Intrinsic connectivity network dynamics in PTSD during amygdala downregulation using real-time fMRI neurofeedback: A preliminary analysis.

Posttraumatic stress disorder (PTSD) has been associated with a disturbance in neural intrinsic connectivity networks (ICN), including the central executive network (CEN), default mode network (DMN), and salience network (SN). Here, we conducted a preliminary investigation examining potential changes in ICN recruitment as a function of real-time fMRI neurofeedback (rt-fMRI-NFB) during symptom provocation where we targeted the downregulation of neural response within the amygdala-a key region-of-interest in PTSD neuropathophysiology. Patients with PTSD (n = 14) completed three sessions of rt-fMRI-NFB with the following conditions: (a) regulate: decrease activation in the amygdala while processing personalized trauma words; (b) view: process trauma words while not attempting to regulate the amygdala; and (c) neutral: process neutral words. We found that recruitment of the left CEN increased over neurofeedback runs during the regulate condition, a finding supported by increased dlPFC activation during the regulate as compared to the view condition. In contrast, DMN task-negative recruitment was stable during neurofeedback runs, albeit was the highest during view conditions and increased (normalized) during rest periods. Critically, SN recruitment was high for both the regulate and the view conditions, a finding potentially indicative of CEN modality switching, adaptive learning, and increasing threat/defense processing in PTSD. In conclusion, this study provides provocative, preliminary evidence that downregulation of the amygdala using rt-fMRI-NFB in PTSD is associated with dynamic changes in ICN, an effect similar to those observed using EEG modalities of neurofeedback.

The neurobiology of emotion regulation in posttraumatic stress disorder: Amygdala downregulation via real-time fMRI neurofeedback.

Amygdala dysregulation has been shown to be central to the pathophysiology of posttraumatic stress disorder (PTSD) representing a critical treatment target. Here, amygdala downregulation was targeted using real-time fMRI neurofeedback (rt-fMRI-nf) in patients with PTSD, allowing us to examine further the regulation of emotional states during symptom provocation. Patients (n = 10) completed three sessions of rt-fMRI-nf with the instruction to downregulate activation in the amygdala, while viewing personalized trauma words. Amygdala downregulation was assessed by contrasting (a) regulate trials, with (b) viewing trauma words and not attempting to regulate. Training was followed by one transfer run not involving neurofeedback. Generalized psychophysiological interaction (gPPI) and dynamic causal modeling (DCM) analyses were also computed to explore task-based functional connectivity and causal structure, respectively. It was found that PTSD patients were able to successfully downregulate both right and left amygdala activation, showing sustained effects within the transfer run. Increased activation in the dorsolateral and ventrolateral prefrontal cortex (PFC), regions related to emotion regulation, was observed during regulate as compared with view conditions. Importantly, activation in the PFC, rostral anterior cingulate cortex, and the insula, were negatively correlated to PTSD dissociative symptoms in the transfer run. Increased functional connectivity between the amygdala- and both the dorsolateral and dorsomedial PFC was found during regulate, as compared with view conditions during neurofeedback training. Finally, our DCM analysis exploring directional structure suggested that amygdala downregulation involves both top-down and bottom-up information flow with regard to observed PFC-amygdala connectivity. This is the first demonstration of successful downregulation of the amygdala using rt-fMRI-nf in PTSD, which was critically sustained in a subsequent transfer run without neurofeedback, and corresponded to increased connectivity with prefrontal regions involved in emotion regulation during the intervention. Hum Brain Mapp 38:541-560, 2017. © 2016 Wiley Periodicals, Inc.

Alpha oscillation neurofeedback modulates amygdala complex connectivity and arousal in posttraumatic stress disorder.

OBJECTIVE: Electroencephalogram (EEG) neurofeedback aimed at reducing the amplitude of the alpha-rhythm has been shown to alter neural networks associated with posttraumatic stress disorder (PTSD), leading to symptom alleviation. Critically, the amygdala is thought to be one of the central brain regions mediating PTSD symptoms. In the current study, we compare directly patterns of amygdala complex connectivity using fMRI, before and after EEG neurofeedback, in order to observe subcortical mechanisms associated with behavioural and alpha oscillatory changes among patients. METHOD: We examined basolateral (BLA), centromedial (CMA), and superficial (SFA) amygdala complex resting-state functional connectivity using a seed-based approach via SPM Anatomy Toolbox. Amygdala complex connectivity was measured in twenty-one individuals with PTSD, before and after a 30-minute session of EEG neurofeedback targeting alpha desynchronization. RESULTS: EEG neurofeedback was associated with a shift in amygdala complex connectivity from areas implicated in defensive, emotional, and fear processing/memory retrieval (left BLA and left SFA to the periaqueductal gray, and left SFA to the left hippocampus) to prefrontal areas implicated in emotion regulation/modulation (right CMA to the medial prefrontal cortex). This shift in amygdala complex connectivity was associated with reduced arousal, greater resting alpha synchronization, and was negatively correlated to PTSD symptom severity. CONCLUSION: These findings have significant implications for developing targeted non-invasive treatment interventions for PTSD patients that utilize alpha oscillatory neurofeedback, showing evidence of neuronal reconfiguration between areas highly implicated in the disorder, in addition to acute symptom alleviation.

Alterations of amygdala-prefrontal connectivity with real-time fMRI neurofeedback in BPD patients.

With the use of real-time functional magnetic resonance imaging neurofeedback (NF), amygdala activitiy can be visualized in real time. In this study, continuous amygdala NF was provided to patients with borderline personality disorder (BPD) with the instruction to down-regulate. During four sessions of NF training, patients viewed aversive pictures and received feedback from a thermometer display, which showed the amygdala blood oxygenation level-dependent signal. Conditions of regulation and viewing without regulation were presented. Each session started with a resting-state scan and was followed by a transfer run without NF. Amygdala regulation, task-related and resting-state functional brain connectivity were analyzed. Self-ratings of dissociation and difficulty in emotion regulation were collected. BPD patients down-regulated right amygdala activation but there were no improvements over time. Task-related amygdala-ventromedial prefrontal cortex connectivity was altered across the four sessions, with an increased connectivity when regulating vs viewing pictures. Resting-state amygdala-lateral prefrontal cortex connectivity was altered and dissociation, as well as scores for 'lack of emotional awareness', decreased with training. Results demonstrated that amygdala NF may improve healthy brain connectivity, as well as emotion regulation. A randomized-controlled trial is needed to investigate whether amygdala NF is instrumental for improving neural regulation and emotion regulation in BPD patients.

fMRI neurofeedback of amygdala response to aversive stimuli enhances prefrontal-limbic brain connectivity.

Down-regulation of the amygdala with real-time fMRI neurofeedback (rtfMRI NF) potentially allows targeting brain circuits of emotion processing and may involve prefrontal-limbic networks underlying effective emotion regulation. Little research has been dedicated to the effect of rtfMRI NF on the functional connectivity of the amygdala and connectivity patterns in amygdala down-regulation with neurofeedback have not been addressed yet. Using psychophysiological interaction analysis of fMRI data, we present evidence that voluntary amygdala down-regulation by rtfMRI NF while viewing aversive pictures was associated with increased connectivity of the right amygdala with the ventromedial prefrontal cortex (vmPFC) in healthy subjects (N=16). In contrast, a control group (N=16) receiving sham feedback did not alter amygdala connectivity (Group×Condition t-contrast: p<.05 at cluster-level). Task-dependent increases in amygdala-vmPFC connectivity were predicted by picture arousal (ß=.59, p<.05). A dynamic causal modeling analysis with Bayesian model selection aimed at further characterizing the underlying causal structure and favored a bottom-up model assuming predominant information flow from the amygdala to the vmPFC (xp=.90). The results were complemented by the observation of task-dependent alterations in functional connectivity of the vmPFC with the visual cortex and the ventrolateral PFC in the experimental group (Condition t-contrast: p<.05 at cluster-level). Taken together, the results underscore the potential of amygdala fMRI neurofeedback to influence functional connectivity in key networks of emotion processing and regulation. This may be beneficial for patients suffering from severe emotion dysregulation by improving neural self-regulation.

Incision and stress regulation in borderline personality disorder: neurobiological mechanisms of self-injurious behaviour.

BACKGROUND: Patients with borderline personality disorder frequently show non-suicidal self-injury (NSSI). In these patients, NSSI often serves to reduce high levels of stress. AIMS: Investigation of neurobiological mechanisms of NSSI in borderline personality disorder. METHOD: In total, 21 women with borderline personality disorder and 17 healthy controls underwent a stress induction, followed by either an incision into the forearm or a sham treatment. Afterwards participants underwent resting-state functional magnetic resonance imaging while aversive tension, heart rate and heart rate variability were assessed. RESULTS: We found a significant influence of incision on subjective and objective stress levels with a stronger decrease of aversive tension in the borderline personality disorder group following incision than sham. Amygdala activity decreased more and functional connectivity with superior frontal gyrus normalised after incision in the borderline personality disorder group. CONCLUSIONS: Decreased stress levels and amygdala activity after incision support the assumption of an influence of NSSI on emotion regulation in individuals with borderline personality disorder and aids in understanding why these patients use self-inflicted pain to reduce inner tension.

Down-regulation of amygdala activation with real-time fMRI neurofeedback in a healthy female sample.

Psychiatric conditions of emotion dysregulation are often characterized by difficulties in regulating the activity of limbic regions such as the amygdala. Real-time functional magnetic resonance imaging (rt-fMRI) allows to feedback brain activation and opens the possibility to establish a neurofeedback (NF) training of amygdala activation, e.g., for subjects suffering from emotion dysregulation. As a first step, we investigated whether feedback of the amygdala response to aversive scenes can improve down-regulation of amygdala activation. One group of healthy female participants received amygdala feedback (N = 16) and a control group was presented with feedback from a control region located in the basal ganglia [N(sum) = 32]. Subjects completed a one-session rt-fMRI-NF training where they viewed aversive pictures and received continuous visual feedback on brain activation (REGULATE condition). In a control condition, subjects were advised to respond naturally to aversive pictures (VIEW), and a neutral condition served as the non-affective control (NEUTRAL). In an adjacent run, subjects were presented with aversive pictures without feedback to test for transfer effects of learning. In a region of interest (ROI) analysis, the VIEW and the REGULATE conditions were contrasted to estimate brain regulation success. The ROI analysis was complemented by an exploratory analysis of activations at the whole-brain level. Both groups showed down-regulation of the amygdala response during training. Feedback from the amygdala but not from the control region was associated with down-regulation of the right amygdala in the transfer test. The whole-brain analysis did not detect significant group interactions. Results of the group whole-brain analyses are discussed. We present a proof-of-concept study using rt-fMRI-NF for amygdala down-regulation in the presence of aversive scenes. Results are in line with a potential benefit of NF training for amygdala regulation.

Transient and sustained BOLD signal time courses affect the detection of emotion-related brain activation in fMRI.

A tremendous amount of effort has been dedicated to unravel the functional neuroanatomy of the processing and regulation of emotion, resulting in a well-described picture of limbic, para-limbic and prefrontal regions involved. Studies applying functional magnetic resonance imaging (fMRI) often use the block-wise presentation of stimuli with affective content, and conventionally model brain activation as a function of stimulus or task duration. However, there is increasing evidence that regional brain responses may not always translate to task duration and rather show stimulus onset-related transient time courses. We assume that brain regions showing transient responses cannot be detected in block designs using a conventional fMRI analysis approach. At the same time, the probability of detecting these regions with conventional analyses may be increased when shorter stimulus timing or a more intense stimulation during a block is used. In a within-subject fMRI study, we presented aversive pictures to 20 healthy subjects and investigated the effect of experimental design (i.e. event-related and block design) on the detection of brain activation in limbic and para-limbic regions of interest of emotion processing. In addition to conventional modeling of sustained activation during blocks of stimulus presentation, we included a second response function into the general linear model (GLM), suited to detect transient time courses at block onset. In the conventional analysis, several regions like the amygdala, thalamus and periaqueductal gray were activated irrespective of design. However, we found a positive BOLD response in the anterior insula (AI) in event-related but not in block-design analyses. GLM analyses suggest that this difference may result from a transient response pattern which cannot be captured by the conventional fMRI analysis approach. Our results indicate that regions with a transient response profile like the AI can be missed in block designs if analyses do not account for transient responses. This may bias conclusions from empirical reports and meta-analyses towards an underestimation of these regions and their role in emotion and emotion regulation. The cognitive processes underlying differential time courses are discussed.

Mind over chatter: plastic up-regulation of the fMRI salience network directly after EEG neurofeedback.

Neurofeedback (NFB) involves a brain-computer interface that allows users to learn to voluntarily control their cortical oscillations, reflected in the electroencephalogram (EEG). Although NFB is being pioneered as a noninvasive tool for treating brain disorders, there is insufficient evidence on the mechanism of its impact on brain function. Furthermore, the dominant rhythm of the human brain is the alpha oscillation (8-12 Hz), yet its behavioral significance remains multifaceted and largely correlative. In this study with 34 healthy participants, we examined whether during the performance of an attentional task, the functional connectivity of distinct fMRI networks would be plastically altered after a 30-min session of voluntary reduction of alpha rhythm (n=17) versus a sham-feedback condition (n=17). We reveal that compared to sham-feedback, NFB induced an increase of connectivity within regions of the salience network involved in intrinsic alertness (dorsal anterior cingulate), which was detectable 30 min after termination of training. The increase in salience network (default-mode network) connectivity was negatively (positively) correlated with changes in 'on task' mind-wandering as well as resting state alpha rhythm. Crucially, we observed a causal dependence between alpha rhythm synchronization during NFB and its subsequent change at resting state, not exhibited by the SHAM group. Our findings provide neurobehavioral evidence for the brain's exquisite functional plasticity, and for a temporally direct impact of NFB on a key cognitive control network, suggesting a promising basis for its use to treat cognitive disorders under physiological conditions.

Alterations in default mode network connectivity during pain processing in borderline personality disorder.

CONTEXT: Recent neuroimaging studies have associated activity in the default mode network (DMN) with self-referential and pain processing, both of which are altered in borderline personality disorder (BPD). In patients with BPD, antinociception has been linked to altered activity in brain regions involved in the cognitive and affective evaluation of pain. Findings in healthy subjects indicate that painful stimulation leads to blood oxygenation level-dependent signal decreases and changes in the functional architecture of the DMN. OBJECTIVES: To connect the previously separate research areas of DMN connectivity and altered pain perception in BPD and to explore DMN connectivity during pain processing in patients with BPD. DESIGN: Case-control study. SETTING: University hospital. PARTICIPANTS: Twenty-five women with BPD, including 23 (92%) with a history of self-harm, and 22 age-matched control subjects. INTERVENTIONS: Psychophysical assessment and functional magnetic resonance imaging during painful heat vs neutral temperature stimulation. MAIN OUTCOME MEASURE: Connectivity of DMN as assessed via independent component analysis and psychophysiological interaction analysis. RESULTS: Compared with control subjects, patients with BPD showed less integration of the left retrosplenial cortex and left superior frontal gyrus into the DMN. Higher BPD symptom severity and trait dissociation were associated with an attenuated signal decrease of the DMN in response to painful stimulation. During pain vs neutral, patients with BPD exhibited less posterior cingulate cortex seed region connectivity with the left dorsolateral prefrontal cortex. CONCLUSIONS: Patients with BPD showed significant alterations in DMN connectivity, with differences in spatial integrity and temporal characteristics. These alterations may reflect a different cognitive and affective appraisal of pain as less self-relevant and aversive as well as a deficiency in the switching between baseline and task-related processing. This deficiency may be related to everyday difficulties of patients with BPD in regulating their emotions, focusing mindfully on 1 task at a time, and efficiently shifting their attention from one task to another.