory and reactive modes of cognitive control. Transcranial Direct Current Stimulation (tDCS) can modulate these cognitive resources. How-ever, there is a lack of research exploring the impact of tDCS on emotional material processing in the prefrontal cortex, particularly in regard to proactive and reactive modes of cognitive control. In this study, 35 healthy volun-teers underwent both real and sham tDCS applied to the right prefrontal cortex in a counterbalanced order, and then completed the Cued Emotion Control Task (CECT). Pupil dilation, a measure of cognitive resource allocation, and behavioral outcomes, such as reaction time and accuracy, were collected. The results indicate that, as com-pared to sham stimulation, active right-sided tDCS reduced performance and resource allocation in both proactive and reactive modes of cognitive control. These findings highlight the importance of further research on the effects of tDCS applied to the right prefrontal cortex on cognitive engagement, particularly for clinical trials utilizing the present electrode montage in combination with cognitive interventions.

INTRODUCTION: Research on stress-related disorders and brain imaging suggests that (acute) stress might impact the capacity to mentally simulate specific episodic future events (EFT) through the effects of cortisol on brain regions supporting this cognitive function, such as the prefrontal cortices. This study aims to examine the mechanisms underlying this link, using transcranial Direct Current Stimulation (tDCS) over the left dorsolateral prefrontal cortex. METHODS: 60 healthy participants were subjected to the Montreal Imaging Stress Task (MIST), followed by either active or sham tDCS. After stimulation, the EFT task was administered. Salivary cortisol was measured throughout the protocol. RESULTS: Higher cortisol AUCi values were linked to less specific episodic future thoughts. Moreover, active tDCS enhanced EFT specificity irrespective of cortisol, especially in high trait ruminators. We did not observe an effect from active tDCS on cortisol AUCi, and equally there was no interaction effect between cortisol AUCi and stimulation condition predictive for EFT specificity. CONCLUSION: Although we did not find evidence for the effects of tDCS on the HPA-system, our data reveal a crucial link between two critical predictors of mental health for the first time, and provide a solution to help rehabilitate EFT deficits.Trial registration: Netherlands National Trial Register identifier: ntr004..

Prior studies suggest that the cerebellum contributes to the prediction of action sequences as well as the detection of social violations. In this dynamic causal modeling study, we explored the effective connectivity of the cerebellum with the cerebrum in processing social action sequences. A first model aimed to explore functional cerebello-cerebral connectivity when learning trait/stereotype-implying action sequences. We found many significant bidirectional connectivities between mentalizing areas of the cerebellum and the cerebrum including the temporo-parietal junction (TPJ) and medial prefrontal cortex (mPFC). Within the cerebrum, we found significant connectivity between the right TPJ and the mPFC, and between the TPJ bilaterally. A second model aimed to investigate cerebello-cerebral connectivity when conflicting information arises. We found many significant closed loops between the cerebellum and cerebral mentalizing (e.g. dorsal mPFC) and executive control areas (e.g. medial and lateral prefrontal cortices). Additional closed loops were found within the cerebral mentalizing and executive networks. The current results confirm prior research on effective connectivity linking the cerebellum with mentalizing areas in the cerebrum for predicting social sequences, and extend it to cerebral executive areas for social violations. Overall, this study emphasizes the critical role of cerebello-cerebral connectivity in understanding social sequences.

Repetitive transcranial magnetic stimulation (rTMS) is a tool that can be used to administer treatment for neuropsychiatric disorders such as major depressive disorder, although the clinical efficacy is still rather modest. Overly general stimulation protocols that consider neither patient-specific depression symptomology nor individualized brain characteristics, such as anatomy or structural and functional connections, may be the cause of the high inter- and intraindividual variability in rTMS clinical responses. Multimodal neuroimaging can provide the necessary insights into individual brain characteristics and can therefore be used to personalize rTMS parameters. Optimal coil positioning should include a three-step process: 1) identify the optimal (indirect) target area based on the exact symptom pattern of the patient; 2) derive the cortical (direct) target location based on functional and/or structural connectomes derived from functional and diffusion magnetic resonance imaging data; and 3) determine the ideal coil position by computational modeling, such that the electric field distribution overlaps with the cortical target. These TMS-induced electric field simulations, derived from anatomical and diffusion magnetic resonance imaging data, can be further applied to compute optimal stimulation intensities. In addition to magnetic resonance imaging, electroencephalography can provide complementary information regarding the ongoing brain oscillations. This information can be used to determine the optimal timing and frequency of the stimuli. The heightened benefits of these personalized stimulation approaches are logically reasoned, but speculative. Randomized clinical trials will be required to compare clinical responses from standard rTMS protocols to personalized protocols. Ultimately, an optimized clinical response may result from precision protocols derived from combinations of personalized stimulation parameters.

Electroconvulsive therapy (ECT) is an effective neuromodulatory therapy for major depressive disorder (MDD). Treatment is associated with regional changes in brain structure and function, indicating activation of neuroplastic processes. To investigate the underlying neurobiological mechanism of macroscopic reorganization following ECT, we longitudinally (before and after ECT in two centers) collected magnetic resonance images for 96 MDD patients. Similar patterns of cortical thickness (CT) changes following ECT were observed in two centers. These CT changes were spatially colocalized with a weighted combination of genes enriched for neuroplasticity-related ontology terms and pathways (e.g., synaptic pruning) as well as with a higher density of D2/3 dopamine receptors. A multiple linear regression model indicated that the region-specific gene expression and receptor density patterns explained 40% of the variance in CT changes after ECT. In conclusion, these findings suggested that dopamine signaling and neuroplasticity-related genes are associated with the ECT-induced morphological reorganization.

Non-invasive brain stimulation (NIBS) techniques have been increasingly used over the dorsolateral prefrontal cortex (DLPFC) to enhance working memory (WM) performance. Not-withstanding, NIBS protocols have shown either small or inconclusive cognitive effects on healthy and neuropsychiatric samples. Therefore, we assessed working memory performance and safety of transcranial direct current stimulation (tDCS), intermittent theta-burst stimulation (iTBS), and both therapies combined vs placebo over the neuronavigated left DLPFC of healthy participants. Twenty-four subjects were included to randomly undergo four sessions of NIBS, once a week: tDCS alone, iTBS alone, combined protocol and placebo. The 2-back task and an adverse effect scale were applied after each NIBS session. Results revealed a significantly faster response for iTBS (b=-21.49, p= 0.04), but not for tDCS and for the interaction tDCS vs. iTBS (b= 13.67, p= 0.26 and b= 40.5, p= 0.20, respectively). No changes were observed for accuracy and no serious adverse effects were found among protocols. Although tolerable, an absence of syner-gistic effects for the combined protocol was seen. Nonetheless, future trials accessing different outcomes for the combined protocols, as well as studies investigating iTBS over the left DLPFC for cognition and exploring sources of variability for tDCS are encouraged. (c) 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Brain imaging studies have shown that stimulation of the left dorsolateral prefrontal cortex (dlPFC), which plays a pivotal role in high-order cognitive control processes, modulates brain reactivity to reward-related cues. Nevertheless, the impact of contextual factors such as reward availability (the reward that is depicted in the cue exposure task) on such modulation effect remains unclear. Here we tested whether a single session of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) over the left dlPFC differently impacts brain reactivity to cues signalling either availability or unavailability of a sports betting opportunity. Employing a within-subject design (verum versus sham HF-rTMS) among thirty-two frequent sports bettors, we first observed that, as compared to the sham condition, verum HF-rTMS modulated brain reactivity to game cues prior to being made (un)available for betting, through simultaneous increases (posterior insula and caudate nucleus) and decreases (occipital pole) in brain activation. Second, verum HF-rTMS led to increased ventral striatal activity towards cues available for betting but did not modulate brain response to cues unavailable for betting. Third, exploratory functional connectivity analyses revealed increased negative coupling in the verum condition between the left dlPFC and the right and left superior frontal gyrus toward available and non-available betting cues, respectively. Taken together, these findings demonstrate that transient stimulation of the left dlPFC led to a general modulation in brain activity and functional connectivity in responses to cues, and that this effect is only partly dependent on cues signalling for reward (un)availability.

BackgroundAs part of repetitive negative thinking (RNT), rumination is a maladaptive cognitive response style to stress or negative mood which can increase the risk of depression and may prohibit complete recovery. Cognitive behavioral therapy (CBT) and transcranial direct current stimulation (tDCS) both proved to be effective in decreasing rumination. However, the combined effects of tDCS and CBT interventions on rumination have not yet been explored. The first aim of this pilot study is to investigate whether the combination of tDCS and CBT has an accumulating positive effect on modulating state rumination. The second aim is to assess the feasibility and safety profile of the proposed combined approach.MethodSeventeen adults aged 32–60 years, suffering from RNT, were referred by their primary care professional to participate in an 8-week group intervention for RNT (“Drop It”) comprising 8 sessions of CBT. Before each CBT session, patients underwent one double-blinded prefrontal active (2 mA for 20 min) or sham tDCS (anode over F3, cathode over the right supraorbital region) combined with an internal cognitive attention task focused on individual RNT, i.e., online tDCS priming. During each session, the Brief State Rumination Inventory was used to assess state rumination.ResultsA mixed effects model analysis revealed no significant differences between the stimulation conditions, weekly sessions, or their interaction in terms of state rumination scores.ConclusionOverall, the combination of online tDCS priming followed by group CBT was found to be safe and feasible. On the other hand, no significant additional effects of this combined approach on state rumination were established. Although our pilot study may have been too small to find significant clinical effects, future larger RCT studies on combined tDCS-CBT treatment protocols may reevaluate the selection of internal cognitive attention tasks and more objective neurophysiological measurements, consider the optimal timing of the combination (concurrently or sequentially), or may add additional tDCS sessions when following CBT.

BackgroundIt has been suggested that individual differences in temperament could be involved in the (non-)response to antidepressant (AD) treatment. However, how neurobiological processes such as brain glucose metabolism may relate to personality features in the treatment-resistant depressed (TRD) state remains largely unclear.MethodsTo examine how brainstem metabolism in the TRD state may predict Cloninger's temperament dimensions Harm Avoidance (HA), Novelty Seeking (NS), and Reward Dependence (RD), we collected 18fluorodeoxyglucose positron emission tomography (18FDG PET) scans in 40 AD-free TRD patients. All participants were assessed with the Temperament and Character Inventory (TCI). We applied a multiple kernel learning (MKL) regression to predict the HA, NS, and RD from brainstem metabolic activity, the origin of respectively serotonergic, dopaminergic, and noradrenergic neurotransmitter (NT) systems.ResultsThe MKL model was able to significantly predict RD but not HA and NS from the brainstem metabolic activity. The MKL pattern regression model identified increased metabolic activity in the pontine nuclei and locus coeruleus, the medial reticular formation, the dorsal/median raphe, and the ventral tegmental area that contributed to the predictions of RD.ConclusionsThe MKL algorithm identified a likely metabolic marker in the brainstem for RD in major depression. Although 18FDG PET does not investigate specific NT systems, the predictive value of brainstem glucose metabolism on RD scores however indicates that this temperament dimension in the TRD state could be mediated by different monoaminergic systems, all involved in higher order reward-related behavior.

Background: Repetitive negative thinking (RNT) is considered to be an important transdiagnostic factor in the onset, course and recurrence of both depressive and anxiety disorders. This study aimed to investigate whether an add-on group intervention ‘Drop it’, compared to treatment as usual, would improve RNT, anxiety and depressive symptoms, as well as quality of life and self-esteem of patients with Major Depressive Disorder (MDD) and/or Generalized Anxiety Disorder (GAD). Methods: Eighty patients were randomly allocated to 8 sessions of group intervention (n = 45) or a delayed treatment control group (n = 35). Both conditions continued their ongoing mental health care. Assessments took place before randomization, 12 weeks later (after group intervention) and at 3- and 9- months follow-up. Results: Although all outcomes improved after the intervention, only the uncontrollability of rumination, worrying, distancing oneself from one’s thoughts, and quality of life remained statistically significant after Bonferroni correction compared to the delayed treatment control group. Conclusions: Group intervention improves RNT and quality of life of patients treated for MDD and/or GAD. Improvements remain stable until 9 months after treatment. Limitations of the study included the small sample size, the lack of a long-term follow-up in the delayed treatment control group and the inclusion of highly educated patients with mainly high comorbid generalized anxiety disorder and depression.

Background: Trauma-based psychotherapy is a first line treatment for post-traumatic stress disorder (PTSD) but not all patients achieve long-term remission. Transcranial direct current stimulation (tDCS) received considerable attention as a neuromodulation method that may improve trauma-based psychotherapy. Objective: We explored the effects of repeated anodal tDCS over the prefrontal cortex (PFC) on fear extinction in mice as a preclinical model for trauma-based psychotherapy. Methods: We performed auditory fear conditioning with moderate or high shock intensity on C57BL6/J mice. Next, mice received anodal tDCS (0.2 mA, 20 min) or sham stimulation over the PFC twice daily for five consecutive days. Extinction training was performed by repeatedly exposing mice to the auditory cue the day after the last stimulation session. Early and late retention of extinction were evaluated one day and three weeks after extinction training respectively. Results: We observed no significant effect of tDCS on the acquisition or retention of fear extinction in mice subjected to fear conditioning with moderate intensity. However, when the intensity of fear con-ditioning was high, tDCS significantly lowered freezing during the acquisition of extinction, regardless of the extinction protocol. Moreover, when tDCS was combined with a strong extinction protocol, we also observed a significant improvement of early extinction recall. Finally, we found that tDCS reduced generalized fear induced by contextual cues when the intensity of conditioning is high and extinction training limited. Conclusions: Our data provide a rationale to further explore anodal tDCS over the PFC as potential support for trauma-based psychotherapy for PTSD. (c) 2021 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

This review focuses on autistic adults and serves 4 purposes: (1) providing an overview of their difficulties regarding mentalizing (understanding others' mental states) and narrative coherence (structured storytelling), (2) highlighting the relations between both skills by examining behavioral observations and shared neural substrates, (3) providing an integrated perspective regarding novel diagnostic tools and support services, and (4) raising awareness of adult autism. We suggest that mentalizing and narrative coherence are related at the behavioral level and neural level. In addition to the traditional mentalizing network, the cerebellum probably serves as an important hub in shared cerebral networks implicated in mentalizing and narrative coherence. Future autism research and support services should tackle new questions within a framework of social cerebellar (dys)functioning.

Introduction Prior resting state fMRI studies have revealed that elevated connectivity between the default mode network (DMN) and subgenual prefrontal cortex (sgPFC) connectivity may underly maladaptive rumination, which is a major risk factor for depression. To further evaluate such relationship, we investigated whether posterior regions of the DMN, showed elevated connectivity with the sgPFC in remitted depressed patients (rMDD) and whether this connectivity was related to maladaptive rumination. Methods We examined whether rMDD (N = 20) had elevated EEG posterior DMN – sgPFC functional connectivity when compared to age and sex matched healthy controls (N = 17), and whether this posterior DMN – sgPFC connectivity positively correlated with rumination. Using minimum norm as the source estimation method, we extracted current density maps from six regions of interest (ROIs) within the posterior DMN. EEG source-space functional connectivity was calculated using the Amplitude Envelope Correlation method. Results Relative to controls, rMDD showed increased posterior cingulate cortex (PCC) – sgPFC connectivity in the beta-3 (25–30 Hz) band. As hypothesized, PCC – sgPFC connectivity was positively associated with rumination for rMDD, even after controlling for depression and anxiety. Limitations The absence of an MDD patient group and the relatively small sample size can limit the generalizability of the results. Conclusions EEG resting state PCC – sgPFC functional connectivity is significantly elevated in rMDD and is associated with rumination, suggesting that EEG PCC – sgPFC connectivity may be useful as a neural marker to identify individuals at risk for depression.

Earlier research demonstrated robust cerebellar involvement in sequencing, including high-level social information sequencing that requires mental state attributions, termed mentalizing. Earlier research also found cerebellar deficiencies in autism spectrum disorders (ASD) which are characterized by social difficulties. However, studies on high-level social sequencing functionality by persons with ASD are almost non-existent. In this study, we, therefore, perform a comparison between behavioral performances of high-functioning ASD and neurotypical participants on the Picture and Verbal Sequencing Tasks. In these tasks, participants are requested to put separate events (depicted in cartoon-like pictures or behavioral sentences, respectively) in their correct chronological order. To do so, some of these events require understanding of high-level social beliefs, of social routines (i.e., scripts), or nonsocial mechanical functionality. As expected, on the Picture Sequencing task, we observed longer response times for persons with ASD (in comparison with neurotypical controls) when ordering sequences requiring an understanding of social beliefs and social scripts, but not when ordering nonsocial mechanical events. This confirms our hypotheses that social sequence processing is impaired in ASD. The verbal version of this task did not reveal differences between groups. Our results are the first step toward new theoretical insights for social impairments of persons with ASD. They highlight the importance of taking into account sequence processing, and indirectly the cerebellum when investigating ASD difficulties.

Introduction: A better understanding of how the hypothalamic-pituitary-adrenal (HPA) axis can be externally regulated is of major importance, especially because hyperreactivity to stress has been proposed as a key factor in the onset and maintenance of many psychiatric conditions. Over the past decades, numerous studies have investigated whether non-invasive brain stimulation (NIBS) can regulate HPA axis reactivity in acute stress situation. As the current results did not allow us to draw clear conclusions, we decided to conduct a systematic review of the literature investigating the effect of a single NIBS session on stress-induced cortisol release. Methods: We searched MEDLINE and Web Of Science for articles indexed through December 2021. Among the 246 articles identified, 15 fulfilled our inclusion criteria with a quality estimated between 52 and 93%. Results: Of the different NIBS used and targeted brain regions, stimulating the left dorsolateral prefrontal cortex, with either high frequency repetitive transcranial magnetic stimulation or anodal transcranial direct current stimulation, seems to be the most appropriate for reducing cortisol release in acute stress situations. Conclusions: Despite the heterogeneity of the stimulation parameters, the characteristics of participants, the modalities of cortisol collection, the timing of the NIBS session in relation to the stressor exposure, and methodological considerations, stimulating the left dorsolateral prefrontal cortex can be efficient to modulate stress-induced cortisol release.

Objective: Although relatively costly and non-scalable, non-invasive neuromodulation interventions are treatment alternatives for neuropsychiatric disorders. The recent developments of highly-deployable transcranial electric stimulation (tES) systems, combined with mobile-Health technologies, could be incorporated in digital trials to overcome methodological barriers and increase equity of access. The study aims are to discuss the implementation of tES digital trials by performing a systematic scoping review and strategic process mapping, evaluate methodological aspects of tES digital trial designs, and provide Delphi-based recommendations for implementing digital trials using tES.Methods: We convened 61 highly-productive specialists and contacted 8 tES companies to assess 71 issues related to tES digitalization readiness, and processes, barriers, advantages, and opportunities for implementing tES digital trials. Delphi-based recommendations (>60% agreement) were provided.Results: The main strengths/opportunities of tES were: (i) non-pharmacological nature (92% of agreement), safety of these techniques (80%), affordability (88%), and potential scalability (78%). As for weaknesses/threats, we listed insufficient supervision (76%) and unclear regulatory status (69%). Many issues related to methodological biases did not reach consensus. Device appraisal showed moderate digitalization readiness, with high safety and potential for trial implementation, but low connectivity.Conclusions: Panelists recognized the potential of tES for scalability, generalizability, and leverage of digital trials processes; with no consensus about aspects regarding methodological biases. Significance: We further propose and discuss a conceptual framework for exploiting shared aspects between mobile-Health tES technologies with digital trials methodology to drive future efforts for digitizing tES trials. (C) 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Although treatment resistance to antidepressant pharmacotherapy is quite common, the phenomenon of refractory major depressive disorder (rMDD) is not well understood. Nevertheless, the metabolic activity of the subgenual anterior cingulate cortex (sgACC) has been put forward as a possible metabolic biomarker of clinical prediction and response, albeit sgACC lateralization differences in functional connectivity have not yet been extensively examined. Also not in the refractory depressed state. To examine sgACC lateralization differences in metabolic connectivity, we recruited 43 right-handed antidepressant-free unipolar melancholic rMDD patients and 32 right-handed healthy controls to participate in this 18FDG PET study and developed a searchlight-based interregional covariance connectivity approach. Compared to non-depressed individuals, sgACC covariance analysis showed stronger metabolic connections with frontolimbic brain regions known to be affected in the depressed state. Furthermore, whereas the left sgACC showed stronger metabolic connections with ventromedial prefrontal cortical regions, implicated in anhedonia, suicidal ideation, and self-referential processes, the right sgACC showed significantly stronger metabolic connections with posterior hippocampal and cerebellar regions, respectively specialized in memory and social processing. Overall, our results substantiate earlier research that the sgACC is a metabolic key player when clinically depressed and that distinct lateralized sgACC metabolic connectivity patterns are present.

Empathy impairments have been linked to alcohol dependence even during abstinent periods. Nonetheless, the neural underpinnings of abstinence-induced empathy deficits remain unclear. In this study, we employed connectome-based predictive modeling (CPM) by using whole brain resting-state functional connectivity (rs-FC) to predict empathy capability of abstinent alcoholics (n = 47) versus healthy controls (n = 59). In addition, the generalizability of the predictive model (i.e., one group treated as a training dataset and another one treated as a test dataset) was performed to determine whether healthy controls and abstinent alcoholics share common neural fingerprints of empathy. Our results showed that abstinent alcoholics relative to healthy controls had decreased empathy capacity. Although no predictive models were observed in the abstinence group, we found that individual empathy scores in the healthy group can be reliably predicted by functional connectivity from the default mode network (DMN) to the sensorimotor network (SMN), occipital network, and cingulo-opercular network (CON). Moreover, the identified connectivity fingerprints of healthy controls could be generalized to predict empathy in the abstinence group. These findings indicate that neural circuits accounting for empathy may be disrupted by alcohol use and the impaired degree varies greatly among abstinent individuals. The large inter-individual variation may impede identification of the predictive model of empathy in alcohol abstainers.

Recent research suggests beneficial effects of cognitive control training (CCT) on repetitive negative thinking (RNT), a key risk factor for internalizing symptomatology. However, relatively little is known regarding predictors of adherence to internet-delivered CCT as well as moderators of treatment effects for this intervention. Answering these questions could improve efficiency of clinical implementation of CCT as an eHealth intervention. The current pre-registered single-arm trial set-out to address these questions using a web-based gamified CCT procedure based on the adaptive Paced Auditory Serial Addition Task. Participants (N = 382) entered the internet-based study, where we observed considerable drop-out during the assessment phase and the first training sessions. Emotional stability and resilience emerged as predictors for deciding not to commence the intervention. Drop-out throughout the course of CCT was explained by age, emotion regulation-, and personality factors. We used latent profile analysis, a probabilistic modeling approach, to identify clusters of participants (User Profiles) based on indicators of baseline cognitive- and emotional functioning, training progress, and user experience. We obtained three User Profiles, reflecting low-, moderate-, and high-risk status. Effortful control, emotion regulation, internalizing symptomatology, resilience, and emotional stability played a central role in these User Profiles. Interestingly, User Profile predicted training related cognitive gains, as well as effects of CCT on anxiety- and stress symptoms, and reappraisal. Our findings suggest that CCT is most effective for the moderate- and high-risk groups. In addition, the high-risk group would likely benefit from a more intensive training procedure or repeated administration of the training procedure over time to foster long-term retention of training related gains.

Background Major depressive episode (MDE) is worldwide one of the most prevalent and disabling mental health conditions. In cases of persistent non-response to treatment, electroconvulsive therapy (ECT) is a safe and effective treatment strategy with high response rates. Unfortunately, longitudinal data show low sustained response rates with 6-month relapse rates as high as 50% using existing relapse prevention strategies. Cognitive side effects of ECT, even though transient, might trigger mechanisms that increase relapse in patients who initially responded to ECT. Among these side effects, reduced cognitive control is an important neurobiological driven vulnerability factor for depression. As such, cognitive control training (CCT) holds promise as a non-pharmacological strategy to improve long-term effects of ECT (i.e., increase remission, and reduce depression relapse). Method/design Eighty-eight patients aged between 18 and 70 years with MDE who start CCT will be included in this randomized controlled trial (RCT). Following (partial) response to ECT treatment (at least a 25% reduction of clinical symptoms), patients will be randomly assigned to a computer based CCT or active placebo control. A first aim of this RCT is to assess the effects of CCT compared to an active placebo condition on depression symptomatology, cognitive complaints, and quality of life. Secondly, we will monitor patients every 2 weeks for a period of 6 months following CCT/active placebo, allowing the detection of potential relapse of depression. Thirdly, we will assess patient evaluation of the addition of cognitive remediation to ECT using qualitative interview methods (satisfaction, acceptability and appropriateness). Finally, in order to further advance our understanding of the mechanisms underlying effects of CCT, exploratory analyses will be conducted using video footage collected during the CCT/active control phase of the study. Discussion Cognitive remediation will be performed following response to ECT, and an extensive follow-up period will be employed. Positive findings would not only benefit patients by decreasing relapse, but also by increasing acceptability of ECT, reducing the burden of cognitive side-effects. Trial registration The study is registered with ClinicalTrials.gov. Study ID: NCT04383509 Trial registration date: 12.05.2020.

Social cognition plays a crucial role in the development and treatment of cocaine dependence. However, studies investigating social cognition, such as empathy and its underlying neural basis, are lacking. To explore the neural interactions among reward and memory circuits, we applied effective connectivity analysis on resting-state fMRI data collected from cocaine-dependent subjects. The relationship between effective connectivity within these two important circuits and empathy ability - evaluated with the Interpersonal Reactivity Index (IRI) - was assessed by machine learning algorithm using multivariate regression analysis. In accordance with the neurocircuitry disruptions of cocaine addiction, the results showed that cocaine-dependent subjects relative to healthy controls had altered resting state effective connectivity between parts of the memory and reward systems. Furthermore, effective connectivity between the memory and reward system could predict the fantasy empathy (FE) subscale scores in cocaine dependence. Overall, our findings provide further evidence for the neural substrates of social cognition in cocaine-dependent patients. These new insights could be useful for the development of new treatment programs for this substance dependency disorder.

Several reports point to the beneficial effects of repetitive transcranial magnetic stimulation (rTMS) in the treatment of resistant obsessive–compulsive disorder (OCD). This study aimed to evaluate the safety and efficacy of rTMS targeting the dmPFC in the treatment of treatment-resistant OCD patients. Twelve patients received 20 sessions of low-frequency (LF) rTMS (1 Hz, 1200 pulses) in a twice daily protocol during 10 weekdays. Y-BOCS and IDS scores modestly but significantly decreased after treatment and at follow-up and HADS anxiety improved at follow-up. LF rTMS may improve OCD, anxiety, and depressive symptoms in treatment-resistant OCD and was a safe and well-tolerated treatment.

The left dorsolateral prefrontal cortex (lDLPFC) is implicated in anticipatory (i.e. during anticipation of emotional stimuli) and online (i.e. during confrontation with emotional stimuli) emotion regulatory processes. However, research that investigates the causal role of the lDLPFC in these processes is lacking. In this study, 74 participants received active or sham transcranial direct current stimulation (tDCS) over the lDLPFC. Participants were told strangers evaluated them. These (rigged) social evaluations were presented, and in 50% of the trials, participants could anticipate the valence (positive or negative) of the upcoming social feedback. Pupil dilation (a marker of cognitive resource allocation) and skin conductance responses (a marker of arousal) were measured. The results indicate that active (compared to sham) tDCS reduced arousal during the confrontation with anticipated feedback but only marginally during the confrontation with unanticipated feedback. When participants were given the opportunity to anticipate the social feedback, tDCS reduced arousal, irrespective of whether one was anticipating or being confronted with the anticipated feedback. Moreover, tDCS reduced cognitive resource allocation during anticipation, which was associated with resource allocation increases during the subsequent confrontation. Altogether, results suggest that the lDLPFC is causally implicated in the interplay between anticipatory and online emotion regulatory processes.

Major Depressive Disorder (MDD) is a widespread mental illness that causes considerable suffering, and neuroimaging studies are trying to reduce this burden by developing biomarkers that can facilitate detection. Prior fMRI- and neurostimulation studies suggest that aberrant subgenual Anterior Cingulate (sgACC)—dorsolateral Prefrontal Cortex (DLPFC) functional connectivity is consistently present within MDD. Combining the need for reliable depression markers with the electroencephalogram’s (EEG) high clinical utility, we investigated whether aberrant EEG sgACC–DLPFC functional connectivity could serve as a marker for depression. Source-space Amplitude Envelope Correlations (AEC) of 20 MDD patients and 20 matched controls were contrasted using non-parametric permutation tests. In addition, extracted AEC values were used to (a) correlate with characteristics of depression and (b) train a Support Vector Machine (SVM) to determine sgACC–DLPFC connectivity’s discriminative power. FDR-thresholded statistical maps showed reduced sgACC–DLPFC AEC connectivity in MDD patients relative to controls. This diminished AEC connectivity is located in the beta-1 (13–17 Hz) band and is associated with patients’ lifetime number of depressive episodes. Using extracted sgACC–DLPFC AEC values, the SVM achieved a classification accuracy of 84.6% (80% sensitivity and 89.5% specificity) indicating that EEG sgACC–DLPFC connectivity has promise as a biomarker for MDD.

Non-invasive brain stimulation (NIBS) interventions are promising for the treatment of psychiatric disorders. Notwithstanding, the NIBS mechanisms of action over the dorsolateral prefrontal cortex (DLPFC), a hub that modulates affective and cognitive processes, have not been completely mapped. We aimed to investigate regional cerebral blood flow (rCBF) changes over the DLPFC and the subgenual anterior cingulate cortex (sgACC) of different NIBS protocols using Single-Photon Emission Computed Tomography (SPECT). A factorial, within-subjects, double-blinded study was performed. Twenty-three healthy subjects randomly underwent four sessions of NIBS applied once a week: transcranial direct current stimulation (tDCS), intermittent theta-burst stimulation (iTBS), combined tDCS + iTBS and placebo. The radiotracer 99m-Technetium-ethylene-cysteine-dimer was injected intravenously during the NIBS session, and SPECT neuroimages were acquired after the session. Results revealed that the combination of tDCS + iTBS increased right sgACC rCBF. Cathodal and anodal tDCS increased and decreased DLPFC rCBF, respectively, while iTBS showed no significant changes compared to the placebo. Our findings suggest that the combined protocol might optimize the activity in the right sgACC and encourage future trials with neuropsychiatric populations. Moreover, mechanistic studies to investigate the effects of tDCS and iTBS over the DLPFC are required.

To study social sequence learning, earlier functional magnetic resonance imaging (fMRI) studies investigated the neural correlates of a novel Belief Serial Reaction Time task in which participants learned sequences of beliefs held by protagonists. The results demonstrated the involvement of the mentalizing network in the posterior cerebellum and cerebral areas (e.g. temporoparietal junction, precuneus and temporal pole) during implicit and explicit social sequence learning. However, little is known about the neural functional interaction between these areas during this task. Dynamic causal modeling analyses for both implicit and explicit belief sequence learning revealed that the posterior cerebellar Crus I & II were effectively connected to cerebral mentalizing areas, especially the bilateral temporoparietal junction, via closed loops (i.e. bidirectional functional connections that initiate and terminate at the same cerebellar and cerebral areas). There were more closed loops during implicit than explicit learning, which may indicate that the posterior cerebellum may be more involved in implicitly learning sequential social information. Our analysis supports the general view that the posterior cerebellum receives incoming signals from critical mentalizing areas in the cerebrum to identify sequences of social actions and then sends signals back to the same cortical mentalizing areas to better prepare for others’ social actions and one’s responses to it.

Introduction Non-invasive brain stimulation (NIBS) as monotherapy has been increasingly used to enhance the activity of brain networks. However, it is unclear whether a combination of distinct NIBS approaches could enhance prefrontal cortical (PFC) activity. Objective We propose to investigate the combined and standalone effects of two NIBS modalities on the PFC through a working memory task, single photon emission computed tomography (SPECT), and salivary cortisol. We hypothesize that the combined protocol will provoke greater changes in the collected measures compared to the remining protocols. Methods A randomized, double-blind, sham-controlled, full-factorial design will be conducted. The effects of transcranial direct current stimulation (tDCS) and intermittent theta-burst stimulation (iTBS) will be investigated over four different sessions (sham tDCS + sham iTBS, anodal tDCS + sham iTBS, anodal tDCS + active iTBS and sham tDCS + active iTBS) in 30 healthy adult volunteers. A 99mTc-ethylene cysteine dimer (99mTC-ECD) will be administered during the NIBS session and neuroimaging will be acquired within one hour. Salivary cortisol will be collected before and after each session and an n-back working memory task will be applied after the end of each NIBS session. The outcomes will be cerebral perfusion alterations (99mTC-ECD SPECT), accuracy and reaction time in the n-back task, and changes in salivary cortisol level. Conclusion The results from this trial can guide future therapeutic protocols for NIBS treatments stimulating the PFC by demonstrating that the combination of NIBS techniques is feasible, tolerable, and can lead to greater enhancement of PFC activity.

The current study aimed to investigate the impact of the COVID-19 pandemic on the mental health of people with OCD and the degree of family accommodation (FA) by live-in family members across phases of the lockdown measures imposed by the Belgian government. Forty-nine OCD patients and 26 live-in family members participated in the study. We assessed OCD symptom severity and FA of the live-in family members, as well as depressive symptoms, anxiety and stress levels and COVID-19 related psychological distress of patients and family members at four different timepoints: one month after the start of the lockdown (T1), during the gradual relaxation (T2), between the two waves (T3) and during the second wave (T4). Results showed that although COVID-19 related stress increased and decreased in accordance with the waxing and waning pattern of the pandemic, OCD symptoms showed an initial slight increase followed by a decrease at T3 and again at T4. Changes in family members’ accommodation of symptoms followed the same course as the OCD symptoms. Furthermore, OCD symptoms correlated with depressive symptoms, anxiety and stress levels and COVID-19 related distress at all timepoints. It is important to involve family members in the treatment of OCD even during a pandemic. Clinicians should also pay attention to symptoms of depression, anxiety and stress during OCD treatment. Further research is necessary to entangle the causal relationship between OCD symptoms, FA and symptoms of depression, anxiety and stress.

Previous neuroimaging studies have highlighted the role of the prefrontal-subcortical circuits in personality trait of novelty seeking (NS), thought to be mediated by the dopaminergic system. However, it remains largely unknown whether cortico-basal-cerebellar connections, heavily influenced by dopamine, are implicated in this temperament dimension as well. The present study aimed to further investigate the relationship between the NS trait and the cortico-basal-cerebellar pathways by using structural covariance network analysis. Ninety-five healthy female volunteers were included in this work, and NS was assessed with the Temperament and Character Inventory (TCI). Our results showed that NS scores were associated with structural connections between the cerebellum and the cerebral cortex, thalamus, and basal ganglia, substantiating the implication of the cortico-basal-cerebellar circuits in the NS construct. In addition, structural connections between visual and sensorimotor regions were also associated with NS scores, indicating that sensory and motor information processing may contribute to NS-related behaviors. Overall, the current findings may deepen our understanding of brain structural circuits related to this temperament dimension.

This study tests the hypothesis that the posterior cerebellum is involved in social cognition by identifying and automatizing sequences of social actions. We applied a belief serial reaction time task (Belief SRT task), which requires mentalizing about two protagonists' beliefs about how many flowers they receive. The protagonists' beliefs could either be true or false depending on their orientation (true belief: oriented towards and directly observing the flowers; or false belief: oriented away and knowing only prior information about flowers). A Control SRT task was created by replacing protagonists and their beliefs with shapes and colors. Participants were explicitly told that there was a standard sequence related to the two protagonists' belief orientations (Belief SRT task) or the shapes' colors (Control SRT task). Both tasks included a Training phase where the standard sequence was repeated and a Test phase where this standard sequence was interrupted by random sequences. As hypothesized, compared with the Control SRT task, the Belief SRT task recruited the posterior cerebellar Crus II and the temporoparietal junction (TPJ) more. Faster response times were correlated with less Crus II activation and with more TPJ activation, suggesting that the Crus II supported automatizing the belief sequence while the TPJ supported inferring the protagonists' beliefs. Also as hypothesized, compared with an implicit version of the Belief SRT task (i.e., participants did not know about the existence of sequences; Ma, Pu, et al., 2021b), the cerebellar Crus I &II was engaged less during initial training and automatic application of the sequence, and the cortical TPJ was activated more in processing random sequences.

Background: Remitted depressed (RMD) individuals form a risk group for developing future depressive episodes. Improving cognitive control may reduce the risk to develop novel depressive symptoms, as beneficial effects of such training were demonstrated in RMD individuals. Method: The current study attempted to replicate and extend these results. In this randomized controlled trial (ClinicalTrials.gov NCT03278756), 68 RMD individuals were allocated to a cognitive control training or an active control condition, each comprised of 10 homework sessions dispersed over two weeks. Primary outcome measures were depressive symptomatology and rumination. Assessment took place before and after training and at 3 and 6 month follow-up. Results: This study showed training-related cognitive transfer and mixed effects on indicators of subjective cognitive functioning, depressive- and anxiety symptoms, as well as broader residual complaints. In addition, we failed to observe previously reported beneficial effects of CCT on indicators of emotion regulation and resilience. Conclusions: Given the partial replication of previously reported effects of cognitive control training in RMD, further research is needed.

Transcutaneous auricular vagus nerve stimulation (taVNS) has been proposed as a potential new tool in the treatment of major depressive disorder. Prior studies have demonstrated that taVNS enhances cognitive control and is able to modulate brain activity in key regions involved in cognitive emotion regulation, such as the anterior cingulate and medial prefrontal cortex, which is known to be impaired in depressed patients. Preclinical studies are lacking but may provide important insights into the working mechanisms of taVNS on cognitive emotion regulatory processes. In this between-subject study, 83 healthy subjects underwent a single-session of active taVNS or sham stimulation, after which cognitive reappraisal was examined using a computer-based cognitive emotion regulation task. Our results indicate that participants receiving active taVNS, compared to sham, were better at using cognitive reappraisal and rated their response to emotion-eliciting pictures as less intense. Yet, even though we found significant differences in behavioral measures of cognitive emotion regulation, no differences between groups were found in terms of physiological responses to the emotional stimuli. Overall, these findings suggest a positive effect of taVNS on the cognitive reappraisal of emotions, but future studies assessing objective measures of neural activity during cognitive emotion regulation following taVNS are warranted.

Background: There is active interest in biomarker discovery for transcutaneous auricular vagus nerve stimulation (taVNS). However, greater understanding of the neurobiological mechanisms is needed to identify candidate markers. Accumulating evidence suggests that taVNS influences activity in solitary and parabrachial nuclei, the primary brainstem relays for the transmission of visceral sensory afferents to the insula. The insula mediates interoception, which concerns the representation and regulation of homeostatic bodily states. Consequently, interoceptive pathways may be relevant to taVNS mechanisms of action. Hypotheses: We hypothesized that taVNS would modulate an EEG-derived marker of interoceptive processing known as the heart-evoked potential (HEP). We also hypothesized that taVNS-induced HEP effects would be localizable to the insula. Methods: Using a within-subject, sham-controlled design, we recorded EEG and ECG concurrent to taVNS in 43 healthy adults. Using ECG and EEG data, we extracted HEPs. Estimation of the cortical sources of the taVNS-dependent HEP responses observed at the scalp were computed using the Boundary Element Method and weighted Minimum Norm Estimation. Statistics were calculated using cluster-based permutation methods. Results: taVNS altered HEP amplitudes at frontocentral and centroparietal electrode sites at various la- tencies. The taVNS-dependent HEP effect was localized to the insula, operculum, somatosensory cortex, and orbital and ventromedial prefrontal regions. Conclusion: The results support the hypothesis that taVNS can access the insula as well as functionally and anatomically connected brain regions. HEPs may serve as an objective, non-invasive outcome parameter for the cortical effects of taVNS. © 2021 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

Social-evaluative threat (SET) – a situation in which one could be negatively evaluated by others – elicits profound (psycho)physiological reactivity which, if chronically present and not adaptively regulated, has deleterious effects on mental and physical health. Decreased self-awareness and increased other-awareness are understood to be an adaptive response to SET. Attentional deployment – the process of selectively attending to certain aspects of emotional stimuli to modulate emotional reactivity – is supported by fronto-parietal and fronto-limbic networks, with the dorsolateral prefrontal cortex being a central hub. The primary aim of the current study was to investigate the effects of active (versus sham) prefrontal transcranial direct current stimulation (tDCS) on self and other-attentional deployment during the exposure to a SET context. Seventy-four female participants received active or sham tDCS and were subsequently exposed to a rigged social feedback paradigm. In this paradigm a series of social evaluations were presented together with a photograph of the supposed evaluator and a self- photograph of the participant, while gaze behavior (time to first fixation, total fixation time) and skin conductance responses (SCRs; a marker of emotional reactivity) were measured. For half of the evaluations, participants could anticipate the valence (negative or positive) of the evaluation a priori. Analyses showed that participants receiving active tDCS were (a) slower to fixate on their self-photograph, (b) spent less time fixating on their self-photograph, and (c) spent more time fixating on the evaluator photograph. During unanticipated evaluations, active tDCS was associated with less time spent fixating on the evaluation. Furthermore, among those receiving active tDCS, SCRs were attenuated as a function of slower times to fixate on the self-photograph. Taken together, these results suggest that in a context of SET, prefrontal tDCS decreases self-attention while increasing other-attention, and that attenuated self-referential attention specifically may be a neurocognitive mechanism through which tDCS reduces emotional reactivity. Moreover, the results suggest that tDCS reduces vigilance toward stimuli that possibly convey threatening information, corroborating past research in this area.

Amyotrophic lateral sclerosis (ALS) is increasingly recognized as a multisystem disorder accompanied by cognitive changes. To date, no effective therapy is available for ALS patients, partly due to disease heterogeneity and an imperfect understanding of the underlying pathophysiological processes. Reliable models that can predict cognitive and motor deficits are needed to improve symptomatic treatment and slow down disease progression. This study aimed to identify individualized functional connectivity-based predictors of cognitive and motor function in ALS by using multiple kernel learning (MKL) regression. Resting-state fMRI scanning was performed on 34 riluzole-naive ALS patients. Motor severity and global cognition were separately measured with the revised ALS functional rating scale (ALSFRS-R) and the Montreal Cognitive Assessment (MoCA). Our results showed that functional connectivity within the default mode network (DMN) as well as between the DMN and the sensorimotor network (SMN), fronto-parietal network (FPN), and salience network (SN) were predictive for MoCA scores. Additionally, the observed connectivity patterns were also predictive for the individual ALSFRS-R scores. Our findings demonstrate that cognitive and motor impairments may share common connectivity fingerprints in ALS patients. Furthermore, the identified brain connectivity signatures may serve as novel targets for effective disease-modifying therapies. Author Summary Amyotrophic lateral sclerosis is recognized as a multisystem disorder, and currently no effective therapy is available for this devastating disease. Reliable models that can predict disease progression may facilitate the development of more efficient symptomatic treatment. This study used multiple kernel learning algorithm to identify a potential functional connectivity-based marker for cognitive and motor functioning in ALS. The results show that cognitive decline and motor progression could be predicted by seed-based functional connectivity from the medial prefrontal cortex/posterior cingulate cortex to the sensorimotor network, fronto-parietal network, and salience network. The identified brain connectivity signatures may serve as novel targets for effective disease-modifying therapies.

OBJECTIVES: Treatment of repetitive negative thinking (RNT) focuses rather on individual than group cognitive behaviour therapy (CBT) treatment. Additionally, little is known on how clients experienced these interventions. This study investigates clients' experiences on participating in a CBT group intervention targeting RNT (RNT-G). DESIGN: Of the 80 participants, 11 were randomly selected for an in-depth, semi-structured interview after treatment. Interviews focused on what participants experienced as important on group aspects, offered interventions, homework tasks, and possible changes. METHODS: All participants were adults, diagnosed with major depressive disorder and/or generalized anxiety disorder and being currently in mental health care treatment. After transcribing the interviews, analyses were performed according to the guidelines of thematic analysis. RESULTS: Four major themes were identified. First, the group format itself was experienced as an important factor of change. The experiences about the different offered interventions during the group formed a second theme. A third theme related to changes in family or professional life and dealing with RNT as a result of the intervention. Finally, group participation, social interactions, and mental health care treatment were experienced as mutually influencing during the intervention. CONCLUSIONS: The results of this study shed some light on which treatment interventions were perceived as beneficial during the RNT-G and should therefore be emphasized in treatment. Further, they indicate that the treatment in a group format was experienced as helpful by the participants. Finally, a positive mutual influence between the group intervention and the ongoing individual treatment was experienced.

The tendency to ruminate (i.e., repetitive negative self-referential thoughts that perpetuate depressive mood) is associated with (a) an elevated propensity to maladaptively experience counterfactual thinking (CFT) and regret, and (b) hypo-activity of the left dorsolateral prefrontal cortex (DLPFC). The goal of this study was to investigate whether anodal transcranial direct current stimulation (tDCS) over the left DLPFC, in function of self-critical rumination tendencies, momentarily reduces counterfactual thinking and regret (assessed via self-report and psychophysiological indices). Eighty healthy participants with different levels of self-critical rumination received either anodal or sham tDCS while performing a decision making task in which they were repeatedly confronted with optimal, suboptimal, and non-optimal choice outcomes. The results showed that among rumination-prone individuals, anodal (versus sham) tDCS was associated with decreased CFT and attenuated psychophysiological reactivity to the differential choice outcomes. Conversely, among low rumination-prone individuals, anodal (versus sham) tDCS was associated with increased CFT and regret, but in absence of any effects on psychophysiological reactivity. Potential working mechanisms for these differential tDCS effects are discussed. Taken together, these results provide initial converging evidence for the adaptive effects of left prefrontal tDCS on CFT and regret to personal choice outcomes among individuals prone to engage in self-critical rumination.

Low resilience is characterized by impairments in attention and emotion regulation mechanisms that depend on prefrontal cortical activity. The aim of this study was to test whether transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex (DLPFC) can augment the effectiveness of a new computerized mouse-based (gaze)contingent training (MCAT) to improve attention and emotion regulation processes (improved reappraisal, reduced rumination) in individuals reporting low resilience levels. The study used a full-factorial between-subject design combining active and sham MCAT and tDCS interventions. One hundred participants reporting low resilience levels were randomly assigned to receive either a single session of: tDCS with sham MCAT treatment (tDCS group), MCAT with sham tDCS (MCAT group), a combination of tDCS and MCAT (combined group), or sham tDCS and sham MCAT (control group). Transfer to attention regulation, reappraisal success, and state rumination was evaluated using an eye-tracking disengagement task and an emotion regulation paradigm, respectively. MCAT, either alone or combined with tDCS, resulted in improved attention regulation. Furthermore, the group receiving combined MCAT and tDCS also showed some evidence of increased reappraisal ability and reduced rumination. MCAT in combination with left DLPFC neuromodulation has potential to maximize transfer to emotion regulation capacities and to promote resilience.

Subanaesthetic ketamine has recently been established as an effective and rapid treatment for major depressive disorder showing antidepressant effects for up to 1 week on average. The use of repeated ketamine infusions has been put forward to augment and to prolong the antidepressant response and increase the remission rates. The underlying neurobiological mechanisms responsible for ketamine's antidepressant effects remain unclear. Nevertheless, it has been shown, both in dogs and humans, that ketamine can alter neuronal perfusion and therefore neuronal function in brain regions involved in psychiatric and behavioural disorders. Consequently, the aim of the current placebo controlled study was to assess the long-term effects on cerebral perfusion of single and repeated subanaesthetic ketamine infusions in dogs. Twelve healthy, laboratory dogs were scanned at six different time points following single and repeated ketamine administration, using Single Photon Emission Computed Tomography with the radiotracer 99mTc-hexamethylpropylene amine oxime. We hypothesised that repeated infusions could lead to more prolonged perfusion alterations in brain regions critical for behaviour regulation. We found that repeated subanaesthetic ketamine administration did not result in more prolonged cerebral perfusion alterations compared to a single ketamine administration.

Background: The interaction between neuropsychiatric symptoms, mild cognitive impairment (MCI), and dementia is complex and remains to be elucidated. An additive or multiplicative effect of neuropsychiatric symptoms such as apathy or depression on cognitive decline has been suggested. Unraveling these interactions may allow the development of better prevention and treatment strategies. In the absence of available treatments for neurodegeneration, a timely and adequate identification of neuropsychiatric symptom changes in cognitive decline is highly relevant and can help identify treatment targets.Methods: An existing memory clinic-based research database of 476 individuals with MCI and 978 individuals with dementia due to Alzheimer's disease (AD) was reanalyzed. Neuropsychiatric symptoms were assessed in a prospective fashion using a battery of neuropsychiatric assessment scales: Middelheim Frontality Score, Behavioral Pathology in Alzheimer's Disease Rating Scale (Behave-AD), Cohen-Mansfield Agitation Inventory, Cornell Scale for Depression in Dementia (CSDD), and Geriatric Depression Scale (30 items). We subtyped subjects suffering from dementia as mild, moderate, or severe according to their Mini-Mental State Examination (MMSE) score and compared neuropsychiatric scores across these groups. A group of 126 subjects suffering from AD with a significant cerebrovascular component was examined separately as well. We compared the prevalence, nature, and severity of neuropsychiatric symptoms between subgroups of patients with MCI and dementia due to AD in a cross-sectional analysis.Results: Affective and sleep-related symptoms are common in MCI and remain constant in prevalence and severity across dementia groups. Depressive symptoms as assessed by the CSDD further increase in severe dementia. Most other neuropsychiatric symptoms (such as agitation and activity disturbances) progress in parallel with severity of cognitive decline. There are no significant differences in neuropsychiatric symptoms when comparing “pure” AD to AD with a significant vascular component.Conclusion: Neuropsychiatric symptoms such as frontal lobe symptoms, psychosis, agitation, aggression, and activity disturbances increase as dementia progresses. Affective symptoms such as anxiety and depressive symptoms, however, are more frequent in MCI than mild dementia but otherwise remain stable throughout the cognitive spectrum, except for an increase in CSDD score in severe dementia. There is no difference in neuropsychiatric symptoms when comparing mixed dementia (defined here as AD + significant cerebrovascular disease) to pure AD.

Objective Research suggests that the combination of different non-invasive brain stimulation techniques, such as intermittent theta-burst stimulation (iTBS) and transcranial direct current stimulation (tDCS), could enhance the effects of stimulation. Studies investigating the combination of tDCS and iTBS over the dorsolateral prefrontal cortex (DLPFC) are lacking. In this within-subjects study, we evaluated the additive effects of iTBS with tDCS on psychophysiological measures of stress. Method Sixty-eight healthy individuals were submitted to a bifrontaltDCS + iTBS and shamtDCS + iTBS protocol targeting the DLPFC with a one-week interval. The Maastricht Acute Stress Test was used to activate the stress system after stimulation. Stress reactivity and recovery were assessed using physiological and self-report measures. Results The stressor evoked significant psychophysiological changes in both stimulation conditions. However, no evidence was found for differences between them in stress reactivity and recovery. Participants reported more pain and feelings of discomfort to the bifrontaltDCS + iTBS protocol. Conclusion In this study set-up, iTBS plus tDCS was not superior to iTBS in downregulating stress in healthy subjects. Significance There is no evidence for an effect of combined tDCS-iTBS of the DLPFC on stress according to the parameters employed in our study. Future studies should explore other stimulation parameters, additive approaches and/or neurobiological markers.

Repetitive negative thinking (RNT) is a core process underlying various psychiatric disorders. ‘Uncontrollability of rumination (UOR)’ is one the most maladaptive factors of rumination, but little is known on how cognitive behavioral focused RNT psychotherapy may alter brain activity. In a subsample of 47 patients suffering from RNT who also underwent brain imaging (registered RCT trial NCT01983033), we evaluated the effect of cognitive behavioral based group psychotherapy (CBGP) (n = 25) as compared to a delayed treatment control group (DTCG) (n = 22) on frontolimbic brain perfusion with a focus on UOR. This RNT construct was measured using the subscale ‘uncontrollability’ of the Dutch version of the Rumination on Sadness Scale (LARSS-U). Brain perfusion was assessed with arterial spin labeling (ASL)-fMRI. LARSS-U scale scores significantly decreased in the CBGP cohort whereas no significant changes emerged in the DTCG group. Compared to the DTCG, this decrease on UOR in the CBGP group was related to significant perfusion increases in the left (dorsolateral) prefrontal cortex, part of the executive network. Besides the fact that CBGP significantly reduced RNT, this attenuation of uncontrollable ruminative thoughts was related to brain perfusion increases areas documented to be involved in the top down control of adaptive emotion regulation and the inhibition of ruminative processes.

An increasing number of studies demonstrated the involvement of the cerebellum in (social) sequence processing. The current preliminary study is the first to investigate the causal involvement of the cerebellum in sequence generation, using low-frequency repetitive transcranial magnetic stimulation (LF-rTMS). By targeting the posterior cerebellum, we hypothesized that the induced neuro-excitability modulation would lead to altered performance on a Picture and Story sequencing task, which involve the generation of the correct chronological order of various social and non-social stories depicted in cartoons or sentences. Our results indicate that participants receiving LF-rTMS over the cerebellum, as compared to sham participants, showed a stronger learning effect from pre to post stimulation for both tasks and for all types of sequences (i.e. mechanical, social scripts, false belief, true belief). No differences between sequence types were observed. Our results suggest a positive effect of LF-rTMS on sequence generation. We conclude that the cerebellum is causally involved in the generation of sequences of social and nonsocial events. Our discussion focuses on recommendations for future studies. This research was supported by a Grant from the Strategic Research Program from the Vrije Universiteit Brussel (SRP57) awarded to FVO.

Major depressive disorder (MDD) and generalized anxiety disorder (GAD) are severe and difficult-to-treat psychiatric illnesses with high rates of comorbidity. Although both disorders are treated with serotonergic based psychotropic agents, little is known on the influence of the serotonergic neurotransmitter system on the occurrence of comorbid GAD when clinically depressed. To investigate this poorly understood clinical question, we examined the involvement of frontolimbic post-synaptic 5-HT2A receptors in 20 medication-resistant depressed (MRD) patients with half of them diagnosed with comorbid GAD with 123I-5-I-R91150 SPECT. To explore whether 5-HT2A receptor-binding indices (BI) associated with comorbid GAD could be related to distinct psychopathological symptoms, all were assessed with the symptom Checklist-90-Revised (SCL-90-R). MRD patients with comorbid GAD displayed significantly higher 5-HT2A receptor BI in the hippocampal–amygdala complex, compared to MRD patients without GAD. Correlation analyses revealed that the 5-HT2A receptor BI in these areas were significantly related to the SCL-90-R subscale hostility (HOS), especially for those MRD patients with comorbid GAD. Comorbid MRD-GAD may be characterized with increased hippocampal–amygdala 5-HT2A receptor BI which could represent enhanced levels in hostility in such kinds of patients. Adapted psychotherapeutic interventions may be warranted.

Background: Frequent exposure to criticism is a known risk factor for various adult psychiatric disorders. Adolescents may be even more vulnerable to (parental) criticism, as their imbalanced brain maturation makes them prone to stronger mood changes and less effective emotional regulation. Identifying which adolescent subgroups are more vulnerable than others could be of great clinical relevance. Perceived criticism (PC) and self-criticism (SC), two related but distinct traits, could well be crucial vulnerability factors.Hypotheses: After exposure to criticism during fMRI scanning, rapid changes in amygdalar functional connectivity (FC) with other brain areas involved in emotion regulation and social cognitive processing will occur. These changes will depend on trait moderators, such as the adolescents' proneness to (a) perceive others as critical of them (PC) or (b) perceive themselves positively or negatively (SC).Methods: Sixty-four healthy 14–17-year-olds were exposed to a series of auditory comments. Changes in mood states were assessed based on the Profile of Mood States (POMS) prior to and after exposure to these segments. Pre- and post-experiment FC of the left and right amygdalae with other brain areas were also measured. Correlates between FC changes and psychometric measures—including the perceived criticism measure (PCM) and self-perception profile for adolescents (SPPA)—were assessed.Results: First, after being criticized, FC increases of the left amygdala seed region with brain areas related to sustained emotional processing were found, but no right amygdalar FC changes. Second, there was a significant positive partial correlation between individual PCM scores and FC changes between the left amygdala seed region and the left precuneus and left superior parietal cortex, both part of the default mode network.Conclusion: Exposure to criticism resulted in a rapid negative mood change accompanied by an increase in FC between the left amygdala and regions known to be involved in sustained emotional processing, but no right amygdalar FC changes. Furthermore, higher PC but not SC was correlated with stronger left amygdalar FC increases with these regions, suggesting an elevated vulnerability for disturbed emotional processing, as observed in mood disorders, in healthy adolescents with higher PCM scores.