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.

Translating Neurocognitive Models of Auditory-Verbal Hallucinations into Therapy: Using Real-time fMRI-Neurofeedback to Treat Voices.

Auditory-verbal hallucinations (AVHs) are frequent and disabling symptoms, which can be refractory to conventional psychopharmacological treatment in more than 25% of the cases. Recent advances in brain imaging allow for a better understanding of the neural underpinnings of AVHs. These findings strengthened transdiagnostic neurocognitive models that characterize these frequent and disabling experiences. At the same time, technical improvements in real-time functional magnetic resonance imaging (fMRI) enabled the development of innovative and non-invasive methods with the potential to relieve psychiatric symptoms, such as fMRI-based neurofeedback (fMRI-NF). During fMRI-NF, brain activity is measured and fed back in real time to the participant in order to help subjects to progressively achieve voluntary control over their own neural activity. Precisely defining the target brain area/network(s) appears critical in fMRI-NF protocols. After reviewing the available neurocognitive models for AVHs, we elaborate on how recent findings in the field may help to develop strong a priori strategies for fMRI-NF target localization. The first approach relies on imaging-based "trait markers" (i.e., persistent traits or vulnerability markers that can also be detected in the presymptomatic and remitted phases of AVHs). The goal of such strategies is to target areas that show aberrant activations during AVHs or are known to be involved in compensatory activation (or resilience processes). Brain regions, from which the NF signal is derived, can be based on structural MRI and neurocognitive knowledge, or functional MRI information collected during specific cognitive tasks. Because hallucinations are acute and intrusive symptoms, a second strategy focuses more on "state markers." In this case, the signal of interest relies on fMRI capture of the neural networks exhibiting increased activity during AVHs occurrences, by means of multivariate pattern recognition methods. The fine-grained activity patterns concomitant to hallucinations can then be fed back to the patients for therapeutic purpose. Considering the potential cost necessary to implement fMRI-NF, proof-of-concept studies are urgently required to define the optimal strategy for application in patients with AVHs. This technique has the potential to establish a new brain imaging-guided psychotherapy for patients that do not respond to conventional treatments and take functional neuroimaging to therapeutic applications.

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.

Cognitive and neural strategies during control of the anterior cingulate cortex by fMRI neurofeedback in patients with schizophrenia.

Cognitive functioning is impaired in patients with schizophrenia, leading to significant disabilities in everyday functioning. Its improvement is an important treatment target. Neurofeedback (NF) seems a promising method to address the neural dysfunctions underlying those cognitive impairments. The anterior cingulate cortex (ACC), a central hub for cognitive processing, is one of the brain regions known to be dysfunctional in schizophrenia. Here we conducted NF training based on real-time functional magnetic resonance imaging (fMRI) in patients with schizophrenia to enable them to control their ACC activity. Training was performed over 3 days in a group of 11 patients with schizophrenia and 11 healthy controls. Social feedback was provided in accordance with the evoked activity in the selected region of interest (ROI). Neural and cognitive strategies were examined off-line. Both groups learned to control the activity of their ACC but used different neural strategies: patients activated the dorsal and healthy controls the rostral subdivision. Patients mainly used imagination of music to elicit activity and the control group imagination of sports. In a stepwise regression analysis, the difference in neural control did not result from the differences in cognitive strategies but from diagnosis alone. Based on social reinforcers, patients with schizophrenia can learn to regulate localized brain activity. However, cognitive strategies and neural network location differ from healthy controls. These data emphasize that for therapeutic interventions in patients with schizophrenia compensatory strategies may emerge. Specific cognitive skills or specific dysfunctional networks should be addressed to train impaired skills. Social NF based on fMRI may be one method to accomplish precise learning targets.

Social reward improves the voluntary control over localized brain activity in fMRI-based neurofeedback training.

Neurofeedback (NF) based on real-time functional magnetic resonance imaging (rt-fMRI) allows voluntary regulation of the activity in a selected brain region. For the training of this regulation, a well-designed feedback system is required. Social reward may serve as an effective incentive in NF paradigms, but its efficiency has not yet been tested. Therefore, we developed a social reward NF paradigm and assessed it in comparison with a typical visual NF paradigm (moving bar). We trained twenty-four healthy participants, on three consecutive days, to control activation in dorsal anterior cingulate cortex (ACC) with fMRI-based NF. In the social feedback group, an avatar gradually smiled when ACC activity increased, whereas in the standard feedback group, a moving bar indicated the activation level. In order to assess a transfer of the NF training both groups were asked to up-regulate their brain activity without receiving feedback immediately before and after the NF training (pre- and post-test). Finally, the effect of the acquired NF training on ACC function was evaluated in a cognitive interference task (Simon task) during the pre- and post-test. Social reward led to stronger activity in the ACC and reward-related areas during the NF training when compared to standard feedback. After the training, both groups were able to regulate ACC without receiving feedback, with a trend for stronger responses in the social feedback group. Moreover, despite a lack of behavioral differences, significant higher ACC activations emerged in the cognitive interference task, reflecting a stronger generalization of the NF training on cognitive interference processing after social feedback. Social reward can increase self-regulation in fMRI-based NF and strengthen its effects on neural processing in related tasks, such as cognitive interference. A particular advantage of social feedback is that a direct external reward is provided as in natural social interactions, opening perspectives for implicit learning paradigms.

Hyperactivation balances sensory processing deficits during mood induction in schizophrenia.

While impairments in emotion recognition are consistently reported in schizophrenia, there is some debate on the experience of emotion. Only few studies investigated neural correlates of emotional experience in schizophrenia. The present functional magnetic resonance imaging study compared a standard visual mood induction paradigm with an audiovisual method aimed at eliciting emotions more automatically. To investigate the interplay of sensory, cognitive and emotional mechanisms during emotion experience, we examined connectivity patterns between brain areas. Sixteen schizophrenia patients and sixteen healthy subjects participated in two different mood inductions (visual and audiovisual) that were administered for different emotions (happiness, sadness and neutral). Confirming the dissociation of behavioral and neural correlates of emotion experience, patients rated their mood similarly to healthy subjects but showed differences in neural activations. Sensory brain areas were activated less, increased activity emerged in higher cortical areas, particularly during audiovisual stimulation. Connectivity was increased between primary and secondary sensory processing areas in schizophrenia. These findings support the hypothesis of a deficit in filtering and processing sensory information alongside increased higher-order cognitive effort compensating for perception deficits in the affective domain. This may suffice to recover emotion experience in ratings of clinically stable patients but may fail during acute psychosis.

Mood modulates auditory laterality of hemodynamic mismatch responses during dichotic listening.

Hemodynamic mismatch responses can be elicited by deviant stimuli in a sequence of standard stimuli even during cognitive demanding tasks. Emotional context is known to modulate lateralized processing. Right-hemispheric negative emotion processing may bias attention to the right and enhance processing of right-ear stimuli. The present study examined the influence of induced mood on lateralized pre-attentive auditory processing of dichotic stimuli using functional magnetic resonance imaging (fMRI). Faces expressing emotions (sad/happy/neutral) were presented in a blocked design while a dichotic oddball sequence with consonant-vowel (CV) syllables in an event-related design was simultaneously administered. Twenty healthy participants were instructed to feel the emotion perceived on the images and to ignore the syllables. Deviant sounds reliably activated bilateral auditory cortices and confirmed attention effects by modulation of visual activity. Sad mood induction activated visual, limbic and right prefrontal areas. A lateralization effect of emotion-attention interaction was reflected in a stronger response to right-ear deviants in the right auditory cortex during sad mood. This imbalance of resources may be a neurophysiological correlate of laterality in sad mood and depression. Conceivably, the compensatory right-hemispheric enhancement of resources elicits increased ipsilateral processing.

Signal quality and Bayesian signal processing in neurofeedback based on real-time fMRI.

Real-time fMRI allows analysis and visualization of the brain activity online, i.e. within one repetition time. It can be used in neurofeedback applications where subjects attempt to control an activation level in a specified region of interest (ROI) of their brain. The signal derived from the ROI is contaminated with noise and artifacts, namely with physiological noise from breathing and heart beat, scanner drift, motion-related artifacts and measurement noise. We developed a Bayesian approach to reduce noise and to remove artifacts in real-time using a modified Kalman filter. The system performs several signal processing operations: subtraction of constant and low-frequency signal components, spike removal and signal smoothing. Quantitative feedback signal quality analysis was used to estimate the quality of the neurofeedback time series and performance of the applied signal processing on different ROIs. The signal-to-noise ratio (SNR) across the entire time series and the group event-related SNR (eSNR) were significantly higher for the processed time series in comparison to the raw data. Applied signal processing improved the t-statistic increasing the significance of blood oxygen level-dependent (BOLD) signal changes. Accordingly, the contrast-to-noise ratio (CNR) of the feedback time series was improved as well. In addition, the data revealed increase of localized self-control across feedback sessions. The new signal processing approach provided reliable neurofeedback, performed precise artifacts removal, reduced noise, and required minimal manual adjustments of parameters. Advanced and fast online signal processing algorithms considerably increased the quality as well as the information content of the control signal which in turn resulted in higher contingency in the neurofeedback loop.

Cognitive versus automatic mechanisms of mood induction differentially activate left and right amygdala.

The amygdala plays a key role in emotional processing. The specific contribution of the amygdala during the experience of one's own emotion, however, remains controversial and requires clarification. There is a long-standing debate on hemispheric lateralization of emotional processes, yet few studies to date directly investigated differential activation patterns for the left and right amygdala. Limited evidence supports right amygdala involvement in automatic processes of emotion and left amygdala involvement in conscious and cognitively controlled emotion processing. The present study investigated differential contributions of the left and right amygdala to cognitive and automatic mechanisms of mood induction. Using functional magnetic resonance imaging (fMRI), we examined hemispheric amygdala responses during two mood induction paradigms: a purely visual method presenting face stimuli and an audiovisual method using faces and music. Amygdala responses in 30 subjects (16 females) showed differences in lateralization patterns depending on the processing mode. The left amygdala exhibited comparable activation levels for both methods. The right amygdala, in contrast, showed increased activity only for the audiovisual condition and this activity was increasing over time. The left amygdala showed augmented activity with higher intensity ratings of negative emotional valence. These results support a left-lateralized cognitive and intentional control of mood and a right-sided more automatic induction of emotion that relies less on explicit reflection processes. The modulation of the left amygdala responses by subjective experience may reflect individual differences in the cognitive effort used to induce the mood. Thus, the central role of the amygdala may not be restricted to the perception of emotion in others but also extend into processes involved in regulation of mood.

Social reinforcement can regulate localized brain activity.

Social learning is essential for adaptive behavior in humans. Neurofeedback based on functional magnetic resonance imaging (fMRI) trains control over localized brain activity. It can disentangle learning processes at the neural level and thus investigate the mechanisms of operant conditioning with explicit social reinforcers. In a pilot study, a computer-generated face provided a positive feedback (smiling) when activity in the anterior cingulate cortex (ACC) increased and gradually returned to a neutral expression when the activity dropped. One female volunteer without previous experience in fMRI underwent training based on a social reinforcer. Directly before and after the neurofeedback runs, neural responses to a cognitive interference task (Simon task) were recorded. We observed a significant increase in activity within ACC during the neurofeedback blocks, correspondent with the a-priori defined anatomical region of interest. In the course of the neurofeedback training, the subject learned to regulate ACC activity and could maintain the control even without direct feedback. Moreover, ACC was activated significantly stronger during Simon task after the neurofeedback training when compared to before. Localized brain activity can be controlled by social reward. The increased ACC activity transferred to a cognitive task with the potential to reduce cognitive interference. Systematic studies are required to explore long-term effects on social behavior and clinical applications.

Virtual faces as a tool to study emotion recognition deficits in schizophrenia.

Studies investigating emotion recognition in patients with schizophrenia predominantly presented photographs of facial expressions. Better control and higher flexibility of emotion displays could be afforded by virtual reality (VR). VR allows the manipulation of facial expression and can simulate social interactions in a controlled and yet more naturalistic environment. However, to our knowledge, there is no study that systematically investigated whether patients with schizophrenia show the same emotion recognition deficits when emotions are expressed by virtual as compared to natural faces. Twenty schizophrenia patients and 20 controls rated pictures of natural and virtual faces with respect to the basic emotion expressed (happiness, sadness, anger, fear, disgust, and neutrality). Consistent with our hypothesis, the results revealed that emotion recognition impairments also emerged for emotions expressed by virtual characters. As virtual in contrast to natural expressions only contain major emotional features, schizophrenia patients already seem to be impaired in the recognition of basic emotional features. This finding has practical implication as it supports the use of virtual emotional expressions for psychiatric research: the ease of changing facial features, animating avatar faces, and creating therapeutic simulations makes validated artificial expressions perfectly suited to study and treat emotion recognition deficits in schizophrenia.

Recognition profile of emotions in natural and virtual faces.

BACKGROUND: Computer-generated virtual faces become increasingly realistic including the simulation of emotional expressions. These faces can be used as well-controlled, realistic and dynamic stimuli in emotion research. However, the validity of virtual facial expressions in comparison to natural emotion displays still needs to be shown for the different emotions and different age groups. METHODOLOGY/PRINCIPAL FINDINGS: Thirty-two healthy volunteers between the age of 20 and 60 rated pictures of natural human faces and faces of virtual characters (avatars) with respect to the expressed emotions: happiness, sadness, anger, fear, disgust, and neutral. Results indicate that virtual emotions were recognized comparable to natural ones. Recognition differences in virtual and natural faces depended on specific emotions: whereas disgust was difficult to convey with the current avatar technology, virtual sadness and fear achieved better recognition results than natural faces. Furthermore, emotion recognition rates decreased for virtual but not natural faces in participants over the age of 40. This specific age effect suggests that media exposure has an influence on emotion recognition. CONCLUSIONS/SIGNIFICANCE: Virtual and natural facial displays of emotion may be equally effective. Improved technology (e.g. better modelling of the naso-labial area) may lead to even better results as compared to trained actors. Due to the ease with which virtual human faces can be animated and manipulated, validated artificial emotional expressions will be of major relevance in future research and therapeutic applications.