Real-time fMRI neurofeedback compared to cognitive behavioral therapy in a pilot study for the treatment of mild and moderate depression.

Real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback was found to reduce depressive symptoms. However, no direct comparison of drug-free patients with an active psychotherapy control group is available. The present study compared rt-fMRI neurofeedback with cognitive behavioral therapy, as the standard treatment in patients declining anti-depressants. Twenty adult, drug-free patients with mild or moderate depression were non-randomly assigned either to a course of eight half-hour sessions of neurofeedback targeting the left medial prefrontal cortex (N = 12) or to a 16-session course of cognitive behavioral therapy (N = 8). Montgomery-Asberg Depression Rating Scale was introduced at baseline, mid-treatment, and end-treatment points. In each group, 8 patients each remained in the study to a mid-treatment evaluation and 6 patients each to the study end-point. ANOVA revealed a depression reduction with a significant effect of Time (F(3,6) = 19.0, p < 0.001, η2 = 0.76). A trend to greater improvement in the cognitive behavioral therapy group compared to neurofeedback emerged (Group × Time; p = 0.078). Percent signal change in the region of interest between up- and down-regulation conditions was significantly correlated with session number (Pearson's r = 0.85, p < 0.001) indicating a learning effect. As limitations, small sample size could lead to insufficient power and non-random allocation to selection bias. Both neurofeedback and cognitive behavioral therapy improved mild and moderate depression. Neurofeedback was not superior to cognitive behavioral therapy. Noteworthy, the neurofeedback training course was associated with continuous improvement in the self-regulation skill, without plateau. This study delivers data to plan clinical trials comparing neurofeedback with cognitive behavioral interventions.

Transdiagnostic alterations in neural emotion regulation circuits - neural substrates of cognitive reappraisal in patients with depression and post-traumatic stress disorder.

BACKGROUND: Impaired cognitive reappraisal, associated with the social functioning and well-being of patients affected by mood or anxiety disorders, is characterized by distinct neural activation patterns across clinical populations. To date, studies dedicated to identifying common and distinct neural activation profiles need to be clarified. The aim of the present study was to investigate transdiagnostic differences and commonalities in brain activation patterns during reappraisal-mediated downregulation of emotions. METHODS: Cognitive reappraisal of negative images was contrasted with maintaining emotions during a control viewing condition. Brain activation in 35 patients with major depressive disorder (MDD), 20 patients with post-traumatic stress disorder (PTSD), and 34 healthy controls (HC) during cognitive reappraisal was compared. Moreover, the neural circuitry of emotion regulation in these clinical populations was examined using seed-to-voxel and voxel-to-voxel functional connectivity analyses. RESULTS: Whole-brain fMRI analyses showed less right-lateralized activation of the inferior, middle, and superior frontal gyrus during cognitive reappraisal compared to viewing of negative images in MDD and PTSD patients compared to HCs. Right IFG activation was negatively correlated with the severity of anxiety and depressive symptomatology. In addition, increased seed-to-voxel connectivity of the right IFG as well as increased voxel-to-voxel connectivity was observed in PTSD patients compared to HCs and MDD patients. CONCLUSIONS: FMRI results therefore suggested a common deficit of depression and anxiety symptomatology reflected by reduced activation in right IFG during cognitive reappraisal as well as diagnosis specific effects in patients with PTSD based on seed-to-voxel and voxel-to-voxel connectivity showing an overactive and hyperconnected salience network. Findings highlight the role of transdiagnostic research to identify disorder specific brain patterns as well as patterns common across disorders.

Data-Driven Approach to the Analysis of Real-Time FMRI Neurofeedback Data: Disorder-Specific Brain Synchrony in PTSD.

Brain-computer interfaces (BCIs) can be used in real-time fMRI neurofeedback (rtfMRI NF) investigations to provide feedback on brain activity to enable voluntary regulation of the blood-oxygen-level dependent (BOLD) signal from localized brain regions. However, the temporal pattern of successful self-regulation is dynamic and complex. In particular, the general linear model (GLM) assumes fixed temporal model functions and misses other dynamics. We propose a novel data-driven analyses approach for rtfMRI NF using intersubject covariance (ISC) analysis. The potential of ISC was examined in a reanalysis of data from 21 healthy individuals and nine patients with post-traumatic stress-disorder (PTSD) performing up-regulation of the anterior cingulate cortex (ACC). ISC in the PTSD group differed from healthy controls in a network including the right inferior frontal gyrus (IFG). In both cohorts, ISC decreased throughout the experiment indicating the development of individual regulation strategies. ISC analyses are a promising approach to reveal novel information on the mechanisms involved in voluntary self-regulation of brain signals and thus extend the results from GLM-based methods. ISC enables a novel set of research questions that can guide future neurofeedback and neuroimaging investigations.

fMRI Neurofeedback-Enhanced Cognitive Reappraisal Training in Depression: A Double-Blind Comparison of Left and Right vlPFC Regulation.

Affective disorders are associated with maladaptive emotion regulation strategies. In particular, the left more than the right ventrolateral prefrontal cortex (vlPFC) may insufficiently regulate emotion processing, e.g., in the amygdala. A double-blind cross-over study investigated NF-supported cognitive reappraisal training in major depression (n = 42) and age- and gender-matched controls (n = 39). In a randomized order, participants trained to upregulate either the left or the right vlPFC during cognitive reappraisal of negative images on two separate days. We wanted to confirm regional specific NF effects with improved learning for left compared to right vlPFC (ClinicalTrials.gov NCT03183947). Brain responses and connectivity were studied with respect to training progress, gender, and clinical outcomes in a 4-week follow-up. Increase of vlPFC activity was stronger after NF training from the left- than the right-hemispheric ROI. This regional-specific NF effect during cognitive reappraisal was present across patients with depression and controls and supports a central role of the left vlPFC for cognitive reappraisal. Further, the activity in the left target region was associated with increased use of cognitive reappraisal strategies (r = 0.48). In the 4-week follow-up, 75% of patients with depression reported a successful application of learned strategies in everyday life and 55% a clinically meaningful symptom improvement suggesting clinical usability.

Auditory mismatch processing: Role of paradigm and stimulus characteristics as detected by fMRI.

Auditory mismatch processing is accompanied by activation of a distributed brain network which can be detected by fMRI. However, the impact of different experimental designs such as event-related or block designs and different stimulus characteristics on the auditory mismatch response and the activity of this network remains controversial. In the present study, we applied five auditory mismatch paradigms with standard experimental designs and recorded fMRI in 31 healthy participants. Brain activity was analyzed using general linear models as well as classification approaches. The results stress a greater role of the type of the applied deviant stimulus compared to the experimental design. Moreover, the absolute number of the deviants as well as the length of the experimental run seems to play a greater role than the experimental design. The present study promotes optimization of experimental paradigms in the context of mismatch research. In particular, our findings contribute to designing auditory mismatch paradigms for application in clinical settings.

Functional connectivity of supplementary motor area during finger-tapping in major depression.

Psychomotor disturbance has been consistently regarded as an essential feature of depressive disorders. Studying objectively measurable motor behaviors like finger-tapping may help advance the diagnostic methods. Twenty-five patients with major depressive disorder (MDD) and 15 healthy participants underwent functional magnetic resonance imaging (fMRI) measurements while tapping their index fingers. The finger-tapping (FT) task was performed by the right hand (the tapping frequency varied between 1, 2 and 4 Hz) or both hands either in synchrony or alternation (the tapping frequency varied between 1 and 2 Hz). A mixed-model ANOVA was used for between- and within-group comparisons of the task accuracy and fMRI percent signal change in the supplementary motor area (SMA) during 26-second sequences of finger-tapping. Furthermore, using seed-based correlation analyses we compared the connectivity of the SMA between the two samples. At the behavioral level, no significant group differences in FT performance between the patient and control groups was observed. The mean fMRI percent signal change of the SMA was significantly elevated at higher levels of speed in both groups. In the MDD group, an increased connectivity of the left SMA with the bilateral cortical and cerebellar motor- and vision-related regions was found. Most importantly, a decreased connectivity between the SMA and the basal ganglia was found at frequencies of 4 Hz. Our findings support the contention that, in depression, brain connectivity measures during motor performance may reveal deviant neural processes that are potentially relevant to measurable (bio)markers for individual diagnosis and treatment.

A Novel Brain-Computer Interface Virtual Environment for Neurofeedback During Functional MRI.

Virtual environments (VEs), in the recent years, have become more prevalent in neuroscience. These VEs can offer great flexibility, replicability, and control over the presented stimuli in an immersive setting. With recent developments, it has become feasible to achieve higher-quality visuals and VEs at a reasonable investment. Our aim in this project was to develop and implement a novel real-time functional magnetic resonance imaging (rt-fMRI)-based neurofeedback (NF) training paradigm, taking into account new technological advances that allow us to integrate complex stimuli into a visually updated and engaging VE. We built upon and developed a first-person shooter in which the dynamic change of the VE was the feedback variable in the brain-computer interface (BCI). We designed a study to assess the feasibility of the BCI in creating an immersive VE for NF training. In a randomized single-blinded fMRI-based NF-training session, 24 participants were randomly allocated into one of two groups: active and reduced contingency NF. All participants completed three runs of the shooter-game VE lasting 10 min each. Brain activity in a supplementary motor area region of interest regulated the possible movement speed of the player's avatar and thus increased the reward probability. The gaming performance revealed that the participants were able to actively engage in game tasks and improve across sessions. All 24 participants reported being able to successfully employ NF strategies during the training while performing in-game tasks with significantly higher perceived NF control ratings in the NF group. Spectral analysis showed significant differential effects on brain activity between the groups. Connectivity analysis revealed significant differences, showing a lowered connectivity in the NF group compared to the reduced contingency-NF group. The self-assessment manikin ratings showed an increase in arousal in both groups but failed significance. Arousal has been linked to presence, or feelings of immersion, supporting the VE's objective. Long paradigms, such as NF in MRI settings, can lead to mental fatigue; therefore, VEs can help overcome such limitations. The rewarding achievements from gaming targets can lead to implicit learning of self-regulation and may broaden the scope of NF applications.

Rt-fMRI neurofeedback-guided cognitive reappraisal training modulates amygdala responsivity in posttraumatic stress disorder.

BACKGROUND: Traumatic experiences are associated with neurofunctional dysregulations in key regions of the emotion regulation circuits. In particular, amygdala responsivity to negative stimuli is exaggerated while engagement of prefrontal regulatory control regions is attenuated. Successful application of emotion regulation (ER) strategies may counteract this disbalance, however, application of learned strategies in daily life is hampered in individuals afflicted by posttraumatic stress disorder (PTSD). We hypothesized that a single session of real-time fMRI (rtfMRI) guided upregulation of prefrontal regions during an emotion regulation task enhances self-control during exposure to negative stimuli and facilitates transfer of the learned ER skills to daily life. METHODS: In a cross-over design, individuals with a PTSD diagnosis after a single traumatic event (n = 20) according to DSM-IV-TR criteria and individuals without a formal psychiatric diagnosis (n = 21) underwent a cognitive reappraisal training. In randomized order, all participants completed two rtfMRI neurofeedback (NF) runs targeting the left lateral prefrontal cortex (lPFC) and two control runs without NF (NoNF) while using cognitive reappraisal to reduce their emotional response to negative scenes. During the NoNF runs, two %%-signs were displayed instead of the two-digit feedback (FB) to achieve a comparable visual stimulation. The project aimed at defining the clinical potential of the training according to three success markers: (1) NF induced changes in left lateral prefrontal cortex and bilateral amygdala activity during the regulation of aversive scenes compared to cognitive reappraisal alone (primary registered outcome), (2) associated changes on the symptomatic and behavioral level such as indicated by PTSD symptom severity and affect ratings, (3) clinical utility such as indicated by perceived efficacy, acceptance, and transfer to daily life measured four weeks after the training. RESULTS: In comparison to the reappraisal without feedback, a neurofeedback-specific decrease in the left lateral PFC (d = 0.54) alongside an attenuation of amygdala responses (d = 0.33) emerged. Reduced amygdala responses during NF were associated with symptom improvement (r = -0.42) and less negative affect (r = -0.63) at follow-up. The difference in symptom scores exceeds requirements for a minimal clinically important difference and corresponds to a medium effect size (d = 0.64). Importantly, 75% of individuals with PTSD used the strategies in daily life during a one-month follow-up period and perceived the training as efficient. CONCLUSION: Our findings suggest beneficial effects of the NF training indicated by reduced amygdala responses that were associated with improved symptom severity and affective state four weeks after the NF training as well as patient-centered perceived control during the training, helpfulness and application of strategies in daily life. However, reduced prefrontal involvement was unexpected. The study suggests good tolerability of the training protocol and potential for clinical use in the treatment of PTSD.

Impaired Subcortical Detection of Auditory Changes in Schizophrenia but Not in Major Depression.

The mismatch negativity is a cortical response to auditory changes and its reduction is a consistent finding in schizophrenia. Recent evidence revealed that the human brain detects auditory changes already at subcortical stages of the auditory pathway. This finding, however, raises the question where in the auditory hierarchy the schizophrenic deficit first evolves and whether the well-known cortical deficit may be a consequence of dysfunction at lower hierarchical levels. Finally, it should be resolved whether mismatch profiles differ between schizophrenia and affective disorders which exhibit auditory processing deficits as well. We used functional magnetic resonance imaging to assess auditory mismatch processing in 29 patients with schizophrenia, 27 patients with major depression, and 31 healthy control subjects. Analysis included whole-brain activation, region of interest, path and connectivity analysis. In schizophrenia, mismatch deficits emerged at all stages of the auditory pathway including the inferior colliculus, thalamus, auditory, and prefrontal cortex. In depression, deficits were observed in the prefrontal cortex only. Path analysis revealed that activation deficits propagated from subcortical to cortical nodes in a feed-forward mechanism. Finally, both patient groups exhibited reduced connectivity along this processing stream. Auditory mismatch impairments in schizophrenia already manifest at the subcortical level. Moreover, subcortical deficits contribute to the well-known cortical deficits and show specificity for schizophrenia. In contrast, depression is associated with cortical dysfunction only. Hence, schizophrenia and major depression exhibit different neural profiles of sensory processing deficits. Our findings add to a converging body of evidence for brainstem and thalamic dysfunction as a hallmark of schizophrenia.

Selective reward responses to violent success events during video games.

Aggressive behavior in violent video games activates the reward system. However, this effect is closely related to game success. Aim of the present study was to investigate whether aggressive behavior has a rewarding value by itself. Functional magnetic resonance imaging (fMRI) was measured in fifteen right-handed males while playing the video game Carmageddon. Neuroimaging data were analyzed based on violent and non-violent success and failure events. Correlations with subjective game experience measured brain-behavior and -affect relationships. Results revealed a differential involvement of the striatal reward system: non-violent success elicited activation of the ventral striatum, whereas violent success activated specifically the dorsal striatum. Subjective game experience correlated with putamen and medial prefrontal cortex activation specifically for violent success. These results emphasize a differential neural processing of violent and non-violent success events in dorsal and ventral striatum. Virtual violence seems to enable selective responses of the reward system and positive in-game experience.

Correction to: Central serotonin modulates neural responses to virtual violent actions in emotion regulation networks.

The article "Central serotonin modulates neural responses to virtual violent actions in emotion regulation networks", written by Dhana Wolf, Martin Klasen, Patrick Eisner, Florian D. Zepf, Mikhail Zvyagintsev, Nicola Palomero­Gallagher, René Weber, Albrecht Eisert, Klaus Mathiak was originally published electronically on the publisher's internet portal (currently SpringerLink) on June, 08, 2018 without open access.

Fronto-parietal and temporal brain dysfunction in depression: A fMRI investigation of auditory mismatch processing.

Mismatch responses reflect neural mechanisms of early cognitive processing in the auditory domain. Disturbances of these mechanisms on multiple levels of neural processing may contribute to clinical symptoms in major depression (MD). A functional magnetic resonance imaging (fMRI) study was conducted to identify neurobiological foundations of altered mismatch processing in MD. Twenty-five patients with major depression and 25 matched healthy individuals completed an auditory mismatch paradigm optimized for fMRI. Brain activity during mismatch processing was compared between groups. Moreover, seed-based connectivity analyses investigated depression-specific brain networks. In patients, mismatch processing was associated with reduced activation in the right auditory cortex as well as in a fronto-parietal attention network. Moreover, functional coupling between the right auditory cortex and frontal areas was reduced in patients. Seed-to voxel analysis on the whole-brain level revealed reduced connectivity between the auditory cortex and the thalamus as well as posterior cingulate. The present study indicates deficits in sensory processing on the level of the auditory cortex in depression. Hyposensitivity in a fronto-parietal network presumably reflects altered attention mechanisms in depression. The observed impairments may contribute to psychopathology by reducing the ability of the affected individuals to orient attention toward important environmental cues.

Neurofeedback of core language network nodes modulates connectivity with the default-mode network: A double-blind fMRI neurofeedback study on auditory verbal hallucinations.

BACKGROUND: The experience of auditory verbal hallucinations in schizophrenia is associated with changes in brain network function. In particular, studies indicate altered functional coupling between nodes of the language and default mode networks. Neurofeedback based on real-time functional magnetic resonance imaging (rtfMRI) can be used to modulate such aberrant network connectivity. METHODS: We investigated resting-state connectivity changes after neurofeedback (NF) in 21 patients with schizophrenia and 35 healthy individuals. All participants underwent two days of neurofeedback training of important nodes of the left-hemispheric language network including the inferior frontal gyrus (IFG) and posterior superior temporal gyrus (pSTG). In a double-blind randomized cross-over design, participants learned to down- and up-regulate their brain activation in the designated target regions based on NF. Prior to and after each training day, a resting state measurement took place. RESULTS: Coupling between nodes of the language and the default mode network (DMN) selectively increased after down-as compared to up-regulation NF. Network analyses revealed more pronounced increases in functional connectivity between nodes of the language network and the DMN in patients compared to healthy individuals. In particular, down-regulation NF led to increased coupling between nodes of the language network and bilateral inferior parietal lobe (IPL) as well as posterior cingulate cortex (PCC)/precuneus in patients. Up-regulation strengthened connectivity with the medial prefrontal cortex (mPFC). Improved well-being four weeks after the training predicted increased functional coupling between the left IFG and left IPL. CONCLUSION: Modulatory effects emerged as increased internetwork communication, indicating that down-regulation NF selectively enhances coupling between language and DM network nodes in patients with AVH. RtfMRI NF may thus be used to modulate brain network function that is relevant to the phenomenology of AVH. Specific effects of self-regulation on symptom improvement have to be explored in therapeutic interventions.

Interpretation of Social Interactions: Functional Imaging of Cognitive-Semiotic Categories During Naturalistic Viewing.

Social interactions arise from patterns of communicative signs, whose perception and interpretation require a multitude of cognitive functions. The semiotic framework of Peirce's Universal Categories (UCs) laid ground for a novel cognitive-semiotic typology of social interactions. During functional magnetic resonance imaging (fMRI), 16 volunteers watched a movie narrative encompassing verbal and non-verbal social interactions. Three types of non-verbal interactions were coded ("unresolved," "non-habitual," and "habitual") based on a typology reflecting Peirce's UCs. As expected, the auditory cortex responded to verbal interactions, but non-verbal interactions modulated temporal areas as well. Conceivably, when speech was lacking, ambiguous visual information (unresolved interactions) primed auditory processing in contrast to learned behavioral patterns (habitual interactions). The latter recruited a parahippocampal-occipital network supporting conceptual processing and associative memory retrieval. Requesting semiotic contextualization, non-habitual interactions activated visuo-spatial and contextual rule-learning areas such as the temporo-parietal junction and right lateral prefrontal cortex. In summary, the cognitive-semiotic typology reflected distinct sensory and association networks underlying the interpretation of observed non-verbal social interactions.

Central serotonin modulates neural responses to virtual violent actions in emotion regulation networks.

Disruptions in the cortico-limbic emotion regulation networks have been linked to depression, anxiety, impulsivity, and aggression. Altered transmission of the central nervous serotonin (5-HT) contributes to dysfunctions in the cognitive control of emotions. To date, studies relating to pharmaco-fMRI challenging of the 5-HT system have focused on emotion processing for facial expressions. We investigated effects of a single-dose selective 5-HT reuptake inhibitor (escitalopram) on emotion regulation during virtual violence. For this purpose, 38 male participants played a violent video game during fMRI scanning. The SSRI reduced neural responses to violent actions in right-hemispheric inferior frontal gyrus and medial prefrontal cortex encompassing the anterior cingulate cortex (ACC), but not to non-violent actions. Within the ACC, the drug effect differentiated areas with high inhibitory 5-HT1A receptor density (subgenual s25) from those with a lower density (pregenual p32, p24). This finding links functional responses during virtual violent actions with 5-HT neurotransmission in emotion regulation networks, underpinning the ecological validity of the 5-HT model in aggressive behavior. Available 5-HT receptor density data suggest that this SSRI effect is only observable when inhibitory and excitatory 5-HT receptors are balanced. The observed early functional changes may impact patient groups receiving SSRI treatment.

Impaired Voluntary Control in PTSD: Probing Self-Regulation of the ACC With Real-Time fMRI.

Background: Post-traumatic stress disorder (PTSD) is characterized by deficits in the self-regulation of cognitions and emotions. Neural networks of emotion regulation may exhibit reduced control mediated by the anterior cingulate cortex (ACC), contributing to aberrant limbic responses in PTSD. Methods: Real-time fMRI neurofeedback (rt-fMRI NF) assessed self-regulation of the ACC in nine patients with PTSD after single trauma exposure and nine matched healthy controls. All participants were instructed to train ACC upregulation on three training days. Results: Both groups achieved regulation, which was associated with wide-spread brain activation encompassing the ACC. Compared to the controls, regulation amplitude and learning rate was lower in patients, correlating with symptom severity. In addition, a frontopolar activation cluster was associated with self-regulation efforts in patients. Conclusions: For the first time, we tested self-regulation of the ACC in patients with PTSD. The observed impairment supports models of ACC-mediated regulation deficits that may contribute to the psychopathology of PTSD. Controlled trials in a larger sample are needed to confirm our findings and to directly investigate whether training of central regulation mechanisms improves emotion regulation in PTSD.

Prosody production networks are modulated by sensory cues and social context.

The neurobiology of emotional prosody production is not well investigated. In particular, the effects of cues and social context are not known. The present study sought to differentiate cued from free emotion generation and the effect of social feedback from a human listener. Online speech filtering enabled functional magnetic resonance imaging during prosodic communication in 30 participants. Emotional vocalizations were (i) free, (ii) auditorily cued, (iii) visually cued or (iv) with interactive feedback. In addition to distributed language networks, cued emotions increased activity in auditory and-in case of visual stimuli-visual cortex. Responses were larger in posterior superior temporal gyrus at the right hemisphere and the ventral striatum when participants were listened to and received feedback from the experimenter. Sensory, language and reward networks contributed to prosody production and were modulated by cues and social context. The right posterior superior temporal gyrus is a central hub for communication in social interactions-in particular for interpersonal evaluation of vocal emotions.

Temporal processing deficit leads to impaired multisensory binding in schizophrenia.

INTRODUCTION: Schizophrenia has been characterised by neurodevelopmental dysconnectivity resulting in cognitive and perceptual dysmetria. Hence patients with schizophrenia may be impaired to detect the temporal relationship between stimuli in different sensory modalities. However, only a few studies described deficit in perception of temporally asynchronous multisensory stimuli in schizophrenia. METHODS: We examined the perceptual bias and the processing time of synchronous and delayed sounds in the streaming-bouncing illusion in 16 patients with schizophrenia and a matched control group of 18 participants. RESULTS: Equal for patients and controls, the synchronous sound biased the percept of two moving squares towards bouncing as opposed to the more frequent streaming percept in the condition without sound. In healthy controls, a delay of the sound presentation significantly reduced the bias and led to prolonged processing time whereas patients with schizophrenia did not differentiate between this condition and the condition with synchronous sound. CONCLUSION: Schizophrenia leads to a prolonged window of simultaneity for audiovisual stimuli. Therefore, temporal processing deficit in schizophrenia can lead to hyperintegration of temporally unmatched multisensory stimuli.

Cortico-limbic connectivity in MAOA-L carriers is vulnerable to acute tryptophan depletion.

INTRODUCTION: A gene-environment interaction between expression genotypes of the monoamine oxidase A (MAOA) and adverse childhood experience increases the risk of antisocial behavior. However, the neural underpinnings of this interaction remain uninvestigated. A cortico-limbic circuit involving the prefrontal cortex (PFC) and the amygdala is central to the suppression of aggressive impulses and is modulated by serotonin (5-HT). MAOA genotypes may modulate the vulnerability of this circuit and increase the risk for emotion regulation deficits after specific life events. Acute tryptophan depletion (ATD) challenges 5-HT regulation and may identify vulnerable neuronal circuits, contributing to the gene-environment interaction. METHODS: Functional magnetic resonance imaging measured the resting-state state activity in 64 healthy males in a double-blind, placebo-controlled study. Cortical maps of amygdala correlation identified the impact of ATD and its interaction with low- (MAOA-L) and high-expression variants (MAOA-H) of MAOA on cortico-limbic connectivity. RESULTS: Across all Regions of Interest (ROIs) exhibiting an ATD effect on cortico-limbic connectivity, MAOA-L carriers were more susceptible to ATD than MAOA-H carriers. In particular, the MAOA-L group exhibited a larger reduction of amygdala connectivity with the right prefrontal cortex and a larger increase of amygdala connectivity with the insula and dorsal PCC. CONCLUSION: MAOA-L carriers were more susceptable to a central 5-HT challenge in cortico-limbic networks. Such vulnerability of the cortical serotonergic system may contribute to the emergence of antisocial behavior after systemic challenges, observed as gene-environment interaction. Hum Brain Mapp 38:1622-1635, 2017. © 2016 Wiley Periodicals, Inc.

Targeting Treatment-Resistant Auditory Verbal Hallucinations in Schizophrenia with fMRI-Based Neurofeedback - Exploring Different Cases of Schizophrenia.

Auditory verbal hallucinations (AVHs) are a hallmark of schizophrenia and can significantly impair patients' emotional, social, and occupational functioning. Despite progress in psychopharmacology, over 25% of schizophrenia patients suffer from treatment-resistant hallucinations. In the search for alternative treatment methods, neurofeedback (NF) emerges as a promising therapy tool. NF based on real-time functional magnetic resonance imaging (rt-fMRI) allows voluntarily change of the activity in a selected brain region - even in patients with schizophrenia. This study explored effects of NF on ongoing AVHs. The selected participants were trained in the self-regulation of activity in the anterior cingulate cortex (ACC), a key monitoring region involved in generation and intensity modulation of AVHs. Using rt-fMRI, three right-handed patients, suffering from schizophrenia and ongoing, treatment-resistant AVHs, learned control over ACC activity on three separate days. The effect of NF training on hallucinations' severity was assessed with the Auditory Vocal Hallucination Rating Scale (AVHRS) and on the affective state - with the Positive and Negative Affect Schedule (PANAS). All patients yielded significant upregulation of the ACC and reported subjective improvement in some aspects of AVHs (AVHRS) such as disturbance and suffering from the voices. In general, mood (PANAS) improved during NF training, though two patients reported worse mood after NF on the third day. ACC and reward system activity during NF learning and specific effects on mood and symptoms varied across the participants. None of them profited from the last training set in the prolonged three-session training. Moreover, individual differences emerged in brain networks activated with NF and in symptom changes, which were related to the patients' symptomatology and disease history. NF based on rt-fMRI seems a promising tool in therapy of AVHs. The patients, who suffered from continuous hallucinations for years, experienced symptom changes that may be attributed to the NF training. In order to assess the effectiveness of NF as a therapeutic method, this effect has to be studied systematically in larger groups; further, long-term effects need to be assessed. Particularly in schizophrenia, future NF studies should take into account the individual differences in reward processing, fatigue, and motivation to develop individualized training protocols.