Meta-analysis of real-time fMRI neurofeedback studies using individual participant data: How is brain regulation mediated?

An increasing number of studies using real-time fMRI neurofeedback have demonstrated that successful regulation of neural activity is possible in various brain regions. Since these studies focused on the regulated region(s), little is known about the target-independent mechanisms associated with neurofeedback-guided control of brain activation, i.e. the regulating network. While the specificity of the activation during self-regulation is an important factor, no study has effectively determined the network involved in self-regulation in general. In an effort to detect regions that are responsible for the act of brain regulation, we performed a post-hoc analysis of data involving different target regions based on studies from different research groups. We included twelve suitable studies that examined nine different target regions amounting to a total of 175 subjects and 899 neurofeedback runs. Data analysis included a standard first- (single subject, extracting main paradigm) and second-level (single subject, all runs) general linear model (GLM) analysis of all participants taking into account the individual timing. Subsequently, at the third level, a random effects model GLM included all subjects of all studies, resulting in an overall mixed effects model. Since four of the twelve studies had a reduced field of view (FoV), we repeated the same analysis in a subsample of eight studies that had a well-overlapping FoV to obtain a more global picture of self-regulation. The GLM analysis revealed that the anterior insula as well as the basal ganglia, notably the striatum, were consistently active during the regulation of brain activation across the studies. The anterior insula has been implicated in interoceptive awareness of the body and cognitive control. Basal ganglia are involved in procedural learning, visuomotor integration and other higher cognitive processes including motivation. The larger FoV analysis yielded additional activations in the anterior cingulate cortex, the dorsolateral and ventrolateral prefrontal cortex, the temporo-parietal area and the visual association areas including the temporo-occipital junction. In conclusion, we demonstrate that several key regions, such as the anterior insula and the basal ganglia, are consistently activated during self-regulation in real-time fMRI neurofeedback independent of the targeted region-of-interest. Our results imply that if the real-time fMRI neurofeedback studies target regions of this regulation network, such as the anterior insula, care should be given whether activation changes are related to successful regulation, or related to the regulation process per se. Furthermore, future research is needed to determine how activation within this regulation network is related to neurofeedback success.

Acquired self-control of insula cortex modulates emotion recognition and brain network connectivity in schizophrenia.

Real-time functional magnetic resonance imaging (rtfMRI) is a novel technique that has allowed subjects to achieve self-regulation of circumscribed brain regions. Despite its anticipated therapeutic benefits, there is no report on successful application of this technique in psychiatric populations. The objectives of the present study were to train schizophrenia patients to achieve volitional control of bilateral anterior insula cortex on multiple days, and to explore the effect of learned self-regulation on face emotion recognition (an extensively studied deficit in schizophrenia) and on brain network connectivity. Nine patients with schizophrenia were trained to regulate the hemodynamic response in bilateral anterior insula with contingent rtfMRI neurofeedback, through a 2-weeks training. At the end of the training stage, patients performed a face emotion recognition task to explore behavioral effects of learned self-regulation. A learning effect in self-regulation was found for bilateral anterior insula, which persisted through the training. Following successful self-regulation, patients recognized disgust faces more accurately and happy faces less accurately. Improvements in disgust recognition were correlated with levels of self-activation of right insula. RtfMRI training led to an increase in the number of the incoming and outgoing effective connections of the anterior insula. This study shows for the first time that patients with schizophrenia can learn volitional brain regulation by rtfMRI feedback training leading to changes in the perception of emotions and modulations of the brain network connectivity. These findings open the door for further studies of rtfMRI in severely ill psychiatric populations, and possible therapeutic applications.

Differential brain responses to cries of infants with autistic disorder and typical development: an fMRI study.

This study used fMRI to measure brain activity during adult processing of cries of infants with autistic disorder (AD) compared to cries of typically developing (TD) infants. Using whole brain analysis, we found that cries of infants with AD compared to those of TD infants elicited enhanced activity in brain regions associated with verbal and prosodic processing, perhaps because altered acoustic patterns of AD cries render them especially difficult to interpret, and increased activity in brain regions associated with emotional processing, indicating that AD cries also elicit more negative feelings and may be perceived as more aversive and/or arousing. Perceived distress engendered by AD cries related to increased activation in brain regions associated with emotional processing. This study supports the hypothesis that cry is an early and meaningful anomaly displayed by children with AD. It could be that cries associated with AD alter parent-child interactions much earlier than the time that reliable AD diagnosis normally occurs.

Acquired control of ventral premotor cortex activity by feedback training: an exploratory real-time FMRI and TMS study.

BACKGROUND: Despite the availability of various options for movement restoration in stroke patients, there is no effective treatment for patients who show little or no functional recovery of upper limb motor function. OBJECTIVE: The present study explored the feasibility of real-time functional magnetic resonance imaging brain-computer interface (fMRI-BCI) as a new tool for rehabilitation of this patient population. METHODS: Healthy adults and chronic subcortical stroke patients with residual movement were trained for 3 days to regulate the blood oxygenation level dependent (BOLD) response in the ventral premotor cortex (PMv), a secondary motor area with extensive anatomic connections with the primary motor cortex. Effect of learned modulation of the PMv was evaluated with BOLD signal changes across training sessions, transcranial magnetic stimulation (TMS), and a visuomotor task. RESULTS: fMRI-BCI feedback training showed learning with a significantly increasing BOLD signal in the PMv over sessions. Participants' capability to learn self-regulation was found to depend linearly on intracortical facilitation and correlated negatively with intracortical inhibition measured by TMS prior to feedback training. After training, intracortical inhibition decreased significantly with the volitional increase of the BOLD response in the PMv, indicating a beneficial effect of self-regulation training on motor cortical output. CONCLUSION: The study provides first evidence for the therapeutic potential of fMRI-BCI in stroke rehabilitation.

Real-time fMRI: a tool for local brain regulation.

Real-time fMRI permits simultaneous measurement and observation of brain activity during an ongoing task. One of the most challenging applications of real-time fMRI in neuroscientific and clinical research is the possibility of acquiring volitional control of localized brain activity using real-time fMRI-based neurofeedback protocols. Real-time fMRI allows the experimenter to noninvasively manipulate brain activity as an independent variable to observe the effects on behavior. Real-time fMRI neurofeedback studies demonstrated that learned control of the local brain activity leads to specific changes in behavior. Here, the authors describe the implementation and application of real-time fMRI with particular emphasis on the self-regulation of local brain activity and the investigation of brain-function relationships. Real-time fMRI represents a promising new approach to cognitive neuroscience that could complement traditional neuroimaging techniques by providing more causal insights into the functional role of circumscribed brain regions in behavior.

Using real-time fMRI to learn voluntary regulation of the anterior insula in the presence of threat-related stimuli.

Previous studies have shown that healthy participants learn to control local brain activity with operant training by using real-time functional magnetic resonance imaging (rt-fMRI). Very little data exist, however, on the dynamics of interaction between critical brain regions during rt-fMRI-based training. Here, we examined self-regulation of stimulus-elicited insula activation and performed a psychophysiological interaction (PPI) analysis of real-time self-regulation data. During voluntary up-regulation of the left anterior insula in the presence of threat-related pictures, differential activations were observed in the ventrolateral prefrontal cortex, the frontal operculum, the middle cingulate cortex and the right insula. Down-regulation in comparison to no-regulation revealed additional activations in right superior temporal cortex, right inferior parietal cortex and right middle frontal cortex. There was a significant learning effect over sessions during up-regulation, documented by a significant improvement of anterior insula control over time. Connectivity analysis revealed that successful up-regulation of the activity in left anterior insula while viewing aversive pictures was directly modulated by dorsomedial and ventrolateral prefrontal cortex. Down-regulation of activity was more difficult to achieve and no learning effect was observed. More extensive training might be necessary for successful down-regulation. These findings illustrate the functional interactions between different brain areas during regulation of anterior insula activity in the presence of threat-related stimuli.

Detection of cerebral reorganization induced by real-time fMRI feedback training of insula activation: a multivariate investigation.

BACKGROUND: Studies with real-time functional magnetic resonance imaging (fMRI) demonstrate that humans volitionally regulate hemodynamic signals from circumscribed regions of the brain, leading to area-specific behavioral consequences. Methods to better determine the nature of dynamic functional interactions between different brain regions and plasticity due to self-regulation training are still in development. OBJECTIVE: The authors investigated changes in brain states while training 6 healthy participants to self-regulate insular cortex by real-time fMRI feedback. METHOD: The authors used multivariate pattern analysis to observe spatial pattern changes and a multivariate Granger causality model to show changes in temporal interactions in multiple brain areas over the course of 5 repeated scans per subject during positive and negative emotional imagery with feedback about the level of insular activation. RESULTS: Feedback training leads to more spatially focused recruitment of areas relevant for learning and emotion. Effective connectivity analysis reveals that initial training is associated with an increase in network density; further training "prunes" presumably redundant connections and "strengthens" relevant connections. CONCLUSIONS: The authors demonstrate the application of multivariate methods for assessing cerebral reorganization during the learning of volitional control of local brain activity. The findings provide insight into mechanisms of training-induced learning techniques for rehabilitation. The authors anticipate that future studies, specifically designed with this hypothesis in mind, may be able to construct a universal index of cerebral reorganization during skill learning based on multiple similar criteria across various skilled tasks. These techniques may be able to discern recovery from compensation, dose-response curves related to training, and ways to determine whether rehabilitation training is actively engaging necessary networks.

Regulation of anterior insular cortex activity using real-time fMRI.

Recent advances in functional magnetic resonance imaging (fMRI) data acquisition and processing techniques have made real-time fMRI (rtfMRI) of localized brain areas feasible, reliable and less susceptible to artefacts. Previous studies have shown that healthy subjects learn to control local brain activity with operant training by using rtfMRI-based neurofeedback. In the present study, we investigated whether healthy subjects could voluntarily gain control over right anterior insular activity. Subjects were provided with continuously updated information of the target ROI's level of activation by visual feedback. All participants were able to successfully regulate BOLD-magnitude in the right anterior insular cortex within three sessions of 4 min each. Training resulted in a significantly increased activation cluster in the anterior portion of the right insula across sessions. An increased activity was also found in the left anterior insula but the percent signal change was lower than in the target ROI. Two different control conditions intended to assess the effects of non-specific feedback and mental imagery demonstrated that the training effect was not due to unspecific activations or non feedback-related cognitive strategies. Both control groups showed no enhanced activation across the sessions, which confirmed our main hypothesis that rtfMRI feedback is area-specific. The increased activity in the right anterior insula during training demonstrates that the effects observed are anatomically specific and self-regulation of right anterior insula only is achievable. This is the first group study investigating the volitional control of emotionally relevant brain region by using rtfMRI training and confirms that self-regulation of local brain activity with rtfMRI is possible.